Bone sarcomas: ESMO–PaedCan–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up
Authors: P.G. Casali, S. Bielack, N. Abecassis, H.T. Aro, S. Bauer, R. Biagini, S. Bonvalot, I. Boukovinas, J V M G Bovee, B. Brennan, T. Brodowicz, J.M. Broto, L. Brugières, A. Buonadonna, E. De Álava, A.P. Dei Tos, X.G. Del Muro, P. Dileo, C. Dhooge, M. Eriksson, F. Fagioli, A. Fedenko, V. Ferraresi, A. Ferrari, S. Ferrari, A.M. Frezza, N. Gaspar, S. Gasperoni, H. Gelderblom, T. Gil, G. Grignani, A. Gronchi, R.L. Haas, B. Hassan, S. Hecker-Nolting, P. Hohenberger, R. Issels, H. Joensuu, R.L. Jones, I. Judson, P. Jutte, S. Kaal, L. Kager, B. Kasper, K. Kopeckova, D.A. Krákorová, R. Ladenstein, A. Le Cesne, I. Lugowska, O. Merimsky, M. Montemurro, B. Morland, M.A. Pantaleo, R. Piana, P. Picci, S. Piperno-Neumann, A.L. Pousa, P. Reichardt, M.H. Robinson, P. Rutkowski, A.A. Safwat, P. Schöffski, S. Sleijfer, S. Stacchiotti, S.J. Strauss, K. Sundby Hall, M. Unk, F. Van Coevorden, W.T.A. van der Graaf, J. Whelan, E. Wardelmann, O. Zaikova, J.Y. Blay
Journal: Annals of Oncology (2018)

Primary bone tumours are rare, accounting for < 0.2% of malignant neoplasms registered in the EUROCARE (European Cancer Registry based study on survival and care of cancer patients) database [1.Stiller C.A. Trama A. Serraino D. Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project.Eur J Cancer. 2013; 49: 684-695Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar]. Different bone tumour subtypes have distinct patterns of incidence, and each has no more than 0.3 incident cases per 100 000 per year. Osteosarcoma (OS) and Ewing sarcoma (ES) have a relatively high incidence in the second decade of life, whereas chondrosarcoma (CS) is more common in older age [2.Whelan J. McTiernan A. Cooper N. et al.Incidence and survival of malignant bone sarcomas in England 1979-2007.Int J Cancer. 2012; 131: E508-E517Crossref PubMed Scopus (0) Google Scholar, 3.Valery P.C. Laversanne M. Bray F. Bone cancer incidence by morphological subtype: a global assessment.Cancer Causes Control. 2015; 26: 1127-1139Crossref PubMed Scopus (32) Google Scholar, 4.Van den Berg H. Kroon H.M. Slaar A. Hogendoorn P. Incidence of biopsy-proven bone tumors in children: a report based on the Dutch pathology registration "PALGA".J Pediatr Orthop. 2008; 28: 29-35Crossref PubMed Scopus (0) Google Scholar]. OS is the first primary cancer of bone (incidence: 0.3 per 100 000 per year). The incidence is higher in adolescents (0.8–1.1 per 100 000 per year at age 15–19 years) [2.Whelan J. McTiernan A. Cooper N. et al.Incidence and survival of malignant bone sarcomas in England 1979-2007.Int J Cancer. 2012; 131: E508-E517Crossref PubMed Scopus (0) Google Scholar, 3.Valery P.C. Laversanne M. Bray F. Bone cancer incidence by morphological subtype: a global assessment.Cancer Causes Control. 2015; 26: 1127-1139Crossref PubMed Scopus (32) Google Scholar]. The male to female ratio is 1.4:1. Most OSs of younger patients arise in an extremity, while the proportion of axial tumour sites increases with age. Risk factors for the occurrence of OS include previous radiotherapy (RT), Paget disease of bone and germline genetic abnormalities associated with Li–Fraumeni syndrome, Werner syndrome, Rothmund–Thomson syndrome, Bloom syndrome and hereditary retinoblastoma [5.Fuchs B. Pritchard D.J. Etiology of osteosarcoma.Clin Orthop Relat Res. 2002; 397: 40-52Crossref PubMed Google Scholar]. CS is the most frequent bone sarcoma of adulthood. The incidence is ∼ 0.2 per 100 000 per year, with a median age at diagnosis between 30 and 60 years. No gender predominance has been reported [2.Whelan J. McTiernan A. Cooper N. et al.Incidence and survival of malignant bone sarcomas in England 1979-2007.Int J Cancer. 2012; 131: E508-E517Crossref PubMed Scopus (0) Google Scholar, 3.Valery P.C. Laversanne M. Bray F. Bone cancer incidence by morphological subtype: a global assessment.Cancer Causes Control. 2015; 26: 1127-1139Crossref PubMed Scopus (32) Google Scholar, 4.Van den Berg H. Kroon H.M. Slaar A. Hogendoorn P. Incidence of biopsy-proven bone tumors in children: a report based on the Dutch pathology registration "PALGA".J Pediatr Orthop. 2008; 28: 29-35Crossref PubMed Scopus (0) Google Scholar, 6.Bovée J.V. Cleton-Jansen A.M. Taminiau A.H. Hogendoorn P.C. Emerging pathways in the development of chondrosarcoma of bone and implications for targeted treatment.Lancet Oncol. 2005; 6: 599-607Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar]. ES is the third most common primary malignant bone tumour. It 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 (1.5:1). In white Caucasians > 25 years old, ES has an incidence of 0.3 per 100 000 per year [1.Stiller C.A. Trama A. Serraino D. Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project.Eur J Cancer. 2013; 49: 684-695Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, 2.Whelan J. McTiernan A. Cooper N. et al.Incidence and survival of malignant bone sarcomas in England 1979-2007.Int J Cancer. 2012; 131: E508-E517Crossref PubMed Scopus (0) Google Scholar, 3.Valery P.C. Laversanne M. Bray F. Bone cancer incidence by morphological subtype: a global assessment.Cancer Causes Control. 2015; 26: 1127-1139Crossref PubMed Scopus (32) Google Scholar, 4.Van den Berg H. Kroon H.M. Slaar A. Hogendoorn P. Incidence of biopsy-proven bone tumors in children: a report based on the Dutch pathology registration "PALGA".J Pediatr Orthop. 2008; 28: 29-35Crossref PubMed Scopus (0) Google Scholar], and it is even rarer in the African and Asian population. The genetic basis for the difference between ethnical groups has been recently linked to a common genomic germline variant, which extends a microsatellite, thereby facilitating the binding of the EWSR1–FLI1 chimeric protein to the EGR2 gene locus, leading to higher expression of the transcription factor early growth response 2 (EGR2) and increased susceptibility to ES [7.Grünewald T.G. Bernard V. Gilardi-Hebenstreit P. et al.Chimeric EWSR1–FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite.Nat Genet. 2015; 47: 1073-1078Crossref PubMed Scopus (0) Google Scholar]. The most common ES primary sites are the extremity bones (50% of all cases), followed by pelvis, ribs and vertebra. However, any bone can potentially be affected and a soft tissue origin is also possible, especially in adults (30% of cases). Chordomas are even rarer compared with other subtypes, with an incidence of ∼ 0.5 per million per year [1.Stiller C.A. Trama A. Serraino D. Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project.Eur J Cancer. 2013; 49: 684-695Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, 2.Whelan J. McTiernan A. Cooper N. et al.Incidence and survival of malignant bone sarcomas in England 1979-2007.Int J Cancer. 2012; 131: E508-E517Crossref PubMed Scopus (0) Google Scholar, 3.Valery P.C. Laversanne M. Bray F. Bone cancer incidence by morphological subtype: a global assessment.Cancer Causes Control. 2015; 26: 1127-1139Crossref PubMed Scopus (32) Google Scholar, 4.Van den Berg H. Kroon H.M. Slaar A. Hogendoorn P. Incidence of biopsy-proven bone tumors in children: a report based on the Dutch pathology registration "PALGA".J Pediatr Orthop. 2008; 28: 29-35Crossref PubMed Scopus (0) 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 OS, CS or ES [8.Pakos E.E. Grimer R.J. Peake D. et al.The 'other' bone sarcomas: prognostic factors and outcomes of spindle cell sarcomas of bone.J Bone Joint Surg Br. 2011; 93: 1271-1278Crossref PubMed Scopus (9) Google Scholar]. Giant cell tumour (GCT) of bone is a benign, locally aggressive and rarely metastatic intramedullary bone tumour composed of mononuclear cells and osteoclast-like multinucleated giant cells, with a variable and unpredictable potential for aggressive growth. It represents ∼ 5% of primary bone tumours, with an incidence of approximately 1 per million per year [9.Liede A. Bach B.A. Stryker S. et al.Regional variation and challenges in estimating the incidence of giant cell tumor of bone.J Bone Joint Surg Am. 2014; 96: 1999-2007Crossref PubMed Scopus (0) Google Scholar]. A general diagnostic strategy for bone sarcomas is shown in Figure 1. The medical history should focus on characteristic symptoms such as duration, intensity and timing of pain. The presence of persistent 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 they are often later signs. The differential diagnosis of a bone sarcoma includes osteomyelitis, benign tumours and bone metastases, all of which outnumber primary bone sarcomas [10.Hauben E.I. Hogendoorn PCW. Epidemiology of primary bone tumors and economical aspects of bone metastases.in: Heymann D. Bone Cancer. Progression and Therapeutic Approaches. 1. Academic Press, London2009: 3-8Google Scholar, 11.Malhas A.M. Grimer R.J. Abudu A. et al.The final diagnosis in patients with a suspected primary malignancy of bone.J Bone Joint Surg Br. 2011; 93: 980-983Crossref PubMed Scopus (6) Google Scholar, 12.Grimer R.J. Briggs T.W. Earlier diagnosis of bone and soft-tissue tumours.J Bone Joint Surg Br. 2010; 92: 1489-1492Crossref PubMed Scopus (46) Google Scholar]. 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 (LCH). For patients aged ≥ 5 years old, the likelihood of a primary bone sarcoma is higher. In adult patients, after 40 years of age, bone metastases and myeloma are the most common diagnoses [12.Grimer R.J. Briggs T.W. Earlier diagnosis of bone and soft-tissue tumours.J Bone Joint Surg Br. 2010; 92: 1489-1492Crossref PubMed Scopus (46) Google Scholar]. Conventional radiograph in two planes is the first radiological investigation. When the diagnosis of malignancy cannot be excluded with certainty on radiographs, the next step should be magnetic resonance imaging (MRI) of the whole compartment with adjacent joints, which is regarded today as the best modality for local staging of extremity and pelvic tumours [13.Meyer J.S. Nadel H.R. Marina N. et al.Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group Bone Tumor Committee.Pediatr Blood Cancer. 2008; 51: 163-170Crossref PubMed Scopus (109) Google Scholar]. Computed tomography (CT) may provide additional information by allowing a better visualisation of calcifications, periosteal bone formation and cortical destruction. It is generally the imaging modality of choice of other primary sites. All patients with a bone lesion that is likely to be a primary malignant bone tumour on a radiological basis should be referred to a bone sarcoma centre or to an institution belonging to a specialised sarcoma network [14.Andreou D. Bielack S.S. Carrle D. et al.The influence of tumor- and treatment-related factors on the development of local recurrence in osteosarcoma after adequate surgery. An analysis of 1355 patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols.Ann Oncol. 2011; 22: 1228-1235Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 15.Blay 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 (99) Google Scholar]. Children and adolescents should be referred to centres which in addition provide age-specific expertise. The biopsy and the pathological diagnosis require expertise in the field and should be discussed in a multidisciplinary setting. The biopsy of a suspected primary malignant bone tumour should be carried out at the reference centre for bone sarcomas, with a primary biopsy under the supervision of a surgical team who will carry out the definitive tumour resection or by a dedicated interventional radiologist [14.Andreou D. Bielack S.S. Carrle D. et al.The influence of tumor- and treatment-related factors on the development of local recurrence in osteosarcoma after adequate surgery. An analysis of 1355 patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols.Ann Oncol. 2011; 22: 1228-1235Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 15.Blay 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 (99) Google Scholar, 16.van den Berg H. Slaar A. Kroon H.M. et al.Results of diagnostic review in pediatric bone tumors and tumorlike lesions.J Pediatr Orthop. 2008; 28: 561-564Crossref PubMed Scopus (18) Google Scholar, 17.Mankin H.J. Lange T.A. Spanier S.S. The hazards of biopsy in patients with malignant primary bone and soft-tissue tumors.J Bone Joint Surg Am. 1982; 64: 1121-1127Crossref PubMed Google Scholar]. In most patients, a core-needle biopsy, taken under imaging control, can be an appropriate alternative to open biopsy. Contamination of surrounding tissue should be minimised, and adequate multiple sampling of representative areas must always be provided. The biopsy approach and area of tumour to be sampled are pre-determined after multidisciplinary review of imaging. If osteomyelitis is a differential diagnosis, samples should be sent for microbiological culture. If required, an open biopsy should be carried out using a longitudinal incision. In aggressive and malignant tumours of bone, the biopsy tract and the channels through which drains have been placed must be considered to be potentially contaminated and must later be removed, together with the resection specimen, in an effort to minimise the risk of a local recurrence. Therefore, biopsy tracts should be clearly marked by means of a small incision or an ink tattoo 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 bone sarcoma is suspected. Samples must be interpreted by an experienced bone sarcoma pathologist, in collaboration with the radiologist, and discussed in a multidisciplinary team. The request form should be completed with all details that might be relevant for diagnosis, including patient's age, the site of the tumour, radiological findings, presence of multiple lesions, family history and preoperative treatments for surgical specimens. With the increasing capability for accurate molecular diagnosis and next-generation sequencing (NGS) technologies, samples should be quickly submitted for pathological assessment. The collection of fresh frozen tissue is strongly encouraged, to enable molecular diagnostics. As an alternative, decalcification in ethylenediaminetetraacetic acid (EDTA) instead of methanoic acid can be considered. Tumour imprints (touch preparations) are used by some, but not all, expert institutions: they might be useful for tumour-specific translocation by fluorescent in situ hybridisation (FISH) in some institutions. Informed consent for tumour banking should be routinely sought as for all rare malignancies, enabling later analyses for research, depending on local regulations. The nature of the bone specimen received for pathology reporting should be recorded, i.e. needle biopsy, curettage or excision (e.g. segmental resection, limb salvage amputation, or another complex resection, such as a hemipelvectomy). It is usually necessary to decalcify the bone tumour biopsy using specific standard operating procedures. The histological features of the tumour should be described and the tumour type (and subtype) specified according to the most recent version of the World Health Organization (WHO) classification [18.Fletcher C.D.M. Bridge J.A. Hogendoorn P.C.W. Mertens F. Pathology and genetics of tumours of soft tissue and bone. World Health Organization. IARC Press, Lyon2013Google Scholar, 19.Abdul-Karim F.W. Bauer T.W. Kilpatrick S.E. et al.Recommendations for the reporting of bone tumors. Association of Directors of Anatomic and Surgical Pathology.Hum Pathol. 2004; 35: 1173-1178Crossref PubMed Scopus (25) Google Scholar]. The results of relevant ancillary investigations (e.g. immunohistochemistry or molecular assessments) should be accurately recorded. Molecular diagnostic techniques currently available include FISH, reverse transcription-polymerase chain reaction (RT-PCR) and NGS technologies. Examples include translocation detection in ES and mesenchymal CS, isocitrate dehydrogenase (IDH1 and IDH2) mutations in conventional CS and MDM2 amplification in parosteal and intramedullary low-grade OS. At the time of the resection of the primary tumour, the size of the tumour in the resected bone should be recorded (three-dimensional measurement in mm) [19.Abdul-Karim F.W. Bauer T.W. Kilpatrick S.E. et al.Recommendations for the reporting of bone tumors. Association of Directors of Anatomic and Surgical Pathology.Hum Pathol. 2004; 35: 1173-1178Crossref PubMed Scopus (25) Google Scholar, 20.Enneking W.F. Spanier S.S. Goodman M.A. A system for the surgical staging of musculoskeletal sarcoma.Clin Orthop Relat Res. 1980; : 106-120PubMed Google Scholar]. The pathology report should also 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 or infiltrated and the distance of tumour from the nearest resection margin measured (in mm). Photographs should be taken of the intact specimen and of the tumour slabs after sawing. A complete, representative slab of the tumour, usually in the longitudinal axis as guided by the radiological images, should be embedded in a grid manner for microscopy. This is especially relevant after neoadjuvant chemotherapy (ChT) to assess response. The tumour should be coded using Systematic Nomenclature of Medicine (SNOMED) or International Classification of Diseases for Oncology (ICD-O) codes. All new cases of bone tumours should be formally discussed in a multidisciplinary team at a bone sarcoma reference centre with the radiologist, the pathologist, the surgeon, the radiation oncologist and the medical and/or paediatric oncologist. The output of the multidisciplinary discussion must be recorded. Several staging systems for bone tumours are in use [20.Enneking W.F. Spanier S.S. Goodman M.A. A system for the surgical staging of musculoskeletal sarcoma.Clin Orthop Relat Res. 1980; : 106-120PubMed Google Scholar, 21.Heck Jr, R.K. Peabody T.D. Simon M.A. Staging of primary malignancies of bone.CA Cancer J Clin. 2006; 56: 366-375Crossref PubMed Scopus (39) Google Scholar, 22.TNM Classification of Malignant Tumours.in: Brierley J.D. Gospodarowicz M.K. Wittekind C. 8. John Wiley & Sons, Inc., Oxford2016Google Scholar]. However, none of them is perfect or generally accepted. Tumour burden (volume) and the presence of detectable metastases are the two main factors that are 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, chest radiographs and CT [23.Picci P. Vanel D. Briccoli A. et al.Computed tomography of pulmonary metastases from osteosarcoma: the less poor technique. A study of 51 patients with histological correlation.Ann Oncol. 2001; 12: 1601-1604Abstract Full Text PDF PubMed Scopus (66) Google Scholar]. Whole-body MRI and positron emission tomography (PET)-CT or PET-MRI are increasingly used for staging (including detection of 'skip' bone lesions) [24.Buchbender C. Heusner T.A. Lauenstein T.C. et al.Oncologic PET/MRI, part 2: bone tumors, soft-tissue tumors, melanoma, and lymphoma.J Nucl Med. 2012; 53: 1244-1252Crossref PubMed Scopus (121) Google Scholar]. Additional appropriate imaging studies and biopsies can be taken from suspicious sites, as the exact staging of the disease has an impact on treatment and outcome. No specific laboratory tests for the diagnosis of bone sarcoma are routinely available. Baseline serum analysis in ES and OS should include alkaline phosphatase (AP) and lactate dehydrogenase (LDH), given their proven prognostic value [25.Bramer J.A. van Linge J.H. Grimer R.J. Scholten R.J. Prognostic factors in localized extremity osteosarcoma: a systematic review.Eur J Surg Oncol. 2009; 35: 1030-1036Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 26.Bielack S.S. Kempf-Bielack B. Delling G. et al.Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols.J Clin Oncol. 2002; 20: 776-790Crossref PubMed Scopus (1491) Google Scholar, 27.Picci P. Sangiorgi L. Rougraff B.T. et al.Relationship of chemotherapy-induced necrosis and surgical margins to local recurrence in osteosarcoma.J Clin Oncol. 1994; 12: 2699-2705Crossref PubMed Google Scholar]. 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 local recurrence. 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 local recurrence. External splintage is recommended. ChT can result in renal, cardiac and auditory dysfunction. Before starting the treatment, baseline renal function testing, assessment of cardiac function [left ventricular ejection fraction (LVEF)] and audiogram (in the case of platinum derivatives) should be carried out. Sperm storage is recommended for male patients of reproductive age. For female patients, a fertility physician is routinely consulted about potential ovarian tissue sampling and cryopreservation in some but not all countries, reflecting a variability of healthcare policies across nations. Given the rarity of the disease and the complexity of management, the accepted standard for bone sarcomas 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. In the case of high-grade OS, ES or pleomorphic sarcoma, following biopsy proven-diagnosis, primary ChT is generally recommended by expert centres. OS usually arises in the metaphysis of a long bone, most commonly around the knee in children and adolescents. Involvement of the axial skeleton and craniofacial bones is primarily observed in older patients. High-grade OS frequently metastasises, the lung being the most frequent metastatic site by far, followed by distant bones. Conventional OS is always high-grade. Parosteal OSs are low-grade malignancies, although they may increase in size and invade the medulla of bone, and transform to high-grade sarcoma, whereas periosteal OS is an intermediate-grade chondroblastic OS, sometimes difficult to distinguish from high-grade surface OS. Adverse prognostic or predictive factors for conventional OS include detectable primary metastases, axial or proximal extremity tumour site, large tumour size, elevated serum AP or LDH and older age [III, B] [25.Bramer J.A. van Linge J.H. Grimer R.J. Scholten R.J. Prognostic factors in localized extremity osteosarcoma: a systematic review.Eur J Surg Oncol. 2009; 35: 1030-1036Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 26.Bielack S.S. Kempf-Bielack B. Delling G. et al.Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols.J Clin Oncol. 2002; 20: 776-790Crossref PubMed Scopus (1491) Google Scholar]. As mentioned above, staging should include local imaging studies, specifically plain radiographs and MRI of the whole affected extremity [III, A]. Curative treatment of high-grade OS consists of ChT and surgery [II, A]. Compared with surgery alone, multimodal ChT treatment of high-grade localised OS increases disease-free survival probability from 10%–20% to > 60%. In general, ChT is administered before and after surgery, although a formal proof that giving ChT preoperatively improves survival is lacking. The extent of histological response to preoperative ChT predicts survival [25.Bramer J.A. van Linge J.H. Grimer R.J. Scholten R.J. Prognostic factors in localized extremity osteosarcoma: a systematic review.Eur J Surg Oncol. 2009; 35: 1030-1036Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 26.Bielack S.S. Kempf-Bielack B. Delling G. et al.Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols.J Clin Oncol. 2002; 20: 776-790Crossref PubMed Scopus (1491) Google Scholar, 27.Picci P. Sangiorgi L. Rougraff B.T. et al.Relationship of chemotherapy-induced necrosis and surgical margins to local recurrence in osteosarcoma.J Clin Oncol. 1994; 12: 2699-2705Crossref PubMed Google Scholar]. Low-grade parosteal OSs are malignancies with a lower metastatic potential and should be treated by surgery alone [IV, B]. Although ChT has been used for periosteal OSs, no benefit for ChT was shown in retrospective analyses [28.Grimer R.J. Bielack S. Flege S. et al.Periosteal osteosarcoma—a European review of outcome.Eur J Cancer. 2005; 41: 2806-2811Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 29.Cesari M. Alberghini M. Vanel D. et al.Periosteal osteosarcoma: a single-institution experience.Cancer. 2011; 117: 1731-1735Crossref PubMed Scopus (0) Google Scholar, 30.Laitinen M. Parry M. Albergo J.I. et al.The prognostic and therapeutic factors which influence the oncological outcome of parosteal osteosarcoma.Bone Joint J. 2015; 97-B: 1698-1703Crossref PubMed Scopus (10) Google Scholar], and its use is not routinely recommended in this setting [IV, D]. Surgery should be carried out by a surgical team familiar with the wide range of surgical reconstructive options. Paediatric and adolescent patients need to be treated by surgeons with great experience in the field of paediatric bone tumours, including age-specific reconstruction challenges, such as the reconstruction of growing bones. The goal of surgery is to safely remove the tumour and yet preserve as much function as possible, striving to obtain microscopically clear surgical margins [27.Picci P. Sangiorgi L. Rougraff B.T. et al.Relationship of chemotherapy-induced necrosis and surgical margins to local recurrence in osteosarcoma.J Clin Oncol. 1994; 12: 2699-2705Crossref PubMed Google Scholar]. Most patients should be considered candidates for limb salvage. Either intralesional or marginal margins increase the local relapse rate, which is associated with reduced overall survival. 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. Pathological fracture does not necessarily necessitate an amputation. In chemosensitive tumours, 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 [31.Bramer J.A. Abudu A.A. Grimer R.J. et al.Do pathological fractures influence survival and local recurrence rate in bony sarcomas?.Eur J Cancer. 2007; 43: 1944-1951Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. Doxorubicin, cisplatin, high-dose methotrexate (HD-MTX) and ifosfamide have antitumour activity in OS [I, A] [32.Ferrari 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 (336) Google Scholar, 33.Whelan J.S. Davis L.E. Osteosarcoma, chondrosarcoma, and chordoma.J Clin Oncol. 2018; 36: 188-193Crossref PubMed Scopus (106) Google Scholar, 34.Bielack S.S. Smeland S. Whelan J.S. et al.Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative map: first results of the EURAMOS-1 good response randomized controlled trial..J Clin Oncol. 2015; 33: 2279-2287Crossref PubMed Scopus (0) Google Scholar, 35.Whelan 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 (151) Google Scholar]. The MAP (doxorubicin/cisplatin/HD-MTX) regimen is most frequently used as the basis of treatment in children and young adult patients [30.Laitinen M. Parry M. Albergo J.I. et al.The prognostic and therapeutic factors which influence the oncological outcome of parosteal osteosarcoma.Bone Joint J. 2015; 97-B: 1698-1703Crossref PubMed Scopus (10) Google Scholar]; however, HD-MTX can be difficult to manage in adults. In patients aged > 40, regimens combining doxorubicin, cisplatin and ifosfamide without HD-MTX can also be used in these patients [III, B] [33.Whelan J.S. Davis L.E. Osteosarcoma, chondrosarcoma, and chordoma.J Clin Oncol. 2018; 36: 188-193Crossref PubMed Scopus (106) Google Scholar, 34.Bielack S.S. Smeland S. Whelan J.S. et al.Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative map: first results of the EURAMOS-1 good response randomized controlled trial..J Clin Oncol. 2015; 33: 2279-2287Crossref PubMed Scopus (0) Google Scholar, 35.Whelan 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 (151) Google Scholar, 36.Marina N.M. Smeland S. Bi