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Seeking international consensus on approaches to primary tumour treatment in Ewing sarcoma

Seeking international consensus on approaches to primary tumour treatment in Ewing sarcoma Background: The local treatment of Ewing sarcoma of bone involves surgery, radiotherapy or both. The selection of treatment depends on the anatomical extent of the tumour, the effectiveness of the proposed treatment, its morbid- ity, and the expectation of cure. However, not only are there variations in the approach to local treatment between individual patients, but also between treatment centres and countries. Our aim was to explore variation in practice and develop consensus statements about local treatment. Methods: A three stage modified Delphi technique was used with international collaborators. This involved an expert panel to identify areas of controversy, an online survey of international collaborators and a consensus meet- ing in London, UK in June 2017. In the consensus meeting, teams of clinicians discussed the local management of selected cases and their responses were collected with electronic voting. Results: Areas of greater or less consensus were identified. The lack of evidence underpinning different approaches was noted and areas for collaborative research became apparent. Conclusion: This has demonstrated that there is an international consensus around many aspects of the local treat- ment of Ewing sarcoma of bone, including the use of specialist MultiDisciplinary Team (MDT ) meetings with access to all appropriate treatments. However, considerable variation remains including the use of different staging investiga- tions, decision making, definitions of response, and radiotherapy doses and timing. Further collaborative work should be undertaken to determine the impact of these variations in order to define best practice. Keywords: Ewing sarcoma, Surgery, Radiotherapy, Limb salvage, Combined modality 80% of patients under 20  years of age at diagnosis [1]. Background Ewing sarcoma can occur in any bone, with a distribution Ewing sarcoma is the second most common primary reflecting the mass of bone in the skeleton [2]. bone tumour occurring in children and young adults, Ewing sarcoma of bone classically presents with pain with an incidence of approximately 1 per million. It typi- and an extra-osseous mass arising from the affected cally occurs in the second and third decades of life, with bone. Characteristic imaging features include a peri- osteal reaction with or without bone destruction on plain radiographs, and an extra-osseous mass on magnetic res- *Correspondence: craig.gerrand@nhs.net Royal National Orthopaedic Hospital, Brockley Hill, Stanmore HA7 4LP, onance imaging (MRI). Most cases demonstrate a trans- Middlesex, UK location involving chromosomes 11 and 22 [3]. Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gerrand et al. Clin Sarcoma Res (2020) 10:21 Page 2 of 13 Treatment is multidisciplinary and highly specialised, Confirmed conference attendees were asked to com - involving chemotherapy, radiotherapy and surgery. Local plete a pre-meeting survey on the Slido platform (https :// therapy decisions are often nuanced, balancing the risks www.sli.do/) (Additional file  1, Appendix  1). The survey and morbidity of surgery and radiotherapy with poten- asked respondents about their specialty, facilities and ser- tial benefits. Approaches to local treatment vary between vices at their centre, and general approach to treatment. countries, reflecting different health care structures and The final phase was based around a multidisciplinary philosophies. In the EICESS 92 study, differences in local conference. The programme included introductory pres - treatment approaches were identified: patients from the entations summarising the principals of imaging and United Kingdom were less likely to receive combined treatment at different anatomical sites. Clinical cases modalities (surgery and radiotherapy) than those treated were then presented to the audience by two radiologists in Germany, and there were differences in local relapse (P O’D and JT, Additional file  1, Appendix  2). Partici- and overall survival [4]. pants were asked about how they would treat each case, Recognising these differences, an international consen - and differences in approach were openly discussed. At sus meeting to discuss the local treatment of Ewing sar- the end of the meeting, cases brought by attendees were coma was held in Birmingham in 2007. This resulted in presented to test the consensus. Participant responses several changes in UK practice, including a pilot in which were collected electronically using Slido (https ://www.sli. a national Ewing Multidisciplinary Team panel (NEMDT) do/). provided central review of cases. This process has been associated with changes in treatment approaches, in Levels of evidence and consensus particular the greater use of combined modalities and Using data from the pre-meeting survey and audience especially of preoperative radiotherapy. In June 2017, a responses, consensus was evaluated as strong (more than second consensus meeting was held in London to explore 75% of participants/respondents agreeing with a state- current differences in local treatment approaches and to ment), moderate (50–75% of participants/respondents inform the NEMDT panel. The specific objectives were agreeing with a statement) or none (no clear agreement). to establish standards for current practice, develop con- Response data are presented for each individual respond- sensus statements to guide local treatment decisions and ent, not by centre. identify areas for further research. Results Methods Participants A modified Delphi method was used comprising a three Pre‑meeting survey stage process of expert panel review, a pre-meeting The pre-meeting survey was sent to 81 clinicians who online survey and case review with electronic voting at expressed an interest in attending, of whom 58 (72%) the meeting. Ewing sarcoma of bone arising in all ana- responded after two reminders. There were representa - tomic sites other than the head and neck were included. tives from 27 centres in 15 countries, treating a median Soft tissue Ewing sarcomas were excluded. of 6–10 patients a year (range < 5 to > 50 cases per year). An expert scientific advisory board was convened in Respondents were orthopaedic surgeons (16/58, 28%), early 2017 to develop the content for the conference. This paediatric oncologists (15/58, 26%), radiation oncologists panel included clinicians from centres in the UK, Nether- (11/58, 19%), radiologists (6/58, 10%), medical oncolo- lands, Germany and the USA (CG, JB, JW, UD, LR, MvdS, gists (5/58, 9%), histopathologists (1/58, 2%), and other DP, BS, LJ). Clinical situations in which the approach to (4/58, 7%). The majority (48/58, 83%) had not attended treatment might vary were identified through discussion the previous consensus meeting in Birmingham in 2007. with the scientific advisory board and from case discus - sions at the UK NEMDT. A list of potential conference Consensus meeting attendees participants was compiled aiming to give a wide geo- There were 59 clinical voting attendees at the meeting. graphical representation, including centres recognised Thirty-four centres from 19 countries were represented. as having differing approaches to the treatment of Ewing There were non-voting attendees from charities and sarcoma and participants in the previous consensus research bodies. Voting attendees were orthopaedic sur- meeting. geons (18/58, 32%), paediatric oncologists (17/58, 29%), radiation oncologists (9/58, 15%), radiologists (3/58, 5%), medical oncologists (8/58, 14%), histopathologists (1/58, 2%), and other (2/58, 4%). Due to constraints on accessing personnel with sufficient expertise, absence of adequate data and because of time constraints within the programme. G errand et al. Clin Sarcoma Res (2020) 10:21 Page 3 of 13 Patient pathways and services level; strong; 54/56, 96%), expert limb fitting/prosthetic The ideal pathway for patients services (Consensus level; strong; 52/56, 93%), specialist Survey respondents confirmed that specialist centres sarcoma rehabilitation (Consensus level; strong; 46/56, routinely perform conventional radiographs in 2 planes 82%), clinical nurse specialist support (Consensus level; (Consensus level: strong; Q2.1a, 52/56, 93%) (summa- strong; 44/56, 79%), clinical trials in Ewing sarcoma rised with other areas of consensus in Table 1), and MRI (Consensus level; strong; 50/56, 89%), and radiotherapy of the whole involved compartment with adjacent joints delivered by intensity modulated radiotherapy (IMRT) (Consensus level: strong; Q2.1b, 55/56, 98%). The major - (Consensus level; strong; 52/56, 93%). Proton beam ther- ity perform staging computed tomography (CT) of the apy was available (Consensus level; strong) in their cen- chest only (Consensus level: moderate; Q2.1d, 34/54, tre (7/56, 13%), elsewhere in the country (20/56, 36%), or 63%) with a smaller proportion performing CT of the abroad (30/56, 54%). Most had access to specialist end chest, abdomen and pelvis (Consensus level: none; Q2.1e, of life/palliative care support (Consensus level; strong; 18/45, 40%). Only a minority of respondents (Consensus 47/56, 84%). level: none; Q2.1c, 13/55, 24%) were in centres routinely Most surgeons have access to customised endopros- offering whole body MRI: more offered positron emis - theses (4.4, 17/19, 89%), modular endoprostheses (18/19, sion tomography (PET/CT) (Consensus level: moderate; 95%), “growing” endoprostheses (18/19, 95%), free flaps/ Q2.1f, 37/53, 70%) and/or isotope bone scan (Consen- vascularised grafts (18/19, 95%), rotationplasty (17/19, sus level: moderate; Q2.1g, 37/56, 66%) and bone mar- 89%), massive allografts (12/19, 63%), and extracorporeal row sampling (Consensus level: moderate; Q2.1h, 40/56, irradiation/reimplantation (13/19, 68%). 71%), depending on the clinical scenario. Timing and approaches to decisions about local treatment Shared decision making The multidisciplinary team It was agreed that patients should have the opportunity Almost all survey respondents routinely discussed to discuss local treatment options as soon after diagnosis patients in a local MDT meeting (Consensus level: strong; as possible (Consensus level: strong; Q4.5o, 15/19, 79% Q3.1, 51/56, 91%), and a smaller number in a national agree/strongly agree). Decisions about local treatment MDT (Consensus level: none; Q3.1, 20/56, 36%) or rou- should be made in collaboration with patients and fami- tinely with teams in other centres (Consensus level: none; lies (Consensus level: strong; Q4.5p, 17/17, 100% agree/ Q3.1, 7/56, 13%). In one centre patients were only dis- strongly agree). cussed selectively outside it, and in an example of good There was moderate consensus that it is sometimes practice, another described how the paediatric oncolo- possible to make a decision about radiotherapy based on gist, surgeon and radiation oncologist held a joint consul- the imaging at presentation (Consensus level: moderate; tation with all patients with pelvic and axial tumours at Q5.6c, 14/26, 54% agree/strongly agree) and strong con- the same clinic visit after diagnosis and again at the time sensus that the radiological response to chemotherapy is of a local control decision. important when considering local therapy options (Con- There is variation in guidelines for standard practice, sensus level: strong, Q3.5a, 50/55, 91% strongly agree/ as respondents reported adopting the EUROEWING agree). 2012 trial protocol (Q3.2, 28/51, 55%), ESMO Clinical Practice Guidelines (20/51, 39%), British Sarcoma Group guidelines (14/51, 27%) and National  Cancer  Institute Decisions about local treatment in the presence of metastatic treatment guidelines (4/51, 8%). Other adopted protocols disease included those of the Childrens Oncology Group (COG), The statement that patients with bone metastases should Scandinavian Sarcoma group, Ewing 2008, the French have the same local treatment as those without did not Combinair trial, EW-1 and EW-2 joint studies of Italian reach consensus (Q3.5e, Agree/Strongly agree 30%, Paediatric Oncology Group (AEIOP) and the Italian Sar- Undecided 26%, Disagree/strongly disagree 45%). With coma group, and the hospital’s own guidelines (e.g. those widespread bone metastases, radiotherapy alone to the of the Tata Memorial Hospital, Mumbai [5]). primary tumour is routinely indicated (Consensus level: strong; Case 1. 44/54, 81% radiotherapy only to the pri- mary tumour, also Case 3, 39/56, 70%, Case 17, 26/42, Access to diagnostic and treatment services 62%). In the presence of oligometastatic bone disease, it The majority of respondents had access to whole body may be reasonable to consider radiotherapy alone for the MRI (Consensus level: strong; Q 3.3, 42/56, 75%), whole primary tumour (Consensus level: strong; Case5, 35/48, body PET/CT (Consensus level: strong; 54/56, 96%), spe- 73%) as well as radiotherapy to the metastases. cialist surgical teams with sarcoma expertise (Consensus Gerrand et al. Clin Sarcoma Res (2020) 10:21 Page 4 of 13 Table 1 Summary of consensus statements Patient pathways and services Imaging at presentation should include Conventional X-rays in 2 planes (Strong) MRI of the whole involved compartment and adjacent joints (Strong) Staging CT of chest (Moderate) PET/CT (Moderate) Isotope bone scan (Moderate) Bone marrow sampling (Moderate) Patients should be managed within a properly constituted MDT (Strong) Services should have access to the following Whole body MRI (Strong) Whole body CT/PET (Strong) Specialist surgical teams (Strong) Expert limb fitting/prosthetic services (Strong) Specialist sarcoma rehabilitation (Strong) Clinical nurse specialist support (Strong) Clinical trials (Strong) Radiotherapy by IMRT (Strong) Radiotherapy by proton beam (Strong) Timing and approaches to decisions about local treatment Patients should have the opportunity to explore local treatment options as soon after diagnosis as possible (Strong) Decisions about local therapy should be made in collaboration with patients and families (Strong) It is possible to make a decision about radiotherapy based on the imaging at presentation in some situations (Moderate) The radiological response to chemotherapy is important when considering local therapy options (Strong) With widespread bone metastases, radiotherapy alone to the primary tumour is routinely indicated (Strong) With oligometastases, radiotherapy alone may be considered as well as treatment to the oligometastases (Strong) Patients with pulmonary metastases should be considered for the same local treatment as those without (Strong), including potentially morbid resec- tions (Moderate) Pathology and molecular biology Patients should have biopsies in the bone cancer centre (Strong) Core needle biopsies or open biopsies are preferred (Strong) Specimens should be tested for cytogenetic abnormalities (Strong) Oligometastases in lymph nodes or bone should be biopsied (Moderate) Tissue is banked for research (Strong) Assessment of histological response is important when considering the effectiveness of local treatment (Strong) An adequate response to chemotherapy should be taken as > 90% necrosis (Moderate) Surgical margin status is a reliable indicator of tumour left in the patient (Moderate) An adequate surgical margin is one in which there is no viable tumour at the edge of the resection specimen (Moderate) Surgery The surgical resection should be planned to include the biopsy track (Strong) An adequate surgical margin is one in which all of the anatomical structures involved at presentation are completely removed (Strong) Where feasible it is reasonable to consider resection of peri-lesional oedema (Moderate) The radiological response to neoadjuvant chemotherapy should be considered when planning surgery (Strong) Pelvic spacers may have a role in reducing the morbidity of radiotherapy (Moderate) Radiotherapy has a negative impact on outcomes after endoprosthetic replacement (moderate) Radiotherapy has an negative impact on outcomes after allograft reconstruction (Moderate) Radiotherapy does not make surgery more difficult technically (Moderate) There is no role for debulking surgery when a tumour cannot be completely resected (Strong) Local recurrence has an impact on overall survival (Strong) G errand et al. Clin Sarcoma Res (2020) 10:21 Page 5 of 13 Table 1 (continued) Anatomical site variations Pelvis and sacrum Tumours which cross the midline in the sacrum are not considered resectable because of the morbidity associated with surgery (Strong) Tumours with major visceral involvement or requiring pelvic organ removal may also be considered too morbid to resect (Moderate) Definitive radiotherapy is indicated for unresectable sacral tumours (Strong) Protons may be advantageous in the sacrum (Strong) Preoperative radiotherapy may be preferred when the tumour volume is large (Moderate) Radiotherapy is likely to be associated with increased complication rates (Strong) Spine Protons may be of some benefit in the spine (Strong) The type of spinal reconstruction can affect the choice of radiotherapy treatment modality (Strong) Patients with a possible Ewing’s tumour of the spine without neurological signs should have a biopsy before decompressive surgery (Strong) Urgent surgery is recommended if there is a Ewing’s tumour of the spine causing neurological compromise (Moderate) Radiotherapy is usually indicated after decompressive surgery (Strong) and should include the original tumour volume and all areas potentially con- taminated by surgery (Strong) Chest A pleural effusion in relation to a chest wall tumour is not a definite indication for radiotherapy preoperatively (Moderate) A pleural effusion in relation to a chest wall tumour may be an indication for post operative radiotherapy (Moderate) Pleural involvement with a primary tumour may be an indication for preoperative (None) or postoperative (Moderate) radiotherapy Extremity Amputation is considered less often than for osteosarcoma (Strong) Amputation may be indicated if negative margins cannot otherwise be achieved (Moderate) If resection of a distal leg tumour would lead to inadequate margins or a foot with poor function, below knee amputation is indicated (Strong) Amputation is less often recommended in the upper extremity (Moderate) In the proximal tibia, amputation does not necessarily lead to better outcomes than proximal tibial replacement and radiotherapy (Moderate) Radiotherapy can be added to surgery in the tibia but accepting a high risk of local complications (Moderate), therefore preoperative radiotherapy may be preferred (Moderate) Local therapy in advanced disease Suspected solitary bone metastases should be biopsied at presentation if possible (Strong) Solitary bone metastases may be treated by surgery, radiotherapy or both if the morbidity is acceptable (Strong) If there are widespread bone metastases, radiotherapy is indicated when symptomatic (Strong) Potentially involved lymph nodes should have sampling or biopsy before chemotherapy if possible (Strong) It is appropriate to surgically resect lymph nodes if there is suspicion of tumour involvement (Moderate) It is reasonable to consider radical surgery such as amputation or hemipelvectomy to treat locally recurrent disease if there are no metastases (Strong) In contrast, patients with pulmonary metastases should 4%). Biopsy tracks are usually marked so that they can be considered for the same local treatment as those with- be excised at the time of definitive surgery (Q2.4, 38/56, out (Consensus level: strong; Q3.5f, 34/52, 65% agree/ 68%). strongly agree). It is reasonable therefore to consider Biopsy specimens are routinely tested for molecular potentially morbid resections, for example of the pelvis, abnormalities, including the EWS translocation (Q2.5, in the presence of pulmonary metastases (Consensus 53/56, 95%). Lymph nodes that may be involved on imag- level: moderate; Case 2, 31/48, 65%). ing should be sampled before chemotherapy (Q2.6, Con- sensus level: moderate, 28/56, 50%). Similarly, suspected Pathology and molecular biology bone oligometastases should be biopsied (Q2.7, Consen- Biopsy techniques and approaches sus level: moderate, 29/56, 52%). Tissue should be rou- Patients usually have biopsies in the bone cancer centre tinely banked for research (Consensus level: strong; Q2.8, (Q2.2, Consensus level: strong), with a core needle biopsy 44/56, 79%). by a radiologist (Q2.3, 26/55, 47%), surgeon (14/55, 25%), or open incisional biopsy by a surgeon (12/55, 22%). Fine needle aspirate was only infrequently used (2/55, Gerrand et al. Clin Sarcoma Res (2020) 10:21 Page 6 of 13 Assessment of response to chemotherapy Complications of surgery The histological response to chemotherapy is important Radiotherapy has a negative impact on outcomes, espe- when considering the effectiveness of local treatment cially infection and prosthetic failure, after endopros- (Consensus level: strong, Q3.5b, 50/54, 92% strongly thetic replacement of a long bone (Consensus level: agree/agree). Some respondents agreed the definition of moderate; Q4.5b, 15/21, 71%), and after allograft recon- an adequate response to chemotherapy should be taken struction (Consensus level: moderate; Q4.5c, 15/21, 71%). as > 90% necrosis (Consensus level: moderate. Q3.5c, Respondents thought radiotherapy did not make surgery 20/31, 64% strongly agree/agree), with others prefer- more difficult technically (Consensus level: moderate; ring 100% necrosis (Consensus level: weak. Q3.5d, 8/32, Q4.5d, 12/21, 57%). 25% strongly agree/agree). However, it was recognised Surgeons did not reach consensus about the statement that the increasing use of preoperative radiotherapy that some patients at high risk of surgical complications will change the interpretation of necrosis in resection should complete chemotherapy before surgical treatment specimens. (Consensus level: none; Q4.5a, 10/21, 48% strongly agree/ agree vs 29% disagree/strongly disagree). Assessment of surgical margins Surgical margin assessment is a reliable predictor of When is a tumour inoperable? tumour remaining in the patient (Consensus level: mod- There is no role for debulking surgery when a tumour erate; Q3.5g, 34/52, 66% strongly agree/agree). An ade- cannot predictably be completely resected (Consensus quate surgical margin is one in which there is no viable level: strong; Q4.5e, 18/20, 80% disagree/strongly disa- tumour at the edge of the resection specimen (Consensus gree that debulking surgery should be considered). level: moderate; Q35h, 33/53, 63% strongly agree/agree). The statement that an adequate surgical margin is one Radiotherapy in which all of the anatomical structures involved before Indications for and timing of radiotherapy chemotherapy have been completely removed did not Radiotherapy may be given pre-operatively, post-opera- reach consensus in the pre-meeting survey (Q3.5i, 17/47, tively or as definitive treatment. Tumour volume may be 37% Strongly agree/agree, 16/47, 35%, strongly disagree/ considered as a relative indication when making a rec- disagree). There was strong consensus that local recur - ommendation for radiotherapy (Consensus level: none; rence at the primary site has an impact on overall sur- Q5.4d, Q83). vival (Consensus level: strong; Q4.5f, 19/20, 95% agree/ There was no consensus as to whether pathologi - strongly agree). cal fracture at presentation was a definite indication for preoperative radiotherapy (Q75, with radiotherapy rec- Surgery ommended always/very often in 29%, and rarely/never Principles of surgery for Ewing sarcoma in 48%), although there was some agreement that radio- When planning surgical resection the biopsy track should therapy should be considered postoperatively (Consensus be removed (Consensus level: strong, Q4.1, 17/19, 89% level: moderate; Q87, 11/21, 53% Very often/always, com- “yes”). pared with 24% rarely/never). In the pre-meeting survey, many respondents did not There was agreement that involved lymph nodes should consider resecting all of the volume/anatomical struc- be included in radiotherapy treatment volumes (Con- tures involved before chemotherapy (Consensus level: sensus level: moderate; Q91, 19/26, 73% agree/strongly moderate; Q4.2, 10/19, 53% “no”). However, most sur- agree). geons considered resecting all of the volume/anatomical If complete resection is possible based on initial imag- structures involved after chemotherapy (Consensus level: ing, the decision about radiotherapy can await assess- strong; Q4.3, 16/19, 84% “yes”). ment of histological response (Consensus level: strong; Where feasible it is reasonable to consider resection of Case 11, 43/56, 77%). peri-lesional oedema which might contain tumour (Con- A poor radiological response to neoadjuvant chemo- sensus level: moderate; Case 4, 32/47, 68%), therapy is a relative indication for preoperative (Con- The radiological response to neoadjuvant chemother - sensus level: moderate; Q77, 61% sometimes/very often/ apy should be considered when planning surgery (Con- always. Consensus level: strong; Case 9, 47/50, 94%) or sensus level: strong; Q4.5n, 17/20, 85% agree/strongly postoperative radiotherapy (Consensus level: strong; agree). Q89, 20/23, 87%, sometimes/very often/always). Pelvic spacers should be considered to reduce the mor- Preoperative radiotherapy may be given when an bidity of radiotherapy (Consensus level: moderate; Q4.5j, inadequate (marginal) margin is anticipated on imag- 11/20, 55% agree/strongly agree). ing. There was strong consensus that a 2  mm margin G errand et al. Clin Sarcoma Res (2020) 10:21 Page 7 of 13 Selection of modalities for planning and delivery after resection and preoperative radiotherapy does not of radiotherapy require further radiotherapy (Consensus level: strong, There is an expectation that the indications for proton Case 8, 35/46, 76%). Tumours close to critical anatomi- beam treatment will expand as it becomes more available cal structures which would be morbid to resect surgically (Consensus: moderate; Q92, 16/24, 67% agree/strongly (e.g. major nerve or blood vessel) should be considered agree). for preoperative radiotherapy (Consensus level: moder- Insertion of a pelvic spacer can be considered to allow ate; Q68, 12/24, 50% always/very often). The expectation delivery of the prescribed radiotherapy dose by reducing of a close or positive surgical margin on the pre-chemo- the dose to normal tissue structures, in particular bowel therapy scan is not a definite indication for preoperative (Consensus level: moderate; Q51, 11/20, 55% agree/ radiotherapy (Consensus level: none; Q69). However, if strongly agree). a close or positive surgical margin is expected based on the post chemotherapy scan, preoperative radiotherapy Anatomical site considerations should be considered (Consensus level: moderate; Q70, Pelvis/sacrum 14/24, 59%). There was strong consensus that sacral tumours which Indications for postoperative radiotherapy include cross the midline should not be resected because the viable tumour at the surgical margin (Consensus level: morbidity of resection including loss of bladder, bowel strong; Q79, 25/25, 100%, Very often/always), incom- and sexual function is thought unacceptable (Consensus plete excision of the pre-chemotherapy tumour volume level: strong; Q4.6, 15/20, 75%. Also Case 15, 36/46, 78%). (Consensus level: moderate; Q80, 15/25, 60% very often/ Similarly, major visceral involvement requiring pelvic always) and poor histological response (Consensus level: organ removal would mean that most surgeons would not moderate; Q81, 17/25, 68% very often/always), usually recommend resection (Consensus level: moderate; Q4.6, defined as < 90% necrosis, although there was variation 14/20, 70%, Case 5). Definitive radiotherapy is indicated in the level of histological response deemed acceptable to for sacral tumours for which surgery is considered too avoid radiotherapy (Consensus level: none; Case 9). morbid (Consensus level: strong; Case 15, 44/44, 100%). Complete excision and good histological response are Protons may be advantageous in this situation in terms of needed to avoid radiotherapy. It is reasonable to add delivery of optimal dose, and reduction in normal tissue postoperative radiotherapy with a margin of < 2  mm toxicity (Consensus level: strong; Case 15, 38/47, 81%). and < 90% necrosis (Consensus level: strong; Case 7, Tumours in the pelvis may be selected for radiotherapy 46/56, 82%). preoperatively (Consensus level: moderate; Q5.4h, 73% sometimes/very often/always) or postoperatively (Con- Radiotherapy dose sensus level: strong; Q5.5h, 20/22, 91% sometimes/very For pre-operative radiotherapy, there was no consensus often/always). for dose (range 45–55.8  Gy), with doses of 45  Gy (27%), Preoperative radiotherapy may be preferred when the 50 Gy (32%), and a range of ‘other’ doses (41%) reported, tumour volume is large (Consensus level: moderate; Case including 50.4 Gy, 54 Gy and 55.8 Gy. 2, 26/50, 52%; Case 10, 40/49, 82%; Consensus level: For post-operative radiotherapy, there was also no con- strong, Case 10, 39/52, 75%). sensus, although the doses used were generally higher Reconstruction is likely to be associated with more than for pre-operative radiotherapy (range 45–60  Gy). complications if radiotherapy has been given and influ - Doses reported were 45  Gy (18%), 50  Gy (23%), ‘other’ ences the choices for reconstruction (Consensus level: (50%), and ≥ 60  Gy (10%). The ‘other’ group included strong, Case 10, 43/49, 88%). 42 Gy, 50.4 Gy, 54 Gy, and 55.8 Gy. For definitive radiotherapy, there was again a lack of Spine consensus, although as with post-operative radiotherapy, Proton beam radiotherapy may be of some benefit in the doses were generally higher than for pre-operative radio- spine (Consensus level: strong; Case 12, 41/44, 93%: Case therapy (range 45–70.2  Gy). Doses reported were 50  Gy 13, 44/50, 88%). Where combined modality treatment (11%), 60  Gy (32%), > 60  Gy (11%) and ‘other’ (47%). The with surgery and radiotherapy is indicated, it is recog- ‘other’ group included 45  Gy, 54  Gy, 55.8  Gy, 59.4  Gy, nised that the type of reconstruction can affect the choice 70.2 Gy. of radiotherapy treatment modality (Consensus level: For all radiotherapy indications, fraction sizes of 1.5 Gy, strong; Case 13, 32/43, 74%). 1.8 Gy and 2 Gy were reported. Patients who present with a possible Ewing tumour of the spine without neurological signs should have a biopsy as a response to systemic treatment is likely and may Gerrand et al. Clin Sarcoma Res (2020) 10:21 Page 8 of 13 allow intralesional decompressive surgery to be avoided In the proximal femur, if complete resection is deemed (Consensus level: strong; Case 14; 49/50, 98%). feasible, then either pre or post op radiotherapy can be If there is deteriorating or objective neurological com- considered. (Case 11). promise, urgent surgery is recommended (Consensus In a case with an intraarticular tumour at the elbow, level: moderate; 29/48, 60%), rather than biopsy and radiotherapy was recommended (Consensus level: chemotherapy/radiotherapy. Radiotherapy is invariably strong; Case 18, 34/47, 72%), preferably postoperatively indicated after decompressive surgery (Consensus level: (Consensus level: moderate; Case 18, 31/50, 62%). strong; Case 14, 41/46, 89%), and should include the original tumour volume and all areas potentially con- Local therapy in advanced disease taminated by surgery (Consensus level: strong; Case 14, General approach to patients with advanced disease 45/51, 88%). Oligometastases in  bone A suspected solitary bone There was no consensus about the use of craniospinal metastasis should be biopsied at presentation if possible radiotherapy for patients with epidural disease (Q5.6d). (Consensus level: strong; Case 4, 45/51, 88%). If there is more than one suspected metastasis it may be reason- able to biopsy more than one (Consensus level: moderate; Chest Case 5. 32/56, 57%). A pleural effusion in association with a chest wall tumour The statement that resection of bone metastases is not a definite indication for radiotherapy preopera - improves survival was not supported (Consensus level: tively (Consensus level: moderate; Q5.4e, 12/21, 57% none; Q4.5h), but bone metastases may be resected if the rarely/never), but may be postoperatively (Consensus morbidity is acceptable (Consensus level: strong; Q4.5i, level: moderate; Q5.5e, 10/20, 50% always/very often). 16/20, 80% agree/strongly agree). A solitary metasta- However, pleural involvement with a primary tumour sis should be treated by surgery, radiotherapy or both may be an indication for radiotherapy either preop- (Consensus level: strong; Case 4, 47/52, 90%, resec- eratively (Consensus level: none; Q5.4f, 7/21, 34% very tion, radiotherapy or both). With greater numbers of often/always) or postoperatively (Consensus level: mod- bone metastases, individual treatment of all metastases erate; Q5.5f, 10/20, 50% very often/sometimes. See also becomes more difficult, but if possible radiotherapy to Case 17). two lesions is reasonable (Consensus level: strong; Case 5, 49/51, 96%). Where widespread bone metastases are present, radio- therapy is indicated when symptomatic (Consensus level: Extremity strong: Case 1, 50/57, 88%). Amputation is considered less often than for other extremity bone tumours (Consensus level: strong; Q4.5l, Lymph node involvement Staging by PET/CT is more 16/20, 80%), but may be considered if negative surgical likely to detect soft tissue/lymph node involvement. margins cannot otherwise be achieved (Consensus level: Potentially involved lymph nodes should have sampling moderate; Q4.7, 14/20, 70%). Alternatively, if resection of or biopsy before chemotherapy whenever possible (Con- a tumour would be associated with inadequate margins sensus level: strong; Case 6; 44/50, 88%). It is appropriate or a foot with poor function, below knee amputation may to surgically resect lymph nodes if there is suspicion of be indicated (consensus level: strong; Case 6. 43/54, 80%). tumour involvement (Consensus level: moderate; Q4.5g, Respondents indicated that amputation would be less 14/20, 70%. Also Case 6, consensus level: moderate; 31/56, often recommended in an upper extremity tumour (Con- 56%). sensus level: moderate; Q4.5l, 10/20, 50%). In proximal tibial tumours, it was agreed that amputa- tion does not necessarily lead to better outcomes than Local therapy in relapsed disease proximal tibial replacement and radiotherapy (Consensus It is reasonable to consider radical surgery such as ampu- level: moderate; Q4.5k, 10/20, 50%). In the tibia, it is rea- tation or hemipelvectomy to treat locally recurrent Ewing sonable to add radiotherapy to surgery while accepting a sarcoma if there are no metastases (Consensus level: high risk of local complications (Consensus: moderate; strong; Q4.5m, 18/20, 90% agree/strongly agree. Case 16, Case 3, 30/51, 59%). In this situation, preoperative radio- 31/48, 65%). therapy is preferred (Consensus level: moderate; Case 3, 36/49, 73%). Preferred reconstructive options would be autograft, endoprostheses or allograft (Case 3). Amputa- tion is a reasonable alternative for some patients. G errand et al. Clin Sarcoma Res (2020) 10:21 Page 9 of 13 Discussion the prognosis is poor (for example with widespread bone Our aim was to define existing international consen - metastases). The majority of patients receive combined sus about the local treatment of Ewing sarcoma of bone treatment. Evidence in favour of one or other treatment in order to inform specialist MDTs and identify areas in approach comes predominantly from retrospective stud- which collaboration to develop more evidence aimed at ies and is difficult to interpret because there is an inher - strengthening future consensus might be worthwhile. We ent bias in treatment selection. have identified an engaged and supportive professional and patient community which actively contributed to Shared decision making this project and constituted a key strength of this report. Shared decision-making involves a collaborative Although we have attempted to collect objective data approach to treatment decisions based on an under- about treatment, our description of the strength of con- standing of the patient’s priorities for their own lives: we sensus is necessarily subjective. The conclusions of this showed strong consensus that decisions should be made paper should therefore be treated with caution and are together with patients and families as early as possible for consideration by treating teams rather than definitive in the treatment pathway. However, there is no evidence recommendations. that this approach is of benefit in patients with Ewing sarcoma specifically and standard mechanisms for sup - The ideal patient pathway and staging porting high quality decisions do not exist. There is an The urgent referral of patients with a suspected Ewing opportunity to develop these and to use existing outcome sarcoma of bone to a specialist centre is established prac- data to allow patients, families and treating teams to tice [6]. Initial evaluation with plain radiographs and MRI make fully informed treatment decisions [11]. of the whole involved compartment and adjacent joints is universally applied. However, we have shown variation Decisions about local treatment in the presence of metastatic in systemic staging with some centres performing CT of disease abdomen and pelvis as well as chest. There is greater vari - Patients with bone metastases at diagnosis have a poor ation in imaging of the skeleton with centres most often prognosis [12], and therefore there was an expected performing whole body isotope bone scan and bone strong consensus for avoiding morbid surgery. The treat - marrow sampling. PET/CT was also widely offered and ment of multiple bone metastases with radiotherapy is may be as useful as bone marrow sampling [7]. However likely reasonable if they are small in number and easily whole body MRI scan was not routinely offered and given treatable, but there is little evidence for improved out- recent evidence about its sensitivity may be a better stag- comes associated with this approach. The better progno - ing investigation [8]. Further evaluation of the optimal sis of patients with pulmonary metastases alone supports staging investigations for Ewing sarcoma is warranted. a more aggressive approach to local treatment, including, for example, surgical resection of the pelvis. However, The multidisciplinary team and decision making decisions about local treatment may be more nuanced The treatment of patients with Ewing sarcoma requires given the lower expectation of cure. a properly constituted MDT with expertise in medi- cal oncology, radiotherapy, and surgery [6, 9]. We have Pathology and molecular biology shown there is almost universal use of MDT discussion, Biopsy techniques and approaches and adoption of a wide range of existing treatment pro- The principles of biopsy of musculoskeletal tumours are tocols. Wide discussion outside the treating MDT, for well established. An image guided needle biopsy is the example in a national forum or with another centre is not most widely adopted technique, with open incisional usual in the majority of countries, although the EICESS biopsy preferred by some. The latter has the advantage 92 experience indicates that a more unified approach of providing more material for diagnostic studies and could be explored to determine if it will improve out research at the risk of greater local contamination. This comes for patients and has been adopted by the CESS may become more important as biological studies, for group in Germany [4, 10]. The wider adoption of national example whole genome sequencing become integrated or international MDT discussions has some intuitive into the diagnostic and treatment pathway. appeal but demands further evidence. Biopsy of other areas of potential involvement, such as lymph nodes or bone metastases can also be important Timing and approaches to decisions about local treatment at presentation and before chemotherapy, particularly if Complete resection of the primary tumour continues as aggressive local treatment such as surgical excision might the preferred approach, with radiotherapy as an alterna- be considered. Evidence is needed to support this more tive if surgery is not feasible, unacceptably morbid or if Gerrand et al. Clin Sarcoma Res (2020) 10:21 Page 10 of 13 aggressive approach to oligometastatic disease including is sufficiently high, it has been suggested that surgery is the identification of patients who might benefit. delayed until the end of chemotherapy. However, no con- sensus was reached on this question. Assessment of response to chemotherapy Radiotherapy There was strong consensus that the histological response Radiotherapy is most frequently delivered with photons, to chemotherapy was important when considering the although as access improves, more patients are receiv- effectiveness of local treatment, although interpretation ing proton beam treatment. Photon radiotherapy is best of this is made more difficult after preoperative radio - delivered via a 3D-conformal CT-plan, or increasingly therapy. The level at which a response is defined as ade - with intensity modulated radiotherapy, which frequently quate varies: Greater than 90% necrosis was accepted by allows for superior dose delivery and normal tissue spar- many participants, but others only consider a complete ing. For some patients, proton beam therapy may offer an histological response as ‘adequate’ [13]. Standardisation advantage in delivering the prescribed radiotherapy dose of radiological response parameters is also needed. (if it is at the higher end of the dose range) or in sparing normal tissues and reducing late toxicity. Surgery We have shown variations in the approach to radiother- Principles of surgery for Ewing sarcoma apy and different approaches to the treatment of patho - At presentation, Ewing sarcomas typically have a large logical fractures, lymph nodes and the indications for and extra-osseous mass which infiltrates local anatomi - timing of radiotherapy. Further evaluation of the optimal cal structures. Although the mass may reduce following delivery of radiotherapy is required in clinical trials. chemotherapy, viable tumour cells may remain in these infiltrated structures. The principle that all of the struc - Anatomical site variations tures involved at presentation should either be surgically Pelvis/sacrum removed or included in the radiation field has become About a quarter of Ewing sarcomas involve the pelvis established within the NEMDT in recent years and and/or sacrum [15]. Pelvic tumours tend to be larger, reached strong consensus after discussion at this meet- with a higher risk of metastasis and poorer survival ing. This included the resection of perilesional oedema [15]. The soft tissue mass associated with a pelvic Ewing if reasonable. In practice, however, local treatment deci- tumour can be large and may involve adjacent critical sions are often more pragmatic, driven by an understand- anatomical structures such as the iliac vessels, bladder ing of what is reasonable, the associated morbidity and and rectum. Local recurrence rates after resection of pel- the expectation of cure. vic tumours can be higher than other sites [16]. Retro- Surgical margin assessment aims to evaluate whether spective series suggest that patients treated with surgery there is residual tumour in the local site, and there is have better overall survival [17] and that those treated some variation in what is believed to be an adequate sur- with surgery and radiotherapy together have lower local gical margin. Future assessments may need to go beyond recurrence rates [18], however there is great variability in the traditional evaluation of the resected specimen and preferences for local control [19, 20]. Furthermore, more be combined with response to chemotherapy to give a recent reports have suggested definitive proton treatment better risk stratification for local recurrence. can be associated with high local control rates [21]. Surgical resection of a pelvic or sacral sarcoma is rou- Complications of surgery tinely associated with surgical complications, long term A key consideration in local treatment is the interac- morbidity and loss of physical function, particularly after tion between surgery and radiotherapy. Radiotherapy resection of the acetabulum and major (often sacral) is associated with an increased risk of wound complica- nerves [22, 23]. The determination of what is a resect - tions and deep implant infection [14]. Furthermore, the able tumour in the pelvis depends to a large extent on the smaller treatment volume and potential for lower doses degree of morbidity acceptable to the patient and their have increased the use of preoperative radiotherapy, par- family. There was consensus that tumours which were ticularly in the pelvis. Disadvantages include an increase too morbid to resect include those which cross the mid- in complications of surgery or that surgery may be more line in the sacrum and those which would require major technically challenging if tissue planes become difficult visceral resection. These are useful guides for treating to identify. However, the latter was not supported in the teams and demand the longer-term collection of physical meeting. functioning outcomes to inform decision making. Complications of surgery such as infection or wound After preoperative radiotherapy, the expected failure can delay the resumption of chemotherapy. There - increased risk of complications means that surgeons fore in some cases where the risk of such complications G errand et al. Clin Sarcoma Res (2020) 10:21 Page 11 of 13 are less likely to recommend allograft or endoprosthetic is a greater emphasis on the preservation of function, reconstruction. After periacetabular resection, a “hang- and teams may rely more on adjuvant radiotherapy to ing hip” reconstruction may therefore be preferred [24]. achieve local control. Reconstruction of the proximal tibia is associated with Spine relatively high surgical complication rates, including Two thirds of patients with Ewing sarcoma of the spine infection [30]. Adding radiotherapy to a surgical recon- undergo urgent decompression at presentation which struction may increase this risk and may lead to a failed complicates subsequent local management [25]. How- reconstruction. In this situation therefore, there was con- ever, there was moderate consensus that a patient with sensus in favour of preoperative radiotherapy but recog- spinal cord compression and neurological compromise nition that amputation may be a reasonable alternative from Ewing sarcoma should undergo urgent surgical for some patients. decompression if it is indicated. Radiotherapy should then include all of the original tumour volume and Local therapy in metastatic and relapsed disease other areas potentially contaminated. Although bone metastases are associated with a dis- For those with spinal tumours who do not have neu- mal outcome, there was support for a more aggressive rological compromise, it is appropriate to treat first approach using focussed radiotherapy and possibly sur- with urgent biopsy and chemotherapy which may lead gery if there are only a small number of bone metastases to a reduction in tumour size and avoid urgent surgical [31]. Similarly, there was some support for an aggressive decompression. approach to potentially involved lymph nodes, including The decision about what is resectable within the spine biopsy or sampling at presentation and surgical resection should be made by a surgeon with relevant site-specific and/or radiotherapy as part of definitive local therapy. experience working within a multidisciplinary team. After isolated local relapse, there will routinely be There may be some benefit to surgical excision if the a question about whether further systemic treatment morbidity is acceptable, but there are no randomised should be supplemented with local treatment. There was trials and local control rates with radiotherapy alone strong consensus that it was reasonable to consider even are high [16, 26]. When surgery is undertaken consid- radical surgery such as hemipelvectomy in this situation, eration should be given to the type and positioning of but it is important to balance the definite morbidity of instrumentation used in reconstruction. Traditional the treatment with any small potential to improve the titanium implants may significantly impair the ability to overall poor outcome, particularly in early relapse. All of deliver PBT and have a deleterious effect on follow-up these settings need further evidence to guide clinicians. MRI imaging. Future research The variation in practice recorded in this initiative high - Chest lights areas in which research and clinical trials could The use of radiotherapy for chest wall tumours is be usefully performed in order to develop stronger evi- related predominantly to pleural involvement either dence-based approaches to primary tumour manage- before or after surgery. A pleural effusion is not on its ment. These include: own an indication for radiotherapy [27]. • The role of new imaging technology for more accu - rate staging. • Developing methods for early and shared decision- Extremity making about local treatment. Ewing sarcoma of the extremity should be treated with • The role and benefit of specialist national MDT wide resection if feasible, and in the majority limb spar- review. ing surgery is possible, with amputation rates around • Definitions of radiological and histological responses 8.4% [15]. Amputation is associated with the best local to chemotherapy. control rates, but usually the greatest loss of function. • Studies of type, timing and dose of radiotherapy. As It should be pointed out that while surgery is certainly an example, incorporation of prospective questions favoured secondary to other important considerations, about radiotherapy delivery within the next genera- overall prognosis may not be influenced by local con - tion of European clinical trials for Ewing sarcoma are trol modality [28]. Exceptions to this rule include sig- already well advanced. nificant resections of the foot or tibia which would result in lower levels of physical functioning than transtibial amputation [29]. In the upper limb there Gerrand et al. Clin Sarcoma Res (2020) 10:21 Page 12 of 13 Hospital, University of Helsinki. Finland; Dr. Akira Kawai, National Cancer Center Re-examination of these areas of consensus in a further Hospital. Japan; Dr. Stijn Krol, Leiden University Medical Center. Netherlands; international workshop, preceded by an updated survey, Dr. Nadia Laack, Mayo Clinic, Rochester. USA; Prof. Ruth Ladenstein, St. Anna would certainly be worthwhile. Kinderkrebsforschung e.V.. Austria; Dr. Carlo Lancia, Leiden University Medical Center. Netherlands; Prof. Siddhartha Laskar, Tata Memorial Hospital. India; Dr. Valerie LAURENCE, Institut CURIE. France; Dr. Franel le Grange, University Conclusion College Hospital, London. UK; Prof. Andreas Leithner, Dept. of Orthopaedics Achieving consensus about local therapy decisions in and Trauma, Medical University of Graz. Austria; Mr. Andy Lewis, Bone Cancer Research Trust. UK; Dr. Christina Linder Stragliotto, Oncology Clinic, Karolinska Ewing sarcoma is possible but several areas lacking con- University Hospital. Sweden; Ms. Elizabeth Lloyd-Dehler, University College sensus remain. There is consensus about the central role Hospital, London. UK; Mr. Jan Loeffen, Sophia Children’s Hospital Erasmus MC of an MDT, and the services patients require for optimal Rotterdam. Netherlands; Dr. Alessandra Longhi, Istituto Ortopedico Rizzoli, Bologna. Italy; Dr. Iwona Lugowska, Cancer Centre Warsaw. Poland; Dr. Roberto treatment. However, variation in approaches between Luksch, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. Italy; Mrs. Lisa centres have been described, the significance of which is Lyngsie Hjalgrim, University Hospital Copenhagen. Denmark; Dr. Marco Man- uncertain. Areas where clinical trials may be developed frini, Istituto Ortopedico Rizzoli. Italy; Dr. Sandrine Marreaud, EORTC. Belgium; Dr. Eric Mascard, Institut Gustave Roussy. France; Dr. Martin McCabe, University have been identified. of Manchester. UK; Ms. Sarah McDonald, Sarcoma UK. UK; Dr. Hans Merks, Academic Medical Center Amsterdam. Netherlands; Dr. Aisha Miah, The Royal Supplementary information Marsden Hospital. UK; Mr. Vanden Eynden Michel, Cliniques Universitaires Saint-Luc. Belgium; Dr. Paul O’Donnell, Royal National Orthopaedic Hospital, Supplementary information accompanies this paper at https ://doi. Stanmore. UK; Sr Antroula Papakonstantinou, Oncology Clinic Karolinska org/10.1186/s1356 9-020-00144 -6. University Hospital. Sweden; Mr. Michael Parry, Royal Orthopaedic Hospital, Bir- mingham. UK; Dr. Shreyaskumar Patel, SARC. USA; Dr. David Peake, University Additional file 1: Appendix 1. Summary of premeeting survey questions. Hospitals Birmingham. UK; Dr. Tamas Perlaky, Semmelweis University. Hungary; Appendix 2. Summary of cases presented. Mr. Rob Pollock, Royal National Orthopaedic Hospital, Stanmore. UK; Prof. Ajay Puri, Tata Memorial Hospital, Mumbai. India; Prof. Anna Raciborska, Institute of Mother and Child, Warsaw. Poland; Mr. R. Lor Randall, Utah University of Califor- Abbreviations nia Davis, Sacramento USA; Dr. Francoise REDINI, INSERM. France; Ms. Denise CT: Computed tomography; IMRT: Intensity modulated radiotherapy; MDT: Reinke, SARC. USA; Dr. Marleen Renard, University Hospital Leuven. Belgium; Multi-disciplinary team; MRI: Magnetic resonance imaging; NEMDT: National Dr. Guenther Richter, Children’s Cancer Research Center, TU-Muenchen. Ewing Multidisciplinary Team panel; PBT: Proton beam therapy; PET/CT: Posi- Germany; Dr. Asif Saifuddin, Royal National Orthopaedic Hospital, Stanmore. tron emission tomography and computed tomography. UK; Dr. Beatrice Seddon, University College Hospital, London. UK; Dr. Sandra Strauss, University College Hospital, London. UK; Mrs. Thale Marie Asp Stroem, Acknowledgements The Norwegian Radium Hospital. Norway; Dr. John Tuckett, Newcastle Upon Many thanks to all those who participated, including patients and profes- Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne. UK; Dr. Claudia sionals, listed here: Dr. Dimosthenis Andreou, Helios Klinikum Bad Saarow, Valverde, Vall d´Hebron University Hospital. Spain; Prof. Michiel van de Sande, Brandenburg, Germany; Dr. Jakob Anninga, Radboud University Medi- Leiden University Medical Center. Netherlands; Dr. Henk van den Berg, Emma cal Center, Netherlands. Netherlands; Dr. Jessica Bate, University Hospital, Children Hospital AMC University of Amsterdam. Netherlands; Dr. Tushar Vora, Southampton. UK; Mr. Tom Beckingsale, Newcastle Upon Tyne Hospitals Tata Memorial Centre, Mumbai. India; Prof. Jeremy Whelan, University College NHS Foundation Trust, Newcastle Upon Tyne. UK; Miss Hannah Birkett, Bone Hospital, London. UK; Ms. Rosie Wilson, Bone Cancer Research Trust. UK; Dr. Cancer Research Trust. UK; Dr. Kjetil Boye, Oslo University Hospital. Norway; Dr. James Wylie, Christie NHS FT. UK Bernadette Brennan, Royal Manchester Children’s Hospital. UK; Dr. Otte Brosjö, Karolinska Institute, Stockholm. Sweden; Prof. Øyvind S Bruland, Norwegian Authors’ contributions Radium Hospital. Norway; Mrs. Silvia Cammelli, University of Bologna. Italy; CG, JB, JW conceived and designed the project. All authors contributed to Dr. Peter Chung, Princess Margaret Cancer Centre, Toronto, Canada. Canada; constructing the details of the project and to the methods employed for Dr. Catherine Coyle, Christie Hospital NHS Foundation Trust. UK; Miss Gillian the consensus meeting and to the acquisition and analysis of the outcomes. Cribb, Robert Jones and Agnes Hunt Orthopaedic Hospital, UK. UK; Mrs. Sona CG, JB, BS, JW have drafted the work. All authors have read and approved Cyprova, University Hospital Motol, Prague. Czech republic; Dr. Zoe Davison, the final manuscript and have agreed both to be personally accountable for Bone Cancer Research Trust. UK; Prof. Catharina Dhooge, Ghent University Hos- the author’s own contributions and to ensure that questions related to the pital. Belgium; Prof. Uta Dirksen, University Hospital Essen. Germany; Dr. Steven accuracy or integrity of any part of the work, even ones in which the author DuBois, Dana-Farber/Boston Children’s Hospital, Boston. USA; Dr. Makoto Endo, was not personally involved, are appropriately investigated, resolved, and the Kyushu University. Japan; Dr. Abigail Evans, University College London. UK; resolution documented in the literature. Miss Caroline Folkestad Evensen, Oslo University Hospital. Norway; Dr. Stefano Ferrari, Istituto Ortopedico Rizzoli. Italy; Ms. Joanne Fleming, Azienda ULSS2 Funding Treviso. Italy; Prof. Philipp Funovics, Medical University of Vienna Depart- The meeting and the National Ewing MDT Fellowship were funded and sup- ment of Orthopaedics. Austria; Dr. Jenny Gains, University College Hospital, ported by the Ewing Sarcoma Research Trust and the Bone Cancer Research London. UK; Dr. Marco Gambarotti, Istituto Ortopedico Rizzoli. Italy; Prof. Habs Trust. Additional support from: EUROEWING Consortium FP7 (Seventh Frame- Gelderblom, Leiden University Medical Center. Netherlands; Mr. Craig Gerrand, work Programme) Grant Agreement No 602856; Create for Chloё; University Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne. College London Hospitals Biomedical Research Centre. UK; Dr. Heidi Glosli, Oslo University Hospital. Norway; Mr. Mel Grainger, Royal Orthopaedic Hospital, Birmingham. UK; Prof. Robert Grimer, Royal Ortho- Availability of data and materials paedic Hospital, Birmingham. UK; Dr. Amrita Guha, Tata Memorial Hospital, Data sharing is not applicable to this article as no datasets were generated or Mumbai. India; Dr. Lianne Haveman, Academic Medical Center Amsterdam. analysed during the current study. Netherlands; Dr. Asle Hesla, Karolinska Institute, Stockholm. Sweden; Prof. Dominique Heymann, University of Sheffield. UK; Dr. Hiroaki Hiraga, Hokkaido Ethics approval and consent to participate Cancer Center. Japan; Mr. Alistair Irwin, Newcastle Upon Tyne Hospitals NHS Not applicable. Foundation Trust, Newcastle Upon Tyne. UK; Dr. Mariam Jafri, University Hos- pitals of Birmingham. UK; Dr. Bhavin Jankharia, Dr. Jankharia’s Imaging Centre. Consent for publication India; Prof. Lee Jeys, Royal Orthopaedic Hospital, Birmingham. UK; Mr. Simon Not applicable. Jordan, Royal Brompton Hospital, London. UK; Dr. Jukka Kanerva, Children’s G errand et al. Clin Sarcoma Res (2020) 10:21 Page 13 of 13 Competing interests 14. Jeys LM, Grimer RJ, Carter SR, Tillman RM. Periprosthetic infection in The authors declare that they have no competing interests. patients treated for an orthopaedic oncological condition. J Bone JtSurg Am. 2005;87:842–9. Author details 15. Lee J, Hoang BH, Ziogas A, Zell J. Analysis of prognostic factors in Royal National Orthopaedic Hospital, Brockley Hill, Stanmore HA7 4LP, Mid- Ewing sarcoma using a population-based cancer registry. Cancer. dlesex, UK. Southampton Children’s Hospital, University Hospital Southamp- 2010;116:1964–73. ton NHS Foundation Trust, Southampton, UK. University College Hospital, 16. Ahmed SK, Randall RL, DuBois SG, Harmsen WS, Krailo M, Marcus KJ, 250 Euston Road, London NW1 2PG, UK. Pediatrics III, Sarcoma Centre, West et al. Identification of patients with localized Ewing sarcoma at higher German Cancer Centre, German Cancer Consortium (DKTK), Center Essen, risk for local failure: a report from the Children’s Oncology Group. Int J University Hospital Essen, University Duisburg, Hufelandstr. 55, 45122 Essen, Radiat Oncol Biol Phys. 2017;99(5):1286–94. https ://doi.org/10.1016/j.ijrob Germany. Department of Orthopaedic Surgery, UC Davis Health, 4860 Y p.2017.08.020. Street, Suite 3800, Sacramento, CA 95817, USA. Leiden University Medical 17. Dramis A, Grimer RJ, Malizos K, Tillman RM, Jeys L, Carter LR. Non-met- Center, Albinusdreef 2, Leiden, The Netherlands. Freeman Hospital, New- astatic pelvic Ewing’s sarcoma: oncologic outcomes and evaluation of castle-upon-Tyne NE7 7DN, UK. Oncology-University Hospitals Birmingham prognostic factors. ActaOrthopBelg. 2016;82:216–21. NHS Foundation Trust, Birmingham B15 2TH, UK. Royal Orthopaedic Hospital, 18. Ahmed SK, Robinson SI, Arndt CAS, Petersen IA, Haddock MG, Rose PS, Bristol Road South, Birmingham B31 2AP, UK. University Hospital Birming- et al. Pelvis Ewing sarcoma: Local control and survival in the modern era. ham, Edgbaston, Birmingham B15 2GW, UK. Pediatr Blood Cancer. 2017;64:e26504. 19. Zhu C, Olson KA, Roth M, Geller DS, Gorlick RG, Gill J, et al. Provider Received: 2 July 2020 Accepted: 6 November 2020 views on the management of Ewing sarcoma of the spine and pelvis. J SurgOncol J SurgOncol. 2018;117:417–24. 20. Andreou D, Ranft A, Gosheger G, Timmermann B, Ladenstein R, Hartmann W, et al. Which factors are associated with local control and survival of patients with localized pelvic Ewing’s sarcoma? A retrospec- tive analysis of data from the Euro-EWING99 Trial. ClinOrthopRelat Res. References 2020;478:290–302. 1. Whelan J, McTiernan A, Cooper N, Wong YK, Francis M, Vernon S, 21. Uezono H, Indelicato DJ, Rotondo RL, Mailhot Vega RB, Bradfield SM, et al. Incidence and survival of malignant bone sarcomas in England Morris CG, et al. Treatment outcomes following proton therapy for Ewing 1979–2007. Int J cancer. 2011;000:1–11. sarcoma of the pelvis. Int J Radiat Oncol. 2020;107(5):974–81. 2. Arora RS, Alston RD, Eden TOB, Geraci M, Birch JM. The contrasting age- 22. Ranft A, Seidel C, Hoffmann C, Paulussen M, Warby A-C, van den Berg H, incidence patterns of bone tumours in teenagers and young adults: et al. Quality of survivorship in a rare disease: clinic functional outcome implications for aetiology. Int J Cancer. 2012;131:1678–85. and physical activity in an observational cohort study of 618 long-term 3. Turc-Carel C, Aurias A, Mugneret F, Lizard S, Sidaner I, Volk C, et al. survivors of Ewing sarcoma. J ClinOncol. 2017;35:1704–12.n Chromosomes in Ewing’s sarcoma. I. An evaluation of 85 cases of 23. Puri A, Gulia A, Jambhekar N, Laskar S. Results of surgical resection in remarkable consistency of t(11;22)(q24;q12). Cancer Genet Cytogenet. pelvic Ewing’s sarcoma. J Surg Oncol. 2012;106(4):417–22. https ://doi. 1988;32:229–38. org/10.1002/jso.23107. 4. Whelan J, Hackshaw A, McTiernan A, Grimer R, Spooner D, Bate J, et al. 24. Fujiwara T, Lex JR, Stevenson JD, Tsuda Y, Clark R, Parry MC, et al. Surgi- Survival is influenced by approaches to local treatment of Ewing sarcoma cal treatment for pelvic Ewing sarcoma: What is a safe and functional within an international randomised controlled trial: analysis of EICESS-92. acetabular reconstruction when combined with modern multidiscipli- Clin Sarcoma Res. 2018;8:6. https ://doi.org/10.1186/s1356 9-018-0093-y. nary treatments? J SurgOncol. 2019;120:985–93. 5. Puri A, Gulia A, Vora T. Guidelines for bone & soft tissue tumors. 2011. 25. Vogin G, Helfre S, Glorion C, Mosseri V, Mascard E, Oberlin O, et al. Local https ://tmc.gov.in/tmh/PDF/BSTFi nal_23Feb .pdf. control and sequelae in localised Ewing tumours of the spine: a French 6. Gerrand C, Athanasou N, Brennan B, Grimer R, Judson I, Morland B, et al. retrospective study. Eur J Cancer. 2013;49:1314–23. UK guidelines for the management of bone sarcomas. Clin Sarcoma Res 26. Sewell MD, Tan K-A, Quraishi NA, Preda C, Varga PP, Williams R. Systematic BioMed Central. 2016;6:1–21. review of en bloc resection in the management of Ewing’s sarcoma of 7. Kasalak Ö, Glaudemans AWJM, Overbosch J, Jutte PC, Kwee TC. Can the mobile spine with respect to local control and disease-free survival. FDG-PET/CT replace blind bone marrow biopsy of the posterior iliac Medicine (Baltimore). 2015;94:e1019. crest in Ewing sarcoma? Skeletal Radiol. 2018;47(3):363–7. https ://doi. 27. Bedetti B, Wiebe K, Ranft A, Aebert H, Schmidt J, Jürgens H, et al. Local org/10.1007/s0025 6-017-2807-2. control in ewing sarcoma of the chest wall: results of the EURO-EWING 8. Kalus S, Saifuddin A. Whole-body MRI vs bone scintigraphy in the staging 99 Trial. Ann SurgOncol. 2015;22:2853–9. https ://doi.org/10.1245/s1043 of Ewing sarcoma of bone: a 12-year single-institution review. Eur Radiol. 4-015-4630-0. 2019;29(10):5700–8. https ://doi.org/10.1007/s0033 0-019-06132 -9. 28. Daw NC, Laack NN, McIlvaine EJ, Krailo M, Womer RB, Granowetter L, 9. National Institute for Health and Clinical Excellence. Improving outcomes et al. Local control modality and outcome for Ewing sarcoma of the for people with sarcoma. The Manual. 2006. https ://www.nice.org.uk/ femur: a report from the Children’s Oncology Group. Ann SurgOncol. guida nce/csg9/resou rces/impro ving-outco mes-for-peopl e-with-sarco 2016;23:3541–7. https ://doi.org/10.1245/s1043 4-016-5269-1. ma-updat e-pdf-77338 1485. 29. Aksnes LH, Bauer HCF, Jebsen NL, Follerås G, Allert C, Haugen GS, et al. 10. Kreyer J, Ranft A, Timmermann B, Juergens H, Jung S, Wiebe K, et al. Limb-sparing surgery preserves more function than amputation: a Impact of the Interdisciplinary Tumor Board of the Cooperative Ewing Scandinavian sarcoma group study of 118 patients. J Bone JtSurg Br. Sarcoma Study Group on local therapy and overall survival of Ewing sar- 2008;90:786–94. coma patients after induction therapy. Pediatr Blood Cancer. 2018. https 30. Jeys LMM, Kulkarni A, Grimer RJJ, Carter SRR, Tillman RMM, Abudu ://doi.org/10.1002/pbc.27384 . A. Endoprosthetic reconstruction for the treatment of musculoskel- 11. Bate J, Wingrove J, Donkin A, Taylor R, Whelan J. Patient perspectives on etal tumors of the appendicular skeleton and pelvis. J Bone JtSurg. a national multidisciplinary team meeting for a rare cancer. Eur J Cancer 2008;90:1265–71. https ://doi.org/10.2106/JBJS.F.01324 . Care (Engl). 2019. https ://doi.org/10.1111/ecc.12971 .n 31. Haeusler J, Ranft A, Boelling T, Gosheger G, Braun-Munzinger G, Vieth V, 12. Ladenstein R, Pötschger U, Le Deley MC, Whelan J, Paulussen M, Oberlin et al. The value of local treatment in patients with primary, disseminated, O, et al. Primary disseminated multifocal Ewing sarcoma: results of the multifocal ewing sarcoma (PDMES). Cancer. 2010;116:443–50. Euro-EWING 99 trial. J ClinOncol. 2010;28:3284–91. 13. Albergo JI, Gaston CL, Laitinen M, Darbyshire A, Jeys LM, Sumathi V, et al. Ewings sarcoma: only patients with 100% of necrosis after chemo- Publisher’s Note therapy should be classified as having a good response. Bone Joint J. Springer Nature remains neutral with regard to jurisdictional claims in pub- 2016;98-B:1138–44. lished maps and institutional affiliations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Sarcoma Research Springer Journals

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Abstract

Background: The local treatment of Ewing sarcoma of bone involves surgery, radiotherapy or both. The selection of treatment depends on the anatomical extent of the tumour, the effectiveness of the proposed treatment, its morbid- ity, and the expectation of cure. However, not only are there variations in the approach to local treatment between individual patients, but also between treatment centres and countries. Our aim was to explore variation in practice and develop consensus statements about local treatment. Methods: A three stage modified Delphi technique was used with international collaborators. This involved an expert panel to identify areas of controversy, an online survey of international collaborators and a consensus meet- ing in London, UK in June 2017. In the consensus meeting, teams of clinicians discussed the local management of selected cases and their responses were collected with electronic voting. Results: Areas of greater or less consensus were identified. The lack of evidence underpinning different approaches was noted and areas for collaborative research became apparent. Conclusion: This has demonstrated that there is an international consensus around many aspects of the local treat- ment of Ewing sarcoma of bone, including the use of specialist MultiDisciplinary Team (MDT ) meetings with access to all appropriate treatments. However, considerable variation remains including the use of different staging investiga- tions, decision making, definitions of response, and radiotherapy doses and timing. Further collaborative work should be undertaken to determine the impact of these variations in order to define best practice. Keywords: Ewing sarcoma, Surgery, Radiotherapy, Limb salvage, Combined modality 80% of patients under 20  years of age at diagnosis [1]. Background Ewing sarcoma can occur in any bone, with a distribution Ewing sarcoma is the second most common primary reflecting the mass of bone in the skeleton [2]. bone tumour occurring in children and young adults, Ewing sarcoma of bone classically presents with pain with an incidence of approximately 1 per million. It typi- and an extra-osseous mass arising from the affected cally occurs in the second and third decades of life, with bone. Characteristic imaging features include a peri- osteal reaction with or without bone destruction on plain radiographs, and an extra-osseous mass on magnetic res- *Correspondence: craig.gerrand@nhs.net Royal National Orthopaedic Hospital, Brockley Hill, Stanmore HA7 4LP, onance imaging (MRI). Most cases demonstrate a trans- Middlesex, UK location involving chromosomes 11 and 22 [3]. Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gerrand et al. Clin Sarcoma Res (2020) 10:21 Page 2 of 13 Treatment is multidisciplinary and highly specialised, Confirmed conference attendees were asked to com - involving chemotherapy, radiotherapy and surgery. Local plete a pre-meeting survey on the Slido platform (https :// therapy decisions are often nuanced, balancing the risks www.sli.do/) (Additional file  1, Appendix  1). The survey and morbidity of surgery and radiotherapy with poten- asked respondents about their specialty, facilities and ser- tial benefits. Approaches to local treatment vary between vices at their centre, and general approach to treatment. countries, reflecting different health care structures and The final phase was based around a multidisciplinary philosophies. In the EICESS 92 study, differences in local conference. The programme included introductory pres - treatment approaches were identified: patients from the entations summarising the principals of imaging and United Kingdom were less likely to receive combined treatment at different anatomical sites. Clinical cases modalities (surgery and radiotherapy) than those treated were then presented to the audience by two radiologists in Germany, and there were differences in local relapse (P O’D and JT, Additional file  1, Appendix  2). Partici- and overall survival [4]. pants were asked about how they would treat each case, Recognising these differences, an international consen - and differences in approach were openly discussed. At sus meeting to discuss the local treatment of Ewing sar- the end of the meeting, cases brought by attendees were coma was held in Birmingham in 2007. This resulted in presented to test the consensus. Participant responses several changes in UK practice, including a pilot in which were collected electronically using Slido (https ://www.sli. a national Ewing Multidisciplinary Team panel (NEMDT) do/). provided central review of cases. This process has been associated with changes in treatment approaches, in Levels of evidence and consensus particular the greater use of combined modalities and Using data from the pre-meeting survey and audience especially of preoperative radiotherapy. In June 2017, a responses, consensus was evaluated as strong (more than second consensus meeting was held in London to explore 75% of participants/respondents agreeing with a state- current differences in local treatment approaches and to ment), moderate (50–75% of participants/respondents inform the NEMDT panel. The specific objectives were agreeing with a statement) or none (no clear agreement). to establish standards for current practice, develop con- Response data are presented for each individual respond- sensus statements to guide local treatment decisions and ent, not by centre. identify areas for further research. Results Methods Participants A modified Delphi method was used comprising a three Pre‑meeting survey stage process of expert panel review, a pre-meeting The pre-meeting survey was sent to 81 clinicians who online survey and case review with electronic voting at expressed an interest in attending, of whom 58 (72%) the meeting. Ewing sarcoma of bone arising in all ana- responded after two reminders. There were representa - tomic sites other than the head and neck were included. tives from 27 centres in 15 countries, treating a median Soft tissue Ewing sarcomas were excluded. of 6–10 patients a year (range < 5 to > 50 cases per year). An expert scientific advisory board was convened in Respondents were orthopaedic surgeons (16/58, 28%), early 2017 to develop the content for the conference. This paediatric oncologists (15/58, 26%), radiation oncologists panel included clinicians from centres in the UK, Nether- (11/58, 19%), radiologists (6/58, 10%), medical oncolo- lands, Germany and the USA (CG, JB, JW, UD, LR, MvdS, gists (5/58, 9%), histopathologists (1/58, 2%), and other DP, BS, LJ). Clinical situations in which the approach to (4/58, 7%). The majority (48/58, 83%) had not attended treatment might vary were identified through discussion the previous consensus meeting in Birmingham in 2007. with the scientific advisory board and from case discus - sions at the UK NEMDT. A list of potential conference Consensus meeting attendees participants was compiled aiming to give a wide geo- There were 59 clinical voting attendees at the meeting. graphical representation, including centres recognised Thirty-four centres from 19 countries were represented. as having differing approaches to the treatment of Ewing There were non-voting attendees from charities and sarcoma and participants in the previous consensus research bodies. Voting attendees were orthopaedic sur- meeting. geons (18/58, 32%), paediatric oncologists (17/58, 29%), radiation oncologists (9/58, 15%), radiologists (3/58, 5%), medical oncologists (8/58, 14%), histopathologists (1/58, 2%), and other (2/58, 4%). Due to constraints on accessing personnel with sufficient expertise, absence of adequate data and because of time constraints within the programme. G errand et al. Clin Sarcoma Res (2020) 10:21 Page 3 of 13 Patient pathways and services level; strong; 54/56, 96%), expert limb fitting/prosthetic The ideal pathway for patients services (Consensus level; strong; 52/56, 93%), specialist Survey respondents confirmed that specialist centres sarcoma rehabilitation (Consensus level; strong; 46/56, routinely perform conventional radiographs in 2 planes 82%), clinical nurse specialist support (Consensus level; (Consensus level: strong; Q2.1a, 52/56, 93%) (summa- strong; 44/56, 79%), clinical trials in Ewing sarcoma rised with other areas of consensus in Table 1), and MRI (Consensus level; strong; 50/56, 89%), and radiotherapy of the whole involved compartment with adjacent joints delivered by intensity modulated radiotherapy (IMRT) (Consensus level: strong; Q2.1b, 55/56, 98%). The major - (Consensus level; strong; 52/56, 93%). Proton beam ther- ity perform staging computed tomography (CT) of the apy was available (Consensus level; strong) in their cen- chest only (Consensus level: moderate; Q2.1d, 34/54, tre (7/56, 13%), elsewhere in the country (20/56, 36%), or 63%) with a smaller proportion performing CT of the abroad (30/56, 54%). Most had access to specialist end chest, abdomen and pelvis (Consensus level: none; Q2.1e, of life/palliative care support (Consensus level; strong; 18/45, 40%). Only a minority of respondents (Consensus 47/56, 84%). level: none; Q2.1c, 13/55, 24%) were in centres routinely Most surgeons have access to customised endopros- offering whole body MRI: more offered positron emis - theses (4.4, 17/19, 89%), modular endoprostheses (18/19, sion tomography (PET/CT) (Consensus level: moderate; 95%), “growing” endoprostheses (18/19, 95%), free flaps/ Q2.1f, 37/53, 70%) and/or isotope bone scan (Consen- vascularised grafts (18/19, 95%), rotationplasty (17/19, sus level: moderate; Q2.1g, 37/56, 66%) and bone mar- 89%), massive allografts (12/19, 63%), and extracorporeal row sampling (Consensus level: moderate; Q2.1h, 40/56, irradiation/reimplantation (13/19, 68%). 71%), depending on the clinical scenario. Timing and approaches to decisions about local treatment Shared decision making The multidisciplinary team It was agreed that patients should have the opportunity Almost all survey respondents routinely discussed to discuss local treatment options as soon after diagnosis patients in a local MDT meeting (Consensus level: strong; as possible (Consensus level: strong; Q4.5o, 15/19, 79% Q3.1, 51/56, 91%), and a smaller number in a national agree/strongly agree). Decisions about local treatment MDT (Consensus level: none; Q3.1, 20/56, 36%) or rou- should be made in collaboration with patients and fami- tinely with teams in other centres (Consensus level: none; lies (Consensus level: strong; Q4.5p, 17/17, 100% agree/ Q3.1, 7/56, 13%). In one centre patients were only dis- strongly agree). cussed selectively outside it, and in an example of good There was moderate consensus that it is sometimes practice, another described how the paediatric oncolo- possible to make a decision about radiotherapy based on gist, surgeon and radiation oncologist held a joint consul- the imaging at presentation (Consensus level: moderate; tation with all patients with pelvic and axial tumours at Q5.6c, 14/26, 54% agree/strongly agree) and strong con- the same clinic visit after diagnosis and again at the time sensus that the radiological response to chemotherapy is of a local control decision. important when considering local therapy options (Con- There is variation in guidelines for standard practice, sensus level: strong, Q3.5a, 50/55, 91% strongly agree/ as respondents reported adopting the EUROEWING agree). 2012 trial protocol (Q3.2, 28/51, 55%), ESMO Clinical Practice Guidelines (20/51, 39%), British Sarcoma Group guidelines (14/51, 27%) and National  Cancer  Institute Decisions about local treatment in the presence of metastatic treatment guidelines (4/51, 8%). Other adopted protocols disease included those of the Childrens Oncology Group (COG), The statement that patients with bone metastases should Scandinavian Sarcoma group, Ewing 2008, the French have the same local treatment as those without did not Combinair trial, EW-1 and EW-2 joint studies of Italian reach consensus (Q3.5e, Agree/Strongly agree 30%, Paediatric Oncology Group (AEIOP) and the Italian Sar- Undecided 26%, Disagree/strongly disagree 45%). With coma group, and the hospital’s own guidelines (e.g. those widespread bone metastases, radiotherapy alone to the of the Tata Memorial Hospital, Mumbai [5]). primary tumour is routinely indicated (Consensus level: strong; Case 1. 44/54, 81% radiotherapy only to the pri- mary tumour, also Case 3, 39/56, 70%, Case 17, 26/42, Access to diagnostic and treatment services 62%). In the presence of oligometastatic bone disease, it The majority of respondents had access to whole body may be reasonable to consider radiotherapy alone for the MRI (Consensus level: strong; Q 3.3, 42/56, 75%), whole primary tumour (Consensus level: strong; Case5, 35/48, body PET/CT (Consensus level: strong; 54/56, 96%), spe- 73%) as well as radiotherapy to the metastases. cialist surgical teams with sarcoma expertise (Consensus Gerrand et al. Clin Sarcoma Res (2020) 10:21 Page 4 of 13 Table 1 Summary of consensus statements Patient pathways and services Imaging at presentation should include Conventional X-rays in 2 planes (Strong) MRI of the whole involved compartment and adjacent joints (Strong) Staging CT of chest (Moderate) PET/CT (Moderate) Isotope bone scan (Moderate) Bone marrow sampling (Moderate) Patients should be managed within a properly constituted MDT (Strong) Services should have access to the following Whole body MRI (Strong) Whole body CT/PET (Strong) Specialist surgical teams (Strong) Expert limb fitting/prosthetic services (Strong) Specialist sarcoma rehabilitation (Strong) Clinical nurse specialist support (Strong) Clinical trials (Strong) Radiotherapy by IMRT (Strong) Radiotherapy by proton beam (Strong) Timing and approaches to decisions about local treatment Patients should have the opportunity to explore local treatment options as soon after diagnosis as possible (Strong) Decisions about local therapy should be made in collaboration with patients and families (Strong) It is possible to make a decision about radiotherapy based on the imaging at presentation in some situations (Moderate) The radiological response to chemotherapy is important when considering local therapy options (Strong) With widespread bone metastases, radiotherapy alone to the primary tumour is routinely indicated (Strong) With oligometastases, radiotherapy alone may be considered as well as treatment to the oligometastases (Strong) Patients with pulmonary metastases should be considered for the same local treatment as those without (Strong), including potentially morbid resec- tions (Moderate) Pathology and molecular biology Patients should have biopsies in the bone cancer centre (Strong) Core needle biopsies or open biopsies are preferred (Strong) Specimens should be tested for cytogenetic abnormalities (Strong) Oligometastases in lymph nodes or bone should be biopsied (Moderate) Tissue is banked for research (Strong) Assessment of histological response is important when considering the effectiveness of local treatment (Strong) An adequate response to chemotherapy should be taken as > 90% necrosis (Moderate) Surgical margin status is a reliable indicator of tumour left in the patient (Moderate) An adequate surgical margin is one in which there is no viable tumour at the edge of the resection specimen (Moderate) Surgery The surgical resection should be planned to include the biopsy track (Strong) An adequate surgical margin is one in which all of the anatomical structures involved at presentation are completely removed (Strong) Where feasible it is reasonable to consider resection of peri-lesional oedema (Moderate) The radiological response to neoadjuvant chemotherapy should be considered when planning surgery (Strong) Pelvic spacers may have a role in reducing the morbidity of radiotherapy (Moderate) Radiotherapy has a negative impact on outcomes after endoprosthetic replacement (moderate) Radiotherapy has an negative impact on outcomes after allograft reconstruction (Moderate) Radiotherapy does not make surgery more difficult technically (Moderate) There is no role for debulking surgery when a tumour cannot be completely resected (Strong) Local recurrence has an impact on overall survival (Strong) G errand et al. Clin Sarcoma Res (2020) 10:21 Page 5 of 13 Table 1 (continued) Anatomical site variations Pelvis and sacrum Tumours which cross the midline in the sacrum are not considered resectable because of the morbidity associated with surgery (Strong) Tumours with major visceral involvement or requiring pelvic organ removal may also be considered too morbid to resect (Moderate) Definitive radiotherapy is indicated for unresectable sacral tumours (Strong) Protons may be advantageous in the sacrum (Strong) Preoperative radiotherapy may be preferred when the tumour volume is large (Moderate) Radiotherapy is likely to be associated with increased complication rates (Strong) Spine Protons may be of some benefit in the spine (Strong) The type of spinal reconstruction can affect the choice of radiotherapy treatment modality (Strong) Patients with a possible Ewing’s tumour of the spine without neurological signs should have a biopsy before decompressive surgery (Strong) Urgent surgery is recommended if there is a Ewing’s tumour of the spine causing neurological compromise (Moderate) Radiotherapy is usually indicated after decompressive surgery (Strong) and should include the original tumour volume and all areas potentially con- taminated by surgery (Strong) Chest A pleural effusion in relation to a chest wall tumour is not a definite indication for radiotherapy preoperatively (Moderate) A pleural effusion in relation to a chest wall tumour may be an indication for post operative radiotherapy (Moderate) Pleural involvement with a primary tumour may be an indication for preoperative (None) or postoperative (Moderate) radiotherapy Extremity Amputation is considered less often than for osteosarcoma (Strong) Amputation may be indicated if negative margins cannot otherwise be achieved (Moderate) If resection of a distal leg tumour would lead to inadequate margins or a foot with poor function, below knee amputation is indicated (Strong) Amputation is less often recommended in the upper extremity (Moderate) In the proximal tibia, amputation does not necessarily lead to better outcomes than proximal tibial replacement and radiotherapy (Moderate) Radiotherapy can be added to surgery in the tibia but accepting a high risk of local complications (Moderate), therefore preoperative radiotherapy may be preferred (Moderate) Local therapy in advanced disease Suspected solitary bone metastases should be biopsied at presentation if possible (Strong) Solitary bone metastases may be treated by surgery, radiotherapy or both if the morbidity is acceptable (Strong) If there are widespread bone metastases, radiotherapy is indicated when symptomatic (Strong) Potentially involved lymph nodes should have sampling or biopsy before chemotherapy if possible (Strong) It is appropriate to surgically resect lymph nodes if there is suspicion of tumour involvement (Moderate) It is reasonable to consider radical surgery such as amputation or hemipelvectomy to treat locally recurrent disease if there are no metastases (Strong) In contrast, patients with pulmonary metastases should 4%). Biopsy tracks are usually marked so that they can be considered for the same local treatment as those with- be excised at the time of definitive surgery (Q2.4, 38/56, out (Consensus level: strong; Q3.5f, 34/52, 65% agree/ 68%). strongly agree). It is reasonable therefore to consider Biopsy specimens are routinely tested for molecular potentially morbid resections, for example of the pelvis, abnormalities, including the EWS translocation (Q2.5, in the presence of pulmonary metastases (Consensus 53/56, 95%). Lymph nodes that may be involved on imag- level: moderate; Case 2, 31/48, 65%). ing should be sampled before chemotherapy (Q2.6, Con- sensus level: moderate, 28/56, 50%). Similarly, suspected Pathology and molecular biology bone oligometastases should be biopsied (Q2.7, Consen- Biopsy techniques and approaches sus level: moderate, 29/56, 52%). Tissue should be rou- Patients usually have biopsies in the bone cancer centre tinely banked for research (Consensus level: strong; Q2.8, (Q2.2, Consensus level: strong), with a core needle biopsy 44/56, 79%). by a radiologist (Q2.3, 26/55, 47%), surgeon (14/55, 25%), or open incisional biopsy by a surgeon (12/55, 22%). Fine needle aspirate was only infrequently used (2/55, Gerrand et al. Clin Sarcoma Res (2020) 10:21 Page 6 of 13 Assessment of response to chemotherapy Complications of surgery The histological response to chemotherapy is important Radiotherapy has a negative impact on outcomes, espe- when considering the effectiveness of local treatment cially infection and prosthetic failure, after endopros- (Consensus level: strong, Q3.5b, 50/54, 92% strongly thetic replacement of a long bone (Consensus level: agree/agree). Some respondents agreed the definition of moderate; Q4.5b, 15/21, 71%), and after allograft recon- an adequate response to chemotherapy should be taken struction (Consensus level: moderate; Q4.5c, 15/21, 71%). as > 90% necrosis (Consensus level: moderate. Q3.5c, Respondents thought radiotherapy did not make surgery 20/31, 64% strongly agree/agree), with others prefer- more difficult technically (Consensus level: moderate; ring 100% necrosis (Consensus level: weak. Q3.5d, 8/32, Q4.5d, 12/21, 57%). 25% strongly agree/agree). However, it was recognised Surgeons did not reach consensus about the statement that the increasing use of preoperative radiotherapy that some patients at high risk of surgical complications will change the interpretation of necrosis in resection should complete chemotherapy before surgical treatment specimens. (Consensus level: none; Q4.5a, 10/21, 48% strongly agree/ agree vs 29% disagree/strongly disagree). Assessment of surgical margins Surgical margin assessment is a reliable predictor of When is a tumour inoperable? tumour remaining in the patient (Consensus level: mod- There is no role for debulking surgery when a tumour erate; Q3.5g, 34/52, 66% strongly agree/agree). An ade- cannot predictably be completely resected (Consensus quate surgical margin is one in which there is no viable level: strong; Q4.5e, 18/20, 80% disagree/strongly disa- tumour at the edge of the resection specimen (Consensus gree that debulking surgery should be considered). level: moderate; Q35h, 33/53, 63% strongly agree/agree). The statement that an adequate surgical margin is one Radiotherapy in which all of the anatomical structures involved before Indications for and timing of radiotherapy chemotherapy have been completely removed did not Radiotherapy may be given pre-operatively, post-opera- reach consensus in the pre-meeting survey (Q3.5i, 17/47, tively or as definitive treatment. Tumour volume may be 37% Strongly agree/agree, 16/47, 35%, strongly disagree/ considered as a relative indication when making a rec- disagree). There was strong consensus that local recur - ommendation for radiotherapy (Consensus level: none; rence at the primary site has an impact on overall sur- Q5.4d, Q83). vival (Consensus level: strong; Q4.5f, 19/20, 95% agree/ There was no consensus as to whether pathologi - strongly agree). cal fracture at presentation was a definite indication for preoperative radiotherapy (Q75, with radiotherapy rec- Surgery ommended always/very often in 29%, and rarely/never Principles of surgery for Ewing sarcoma in 48%), although there was some agreement that radio- When planning surgical resection the biopsy track should therapy should be considered postoperatively (Consensus be removed (Consensus level: strong, Q4.1, 17/19, 89% level: moderate; Q87, 11/21, 53% Very often/always, com- “yes”). pared with 24% rarely/never). In the pre-meeting survey, many respondents did not There was agreement that involved lymph nodes should consider resecting all of the volume/anatomical struc- be included in radiotherapy treatment volumes (Con- tures involved before chemotherapy (Consensus level: sensus level: moderate; Q91, 19/26, 73% agree/strongly moderate; Q4.2, 10/19, 53% “no”). However, most sur- agree). geons considered resecting all of the volume/anatomical If complete resection is possible based on initial imag- structures involved after chemotherapy (Consensus level: ing, the decision about radiotherapy can await assess- strong; Q4.3, 16/19, 84% “yes”). ment of histological response (Consensus level: strong; Where feasible it is reasonable to consider resection of Case 11, 43/56, 77%). peri-lesional oedema which might contain tumour (Con- A poor radiological response to neoadjuvant chemo- sensus level: moderate; Case 4, 32/47, 68%), therapy is a relative indication for preoperative (Con- The radiological response to neoadjuvant chemother - sensus level: moderate; Q77, 61% sometimes/very often/ apy should be considered when planning surgery (Con- always. Consensus level: strong; Case 9, 47/50, 94%) or sensus level: strong; Q4.5n, 17/20, 85% agree/strongly postoperative radiotherapy (Consensus level: strong; agree). Q89, 20/23, 87%, sometimes/very often/always). Pelvic spacers should be considered to reduce the mor- Preoperative radiotherapy may be given when an bidity of radiotherapy (Consensus level: moderate; Q4.5j, inadequate (marginal) margin is anticipated on imag- 11/20, 55% agree/strongly agree). ing. There was strong consensus that a 2  mm margin G errand et al. Clin Sarcoma Res (2020) 10:21 Page 7 of 13 Selection of modalities for planning and delivery after resection and preoperative radiotherapy does not of radiotherapy require further radiotherapy (Consensus level: strong, There is an expectation that the indications for proton Case 8, 35/46, 76%). Tumours close to critical anatomi- beam treatment will expand as it becomes more available cal structures which would be morbid to resect surgically (Consensus: moderate; Q92, 16/24, 67% agree/strongly (e.g. major nerve or blood vessel) should be considered agree). for preoperative radiotherapy (Consensus level: moder- Insertion of a pelvic spacer can be considered to allow ate; Q68, 12/24, 50% always/very often). The expectation delivery of the prescribed radiotherapy dose by reducing of a close or positive surgical margin on the pre-chemo- the dose to normal tissue structures, in particular bowel therapy scan is not a definite indication for preoperative (Consensus level: moderate; Q51, 11/20, 55% agree/ radiotherapy (Consensus level: none; Q69). However, if strongly agree). a close or positive surgical margin is expected based on the post chemotherapy scan, preoperative radiotherapy Anatomical site considerations should be considered (Consensus level: moderate; Q70, Pelvis/sacrum 14/24, 59%). There was strong consensus that sacral tumours which Indications for postoperative radiotherapy include cross the midline should not be resected because the viable tumour at the surgical margin (Consensus level: morbidity of resection including loss of bladder, bowel strong; Q79, 25/25, 100%, Very often/always), incom- and sexual function is thought unacceptable (Consensus plete excision of the pre-chemotherapy tumour volume level: strong; Q4.6, 15/20, 75%. Also Case 15, 36/46, 78%). (Consensus level: moderate; Q80, 15/25, 60% very often/ Similarly, major visceral involvement requiring pelvic always) and poor histological response (Consensus level: organ removal would mean that most surgeons would not moderate; Q81, 17/25, 68% very often/always), usually recommend resection (Consensus level: moderate; Q4.6, defined as < 90% necrosis, although there was variation 14/20, 70%, Case 5). Definitive radiotherapy is indicated in the level of histological response deemed acceptable to for sacral tumours for which surgery is considered too avoid radiotherapy (Consensus level: none; Case 9). morbid (Consensus level: strong; Case 15, 44/44, 100%). Complete excision and good histological response are Protons may be advantageous in this situation in terms of needed to avoid radiotherapy. It is reasonable to add delivery of optimal dose, and reduction in normal tissue postoperative radiotherapy with a margin of < 2  mm toxicity (Consensus level: strong; Case 15, 38/47, 81%). and < 90% necrosis (Consensus level: strong; Case 7, Tumours in the pelvis may be selected for radiotherapy 46/56, 82%). preoperatively (Consensus level: moderate; Q5.4h, 73% sometimes/very often/always) or postoperatively (Con- Radiotherapy dose sensus level: strong; Q5.5h, 20/22, 91% sometimes/very For pre-operative radiotherapy, there was no consensus often/always). for dose (range 45–55.8  Gy), with doses of 45  Gy (27%), Preoperative radiotherapy may be preferred when the 50 Gy (32%), and a range of ‘other’ doses (41%) reported, tumour volume is large (Consensus level: moderate; Case including 50.4 Gy, 54 Gy and 55.8 Gy. 2, 26/50, 52%; Case 10, 40/49, 82%; Consensus level: For post-operative radiotherapy, there was also no con- strong, Case 10, 39/52, 75%). sensus, although the doses used were generally higher Reconstruction is likely to be associated with more than for pre-operative radiotherapy (range 45–60  Gy). complications if radiotherapy has been given and influ - Doses reported were 45  Gy (18%), 50  Gy (23%), ‘other’ ences the choices for reconstruction (Consensus level: (50%), and ≥ 60  Gy (10%). The ‘other’ group included strong, Case 10, 43/49, 88%). 42 Gy, 50.4 Gy, 54 Gy, and 55.8 Gy. For definitive radiotherapy, there was again a lack of Spine consensus, although as with post-operative radiotherapy, Proton beam radiotherapy may be of some benefit in the doses were generally higher than for pre-operative radio- spine (Consensus level: strong; Case 12, 41/44, 93%: Case therapy (range 45–70.2  Gy). Doses reported were 50  Gy 13, 44/50, 88%). Where combined modality treatment (11%), 60  Gy (32%), > 60  Gy (11%) and ‘other’ (47%). The with surgery and radiotherapy is indicated, it is recog- ‘other’ group included 45  Gy, 54  Gy, 55.8  Gy, 59.4  Gy, nised that the type of reconstruction can affect the choice 70.2 Gy. of radiotherapy treatment modality (Consensus level: For all radiotherapy indications, fraction sizes of 1.5 Gy, strong; Case 13, 32/43, 74%). 1.8 Gy and 2 Gy were reported. Patients who present with a possible Ewing tumour of the spine without neurological signs should have a biopsy as a response to systemic treatment is likely and may Gerrand et al. Clin Sarcoma Res (2020) 10:21 Page 8 of 13 allow intralesional decompressive surgery to be avoided In the proximal femur, if complete resection is deemed (Consensus level: strong; Case 14; 49/50, 98%). feasible, then either pre or post op radiotherapy can be If there is deteriorating or objective neurological com- considered. (Case 11). promise, urgent surgery is recommended (Consensus In a case with an intraarticular tumour at the elbow, level: moderate; 29/48, 60%), rather than biopsy and radiotherapy was recommended (Consensus level: chemotherapy/radiotherapy. Radiotherapy is invariably strong; Case 18, 34/47, 72%), preferably postoperatively indicated after decompressive surgery (Consensus level: (Consensus level: moderate; Case 18, 31/50, 62%). strong; Case 14, 41/46, 89%), and should include the original tumour volume and all areas potentially con- Local therapy in advanced disease taminated by surgery (Consensus level: strong; Case 14, General approach to patients with advanced disease 45/51, 88%). Oligometastases in  bone A suspected solitary bone There was no consensus about the use of craniospinal metastasis should be biopsied at presentation if possible radiotherapy for patients with epidural disease (Q5.6d). (Consensus level: strong; Case 4, 45/51, 88%). If there is more than one suspected metastasis it may be reason- able to biopsy more than one (Consensus level: moderate; Chest Case 5. 32/56, 57%). A pleural effusion in association with a chest wall tumour The statement that resection of bone metastases is not a definite indication for radiotherapy preopera - improves survival was not supported (Consensus level: tively (Consensus level: moderate; Q5.4e, 12/21, 57% none; Q4.5h), but bone metastases may be resected if the rarely/never), but may be postoperatively (Consensus morbidity is acceptable (Consensus level: strong; Q4.5i, level: moderate; Q5.5e, 10/20, 50% always/very often). 16/20, 80% agree/strongly agree). A solitary metasta- However, pleural involvement with a primary tumour sis should be treated by surgery, radiotherapy or both may be an indication for radiotherapy either preop- (Consensus level: strong; Case 4, 47/52, 90%, resec- eratively (Consensus level: none; Q5.4f, 7/21, 34% very tion, radiotherapy or both). With greater numbers of often/always) or postoperatively (Consensus level: mod- bone metastases, individual treatment of all metastases erate; Q5.5f, 10/20, 50% very often/sometimes. See also becomes more difficult, but if possible radiotherapy to Case 17). two lesions is reasonable (Consensus level: strong; Case 5, 49/51, 96%). Where widespread bone metastases are present, radio- therapy is indicated when symptomatic (Consensus level: Extremity strong: Case 1, 50/57, 88%). Amputation is considered less often than for other extremity bone tumours (Consensus level: strong; Q4.5l, Lymph node involvement Staging by PET/CT is more 16/20, 80%), but may be considered if negative surgical likely to detect soft tissue/lymph node involvement. margins cannot otherwise be achieved (Consensus level: Potentially involved lymph nodes should have sampling moderate; Q4.7, 14/20, 70%). Alternatively, if resection of or biopsy before chemotherapy whenever possible (Con- a tumour would be associated with inadequate margins sensus level: strong; Case 6; 44/50, 88%). It is appropriate or a foot with poor function, below knee amputation may to surgically resect lymph nodes if there is suspicion of be indicated (consensus level: strong; Case 6. 43/54, 80%). tumour involvement (Consensus level: moderate; Q4.5g, Respondents indicated that amputation would be less 14/20, 70%. Also Case 6, consensus level: moderate; 31/56, often recommended in an upper extremity tumour (Con- 56%). sensus level: moderate; Q4.5l, 10/20, 50%). In proximal tibial tumours, it was agreed that amputa- tion does not necessarily lead to better outcomes than Local therapy in relapsed disease proximal tibial replacement and radiotherapy (Consensus It is reasonable to consider radical surgery such as ampu- level: moderate; Q4.5k, 10/20, 50%). In the tibia, it is rea- tation or hemipelvectomy to treat locally recurrent Ewing sonable to add radiotherapy to surgery while accepting a sarcoma if there are no metastases (Consensus level: high risk of local complications (Consensus: moderate; strong; Q4.5m, 18/20, 90% agree/strongly agree. Case 16, Case 3, 30/51, 59%). In this situation, preoperative radio- 31/48, 65%). therapy is preferred (Consensus level: moderate; Case 3, 36/49, 73%). Preferred reconstructive options would be autograft, endoprostheses or allograft (Case 3). Amputa- tion is a reasonable alternative for some patients. G errand et al. Clin Sarcoma Res (2020) 10:21 Page 9 of 13 Discussion the prognosis is poor (for example with widespread bone Our aim was to define existing international consen - metastases). The majority of patients receive combined sus about the local treatment of Ewing sarcoma of bone treatment. Evidence in favour of one or other treatment in order to inform specialist MDTs and identify areas in approach comes predominantly from retrospective stud- which collaboration to develop more evidence aimed at ies and is difficult to interpret because there is an inher - strengthening future consensus might be worthwhile. We ent bias in treatment selection. have identified an engaged and supportive professional and patient community which actively contributed to Shared decision making this project and constituted a key strength of this report. Shared decision-making involves a collaborative Although we have attempted to collect objective data approach to treatment decisions based on an under- about treatment, our description of the strength of con- standing of the patient’s priorities for their own lives: we sensus is necessarily subjective. The conclusions of this showed strong consensus that decisions should be made paper should therefore be treated with caution and are together with patients and families as early as possible for consideration by treating teams rather than definitive in the treatment pathway. However, there is no evidence recommendations. that this approach is of benefit in patients with Ewing sarcoma specifically and standard mechanisms for sup - The ideal patient pathway and staging porting high quality decisions do not exist. There is an The urgent referral of patients with a suspected Ewing opportunity to develop these and to use existing outcome sarcoma of bone to a specialist centre is established prac- data to allow patients, families and treating teams to tice [6]. Initial evaluation with plain radiographs and MRI make fully informed treatment decisions [11]. of the whole involved compartment and adjacent joints is universally applied. However, we have shown variation Decisions about local treatment in the presence of metastatic in systemic staging with some centres performing CT of disease abdomen and pelvis as well as chest. There is greater vari - Patients with bone metastases at diagnosis have a poor ation in imaging of the skeleton with centres most often prognosis [12], and therefore there was an expected performing whole body isotope bone scan and bone strong consensus for avoiding morbid surgery. The treat - marrow sampling. PET/CT was also widely offered and ment of multiple bone metastases with radiotherapy is may be as useful as bone marrow sampling [7]. However likely reasonable if they are small in number and easily whole body MRI scan was not routinely offered and given treatable, but there is little evidence for improved out- recent evidence about its sensitivity may be a better stag- comes associated with this approach. The better progno - ing investigation [8]. Further evaluation of the optimal sis of patients with pulmonary metastases alone supports staging investigations for Ewing sarcoma is warranted. a more aggressive approach to local treatment, including, for example, surgical resection of the pelvis. However, The multidisciplinary team and decision making decisions about local treatment may be more nuanced The treatment of patients with Ewing sarcoma requires given the lower expectation of cure. a properly constituted MDT with expertise in medi- cal oncology, radiotherapy, and surgery [6, 9]. We have Pathology and molecular biology shown there is almost universal use of MDT discussion, Biopsy techniques and approaches and adoption of a wide range of existing treatment pro- The principles of biopsy of musculoskeletal tumours are tocols. Wide discussion outside the treating MDT, for well established. An image guided needle biopsy is the example in a national forum or with another centre is not most widely adopted technique, with open incisional usual in the majority of countries, although the EICESS biopsy preferred by some. The latter has the advantage 92 experience indicates that a more unified approach of providing more material for diagnostic studies and could be explored to determine if it will improve out research at the risk of greater local contamination. This comes for patients and has been adopted by the CESS may become more important as biological studies, for group in Germany [4, 10]. The wider adoption of national example whole genome sequencing become integrated or international MDT discussions has some intuitive into the diagnostic and treatment pathway. appeal but demands further evidence. Biopsy of other areas of potential involvement, such as lymph nodes or bone metastases can also be important Timing and approaches to decisions about local treatment at presentation and before chemotherapy, particularly if Complete resection of the primary tumour continues as aggressive local treatment such as surgical excision might the preferred approach, with radiotherapy as an alterna- be considered. Evidence is needed to support this more tive if surgery is not feasible, unacceptably morbid or if Gerrand et al. Clin Sarcoma Res (2020) 10:21 Page 10 of 13 aggressive approach to oligometastatic disease including is sufficiently high, it has been suggested that surgery is the identification of patients who might benefit. delayed until the end of chemotherapy. However, no con- sensus was reached on this question. Assessment of response to chemotherapy Radiotherapy There was strong consensus that the histological response Radiotherapy is most frequently delivered with photons, to chemotherapy was important when considering the although as access improves, more patients are receiv- effectiveness of local treatment, although interpretation ing proton beam treatment. Photon radiotherapy is best of this is made more difficult after preoperative radio - delivered via a 3D-conformal CT-plan, or increasingly therapy. The level at which a response is defined as ade - with intensity modulated radiotherapy, which frequently quate varies: Greater than 90% necrosis was accepted by allows for superior dose delivery and normal tissue spar- many participants, but others only consider a complete ing. For some patients, proton beam therapy may offer an histological response as ‘adequate’ [13]. Standardisation advantage in delivering the prescribed radiotherapy dose of radiological response parameters is also needed. (if it is at the higher end of the dose range) or in sparing normal tissues and reducing late toxicity. Surgery We have shown variations in the approach to radiother- Principles of surgery for Ewing sarcoma apy and different approaches to the treatment of patho - At presentation, Ewing sarcomas typically have a large logical fractures, lymph nodes and the indications for and extra-osseous mass which infiltrates local anatomi - timing of radiotherapy. Further evaluation of the optimal cal structures. Although the mass may reduce following delivery of radiotherapy is required in clinical trials. chemotherapy, viable tumour cells may remain in these infiltrated structures. The principle that all of the struc - Anatomical site variations tures involved at presentation should either be surgically Pelvis/sacrum removed or included in the radiation field has become About a quarter of Ewing sarcomas involve the pelvis established within the NEMDT in recent years and and/or sacrum [15]. Pelvic tumours tend to be larger, reached strong consensus after discussion at this meet- with a higher risk of metastasis and poorer survival ing. This included the resection of perilesional oedema [15]. The soft tissue mass associated with a pelvic Ewing if reasonable. In practice, however, local treatment deci- tumour can be large and may involve adjacent critical sions are often more pragmatic, driven by an understand- anatomical structures such as the iliac vessels, bladder ing of what is reasonable, the associated morbidity and and rectum. Local recurrence rates after resection of pel- the expectation of cure. vic tumours can be higher than other sites [16]. Retro- Surgical margin assessment aims to evaluate whether spective series suggest that patients treated with surgery there is residual tumour in the local site, and there is have better overall survival [17] and that those treated some variation in what is believed to be an adequate sur- with surgery and radiotherapy together have lower local gical margin. Future assessments may need to go beyond recurrence rates [18], however there is great variability in the traditional evaluation of the resected specimen and preferences for local control [19, 20]. Furthermore, more be combined with response to chemotherapy to give a recent reports have suggested definitive proton treatment better risk stratification for local recurrence. can be associated with high local control rates [21]. Surgical resection of a pelvic or sacral sarcoma is rou- Complications of surgery tinely associated with surgical complications, long term A key consideration in local treatment is the interac- morbidity and loss of physical function, particularly after tion between surgery and radiotherapy. Radiotherapy resection of the acetabulum and major (often sacral) is associated with an increased risk of wound complica- nerves [22, 23]. The determination of what is a resect - tions and deep implant infection [14]. Furthermore, the able tumour in the pelvis depends to a large extent on the smaller treatment volume and potential for lower doses degree of morbidity acceptable to the patient and their have increased the use of preoperative radiotherapy, par- family. There was consensus that tumours which were ticularly in the pelvis. Disadvantages include an increase too morbid to resect include those which cross the mid- in complications of surgery or that surgery may be more line in the sacrum and those which would require major technically challenging if tissue planes become difficult visceral resection. These are useful guides for treating to identify. However, the latter was not supported in the teams and demand the longer-term collection of physical meeting. functioning outcomes to inform decision making. Complications of surgery such as infection or wound After preoperative radiotherapy, the expected failure can delay the resumption of chemotherapy. There - increased risk of complications means that surgeons fore in some cases where the risk of such complications G errand et al. Clin Sarcoma Res (2020) 10:21 Page 11 of 13 are less likely to recommend allograft or endoprosthetic is a greater emphasis on the preservation of function, reconstruction. After periacetabular resection, a “hang- and teams may rely more on adjuvant radiotherapy to ing hip” reconstruction may therefore be preferred [24]. achieve local control. Reconstruction of the proximal tibia is associated with Spine relatively high surgical complication rates, including Two thirds of patients with Ewing sarcoma of the spine infection [30]. Adding radiotherapy to a surgical recon- undergo urgent decompression at presentation which struction may increase this risk and may lead to a failed complicates subsequent local management [25]. How- reconstruction. In this situation therefore, there was con- ever, there was moderate consensus that a patient with sensus in favour of preoperative radiotherapy but recog- spinal cord compression and neurological compromise nition that amputation may be a reasonable alternative from Ewing sarcoma should undergo urgent surgical for some patients. decompression if it is indicated. Radiotherapy should then include all of the original tumour volume and Local therapy in metastatic and relapsed disease other areas potentially contaminated. Although bone metastases are associated with a dis- For those with spinal tumours who do not have neu- mal outcome, there was support for a more aggressive rological compromise, it is appropriate to treat first approach using focussed radiotherapy and possibly sur- with urgent biopsy and chemotherapy which may lead gery if there are only a small number of bone metastases to a reduction in tumour size and avoid urgent surgical [31]. Similarly, there was some support for an aggressive decompression. approach to potentially involved lymph nodes, including The decision about what is resectable within the spine biopsy or sampling at presentation and surgical resection should be made by a surgeon with relevant site-specific and/or radiotherapy as part of definitive local therapy. experience working within a multidisciplinary team. After isolated local relapse, there will routinely be There may be some benefit to surgical excision if the a question about whether further systemic treatment morbidity is acceptable, but there are no randomised should be supplemented with local treatment. There was trials and local control rates with radiotherapy alone strong consensus that it was reasonable to consider even are high [16, 26]. When surgery is undertaken consid- radical surgery such as hemipelvectomy in this situation, eration should be given to the type and positioning of but it is important to balance the definite morbidity of instrumentation used in reconstruction. Traditional the treatment with any small potential to improve the titanium implants may significantly impair the ability to overall poor outcome, particularly in early relapse. All of deliver PBT and have a deleterious effect on follow-up these settings need further evidence to guide clinicians. MRI imaging. Future research The variation in practice recorded in this initiative high - Chest lights areas in which research and clinical trials could The use of radiotherapy for chest wall tumours is be usefully performed in order to develop stronger evi- related predominantly to pleural involvement either dence-based approaches to primary tumour manage- before or after surgery. A pleural effusion is not on its ment. These include: own an indication for radiotherapy [27]. • The role of new imaging technology for more accu - rate staging. • Developing methods for early and shared decision- Extremity making about local treatment. Ewing sarcoma of the extremity should be treated with • The role and benefit of specialist national MDT wide resection if feasible, and in the majority limb spar- review. ing surgery is possible, with amputation rates around • Definitions of radiological and histological responses 8.4% [15]. Amputation is associated with the best local to chemotherapy. control rates, but usually the greatest loss of function. • Studies of type, timing and dose of radiotherapy. As It should be pointed out that while surgery is certainly an example, incorporation of prospective questions favoured secondary to other important considerations, about radiotherapy delivery within the next genera- overall prognosis may not be influenced by local con - tion of European clinical trials for Ewing sarcoma are trol modality [28]. Exceptions to this rule include sig- already well advanced. nificant resections of the foot or tibia which would result in lower levels of physical functioning than transtibial amputation [29]. In the upper limb there Gerrand et al. Clin Sarcoma Res (2020) 10:21 Page 12 of 13 Hospital, University of Helsinki. Finland; Dr. Akira Kawai, National Cancer Center Re-examination of these areas of consensus in a further Hospital. Japan; Dr. Stijn Krol, Leiden University Medical Center. Netherlands; international workshop, preceded by an updated survey, Dr. Nadia Laack, Mayo Clinic, Rochester. USA; Prof. Ruth Ladenstein, St. Anna would certainly be worthwhile. Kinderkrebsforschung e.V.. Austria; Dr. Carlo Lancia, Leiden University Medical Center. Netherlands; Prof. Siddhartha Laskar, Tata Memorial Hospital. India; Dr. Valerie LAURENCE, Institut CURIE. France; Dr. Franel le Grange, University Conclusion College Hospital, London. UK; Prof. Andreas Leithner, Dept. of Orthopaedics Achieving consensus about local therapy decisions in and Trauma, Medical University of Graz. Austria; Mr. Andy Lewis, Bone Cancer Research Trust. UK; Dr. Christina Linder Stragliotto, Oncology Clinic, Karolinska Ewing sarcoma is possible but several areas lacking con- University Hospital. Sweden; Ms. Elizabeth Lloyd-Dehler, University College sensus remain. There is consensus about the central role Hospital, London. UK; Mr. Jan Loeffen, Sophia Children’s Hospital Erasmus MC of an MDT, and the services patients require for optimal Rotterdam. Netherlands; Dr. Alessandra Longhi, Istituto Ortopedico Rizzoli, Bologna. Italy; Dr. Iwona Lugowska, Cancer Centre Warsaw. Poland; Dr. Roberto treatment. However, variation in approaches between Luksch, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. Italy; Mrs. Lisa centres have been described, the significance of which is Lyngsie Hjalgrim, University Hospital Copenhagen. Denmark; Dr. Marco Man- uncertain. Areas where clinical trials may be developed frini, Istituto Ortopedico Rizzoli. Italy; Dr. Sandrine Marreaud, EORTC. Belgium; Dr. Eric Mascard, Institut Gustave Roussy. France; Dr. Martin McCabe, University have been identified. of Manchester. UK; Ms. Sarah McDonald, Sarcoma UK. UK; Dr. Hans Merks, Academic Medical Center Amsterdam. Netherlands; Dr. Aisha Miah, The Royal Supplementary information Marsden Hospital. UK; Mr. Vanden Eynden Michel, Cliniques Universitaires Saint-Luc. Belgium; Dr. Paul O’Donnell, Royal National Orthopaedic Hospital, Supplementary information accompanies this paper at https ://doi. Stanmore. UK; Sr Antroula Papakonstantinou, Oncology Clinic Karolinska org/10.1186/s1356 9-020-00144 -6. University Hospital. Sweden; Mr. Michael Parry, Royal Orthopaedic Hospital, Bir- mingham. UK; Dr. Shreyaskumar Patel, SARC. USA; Dr. David Peake, University Additional file 1: Appendix 1. Summary of premeeting survey questions. Hospitals Birmingham. UK; Dr. Tamas Perlaky, Semmelweis University. Hungary; Appendix 2. Summary of cases presented. Mr. Rob Pollock, Royal National Orthopaedic Hospital, Stanmore. UK; Prof. Ajay Puri, Tata Memorial Hospital, Mumbai. India; Prof. Anna Raciborska, Institute of Mother and Child, Warsaw. Poland; Mr. R. Lor Randall, Utah University of Califor- Abbreviations nia Davis, Sacramento USA; Dr. Francoise REDINI, INSERM. France; Ms. Denise CT: Computed tomography; IMRT: Intensity modulated radiotherapy; MDT: Reinke, SARC. USA; Dr. Marleen Renard, University Hospital Leuven. Belgium; Multi-disciplinary team; MRI: Magnetic resonance imaging; NEMDT: National Dr. Guenther Richter, Children’s Cancer Research Center, TU-Muenchen. Ewing Multidisciplinary Team panel; PBT: Proton beam therapy; PET/CT: Posi- Germany; Dr. Asif Saifuddin, Royal National Orthopaedic Hospital, Stanmore. tron emission tomography and computed tomography. UK; Dr. Beatrice Seddon, University College Hospital, London. UK; Dr. Sandra Strauss, University College Hospital, London. UK; Mrs. Thale Marie Asp Stroem, Acknowledgements The Norwegian Radium Hospital. Norway; Dr. John Tuckett, Newcastle Upon Many thanks to all those who participated, including patients and profes- Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne. UK; Dr. Claudia sionals, listed here: Dr. Dimosthenis Andreou, Helios Klinikum Bad Saarow, Valverde, Vall d´Hebron University Hospital. Spain; Prof. Michiel van de Sande, Brandenburg, Germany; Dr. Jakob Anninga, Radboud University Medi- Leiden University Medical Center. Netherlands; Dr. Henk van den Berg, Emma cal Center, Netherlands. Netherlands; Dr. Jessica Bate, University Hospital, Children Hospital AMC University of Amsterdam. Netherlands; Dr. Tushar Vora, Southampton. UK; Mr. Tom Beckingsale, Newcastle Upon Tyne Hospitals Tata Memorial Centre, Mumbai. India; Prof. Jeremy Whelan, University College NHS Foundation Trust, Newcastle Upon Tyne. UK; Miss Hannah Birkett, Bone Hospital, London. UK; Ms. Rosie Wilson, Bone Cancer Research Trust. UK; Dr. Cancer Research Trust. UK; Dr. Kjetil Boye, Oslo University Hospital. Norway; Dr. James Wylie, Christie NHS FT. UK Bernadette Brennan, Royal Manchester Children’s Hospital. UK; Dr. Otte Brosjö, Karolinska Institute, Stockholm. Sweden; Prof. Øyvind S Bruland, Norwegian Authors’ contributions Radium Hospital. Norway; Mrs. Silvia Cammelli, University of Bologna. Italy; CG, JB, JW conceived and designed the project. All authors contributed to Dr. Peter Chung, Princess Margaret Cancer Centre, Toronto, Canada. Canada; constructing the details of the project and to the methods employed for Dr. Catherine Coyle, Christie Hospital NHS Foundation Trust. UK; Miss Gillian the consensus meeting and to the acquisition and analysis of the outcomes. Cribb, Robert Jones and Agnes Hunt Orthopaedic Hospital, UK. UK; Mrs. Sona CG, JB, BS, JW have drafted the work. All authors have read and approved Cyprova, University Hospital Motol, Prague. Czech republic; Dr. Zoe Davison, the final manuscript and have agreed both to be personally accountable for Bone Cancer Research Trust. UK; Prof. Catharina Dhooge, Ghent University Hos- the author’s own contributions and to ensure that questions related to the pital. Belgium; Prof. Uta Dirksen, University Hospital Essen. Germany; Dr. Steven accuracy or integrity of any part of the work, even ones in which the author DuBois, Dana-Farber/Boston Children’s Hospital, Boston. USA; Dr. Makoto Endo, was not personally involved, are appropriately investigated, resolved, and the Kyushu University. Japan; Dr. Abigail Evans, University College London. UK; resolution documented in the literature. Miss Caroline Folkestad Evensen, Oslo University Hospital. Norway; Dr. Stefano Ferrari, Istituto Ortopedico Rizzoli. Italy; Ms. Joanne Fleming, Azienda ULSS2 Funding Treviso. Italy; Prof. Philipp Funovics, Medical University of Vienna Depart- The meeting and the National Ewing MDT Fellowship were funded and sup- ment of Orthopaedics. Austria; Dr. Jenny Gains, University College Hospital, ported by the Ewing Sarcoma Research Trust and the Bone Cancer Research London. UK; Dr. Marco Gambarotti, Istituto Ortopedico Rizzoli. Italy; Prof. Habs Trust. Additional support from: EUROEWING Consortium FP7 (Seventh Frame- Gelderblom, Leiden University Medical Center. Netherlands; Mr. Craig Gerrand, work Programme) Grant Agreement No 602856; Create for Chloё; University Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne. College London Hospitals Biomedical Research Centre. UK; Dr. Heidi Glosli, Oslo University Hospital. Norway; Mr. Mel Grainger, Royal Orthopaedic Hospital, Birmingham. UK; Prof. Robert Grimer, Royal Ortho- Availability of data and materials paedic Hospital, Birmingham. UK; Dr. Amrita Guha, Tata Memorial Hospital, Data sharing is not applicable to this article as no datasets were generated or Mumbai. India; Dr. Lianne Haveman, Academic Medical Center Amsterdam. analysed during the current study. Netherlands; Dr. Asle Hesla, Karolinska Institute, Stockholm. Sweden; Prof. Dominique Heymann, University of Sheffield. UK; Dr. Hiroaki Hiraga, Hokkaido Ethics approval and consent to participate Cancer Center. Japan; Mr. Alistair Irwin, Newcastle Upon Tyne Hospitals NHS Not applicable. Foundation Trust, Newcastle Upon Tyne. UK; Dr. Mariam Jafri, University Hos- pitals of Birmingham. UK; Dr. Bhavin Jankharia, Dr. Jankharia’s Imaging Centre. Consent for publication India; Prof. Lee Jeys, Royal Orthopaedic Hospital, Birmingham. UK; Mr. Simon Not applicable. Jordan, Royal Brompton Hospital, London. UK; Dr. Jukka Kanerva, Children’s G errand et al. Clin Sarcoma Res (2020) 10:21 Page 13 of 13 Competing interests 14. Jeys LM, Grimer RJ, Carter SR, Tillman RM. Periprosthetic infection in The authors declare that they have no competing interests. patients treated for an orthopaedic oncological condition. J Bone JtSurg Am. 2005;87:842–9. Author details 15. Lee J, Hoang BH, Ziogas A, Zell J. Analysis of prognostic factors in Royal National Orthopaedic Hospital, Brockley Hill, Stanmore HA7 4LP, Mid- Ewing sarcoma using a population-based cancer registry. Cancer. dlesex, UK. Southampton Children’s Hospital, University Hospital Southamp- 2010;116:1964–73. ton NHS Foundation Trust, Southampton, UK. University College Hospital, 16. Ahmed SK, Randall RL, DuBois SG, Harmsen WS, Krailo M, Marcus KJ, 250 Euston Road, London NW1 2PG, UK. Pediatrics III, Sarcoma Centre, West et al. Identification of patients with localized Ewing sarcoma at higher German Cancer Centre, German Cancer Consortium (DKTK), Center Essen, risk for local failure: a report from the Children’s Oncology Group. Int J University Hospital Essen, University Duisburg, Hufelandstr. 55, 45122 Essen, Radiat Oncol Biol Phys. 2017;99(5):1286–94. https ://doi.org/10.1016/j.ijrob Germany. Department of Orthopaedic Surgery, UC Davis Health, 4860 Y p.2017.08.020. Street, Suite 3800, Sacramento, CA 95817, USA. Leiden University Medical 17. Dramis A, Grimer RJ, Malizos K, Tillman RM, Jeys L, Carter LR. Non-met- Center, Albinusdreef 2, Leiden, The Netherlands. Freeman Hospital, New- astatic pelvic Ewing’s sarcoma: oncologic outcomes and evaluation of castle-upon-Tyne NE7 7DN, UK. Oncology-University Hospitals Birmingham prognostic factors. ActaOrthopBelg. 2016;82:216–21. NHS Foundation Trust, Birmingham B15 2TH, UK. Royal Orthopaedic Hospital, 18. Ahmed SK, Robinson SI, Arndt CAS, Petersen IA, Haddock MG, Rose PS, Bristol Road South, Birmingham B31 2AP, UK. University Hospital Birming- et al. Pelvis Ewing sarcoma: Local control and survival in the modern era. ham, Edgbaston, Birmingham B15 2GW, UK. Pediatr Blood Cancer. 2017;64:e26504. 19. Zhu C, Olson KA, Roth M, Geller DS, Gorlick RG, Gill J, et al. Provider Received: 2 July 2020 Accepted: 6 November 2020 views on the management of Ewing sarcoma of the spine and pelvis. J SurgOncol J SurgOncol. 2018;117:417–24. 20. Andreou D, Ranft A, Gosheger G, Timmermann B, Ladenstein R, Hartmann W, et al. Which factors are associated with local control and survival of patients with localized pelvic Ewing’s sarcoma? A retrospec- tive analysis of data from the Euro-EWING99 Trial. ClinOrthopRelat Res. References 2020;478:290–302. 1. Whelan J, McTiernan A, Cooper N, Wong YK, Francis M, Vernon S, 21. Uezono H, Indelicato DJ, Rotondo RL, Mailhot Vega RB, Bradfield SM, et al. Incidence and survival of malignant bone sarcomas in England Morris CG, et al. Treatment outcomes following proton therapy for Ewing 1979–2007. Int J cancer. 2011;000:1–11. sarcoma of the pelvis. Int J Radiat Oncol. 2020;107(5):974–81. 2. Arora RS, Alston RD, Eden TOB, Geraci M, Birch JM. The contrasting age- 22. Ranft A, Seidel C, Hoffmann C, Paulussen M, Warby A-C, van den Berg H, incidence patterns of bone tumours in teenagers and young adults: et al. Quality of survivorship in a rare disease: clinic functional outcome implications for aetiology. Int J Cancer. 2012;131:1678–85. and physical activity in an observational cohort study of 618 long-term 3. Turc-Carel C, Aurias A, Mugneret F, Lizard S, Sidaner I, Volk C, et al. survivors of Ewing sarcoma. J ClinOncol. 2017;35:1704–12.n Chromosomes in Ewing’s sarcoma. I. An evaluation of 85 cases of 23. Puri A, Gulia A, Jambhekar N, Laskar S. Results of surgical resection in remarkable consistency of t(11;22)(q24;q12). Cancer Genet Cytogenet. pelvic Ewing’s sarcoma. J Surg Oncol. 2012;106(4):417–22. https ://doi. 1988;32:229–38. org/10.1002/jso.23107. 4. Whelan J, Hackshaw A, McTiernan A, Grimer R, Spooner D, Bate J, et al. 24. Fujiwara T, Lex JR, Stevenson JD, Tsuda Y, Clark R, Parry MC, et al. Surgi- Survival is influenced by approaches to local treatment of Ewing sarcoma cal treatment for pelvic Ewing sarcoma: What is a safe and functional within an international randomised controlled trial: analysis of EICESS-92. acetabular reconstruction when combined with modern multidiscipli- Clin Sarcoma Res. 2018;8:6. https ://doi.org/10.1186/s1356 9-018-0093-y. nary treatments? J SurgOncol. 2019;120:985–93. 5. Puri A, Gulia A, Vora T. Guidelines for bone & soft tissue tumors. 2011. 25. Vogin G, Helfre S, Glorion C, Mosseri V, Mascard E, Oberlin O, et al. Local https ://tmc.gov.in/tmh/PDF/BSTFi nal_23Feb .pdf. control and sequelae in localised Ewing tumours of the spine: a French 6. Gerrand C, Athanasou N, Brennan B, Grimer R, Judson I, Morland B, et al. retrospective study. Eur J Cancer. 2013;49:1314–23. UK guidelines for the management of bone sarcomas. Clin Sarcoma Res 26. Sewell MD, Tan K-A, Quraishi NA, Preda C, Varga PP, Williams R. Systematic BioMed Central. 2016;6:1–21. review of en bloc resection in the management of Ewing’s sarcoma of 7. Kasalak Ö, Glaudemans AWJM, Overbosch J, Jutte PC, Kwee TC. Can the mobile spine with respect to local control and disease-free survival. FDG-PET/CT replace blind bone marrow biopsy of the posterior iliac Medicine (Baltimore). 2015;94:e1019. crest in Ewing sarcoma? Skeletal Radiol. 2018;47(3):363–7. https ://doi. 27. Bedetti B, Wiebe K, Ranft A, Aebert H, Schmidt J, Jürgens H, et al. Local org/10.1007/s0025 6-017-2807-2. control in ewing sarcoma of the chest wall: results of the EURO-EWING 8. Kalus S, Saifuddin A. Whole-body MRI vs bone scintigraphy in the staging 99 Trial. Ann SurgOncol. 2015;22:2853–9. https ://doi.org/10.1245/s1043 of Ewing sarcoma of bone: a 12-year single-institution review. Eur Radiol. 4-015-4630-0. 2019;29(10):5700–8. https ://doi.org/10.1007/s0033 0-019-06132 -9. 28. Daw NC, Laack NN, McIlvaine EJ, Krailo M, Womer RB, Granowetter L, 9. National Institute for Health and Clinical Excellence. Improving outcomes et al. Local control modality and outcome for Ewing sarcoma of the for people with sarcoma. The Manual. 2006. https ://www.nice.org.uk/ femur: a report from the Children’s Oncology Group. Ann SurgOncol. guida nce/csg9/resou rces/impro ving-outco mes-for-peopl e-with-sarco 2016;23:3541–7. https ://doi.org/10.1245/s1043 4-016-5269-1. ma-updat e-pdf-77338 1485. 29. Aksnes LH, Bauer HCF, Jebsen NL, Follerås G, Allert C, Haugen GS, et al. 10. Kreyer J, Ranft A, Timmermann B, Juergens H, Jung S, Wiebe K, et al. Limb-sparing surgery preserves more function than amputation: a Impact of the Interdisciplinary Tumor Board of the Cooperative Ewing Scandinavian sarcoma group study of 118 patients. J Bone JtSurg Br. Sarcoma Study Group on local therapy and overall survival of Ewing sar- 2008;90:786–94. coma patients after induction therapy. Pediatr Blood Cancer. 2018. https 30. Jeys LMM, Kulkarni A, Grimer RJJ, Carter SRR, Tillman RMM, Abudu ://doi.org/10.1002/pbc.27384 . A. Endoprosthetic reconstruction for the treatment of musculoskel- 11. Bate J, Wingrove J, Donkin A, Taylor R, Whelan J. Patient perspectives on etal tumors of the appendicular skeleton and pelvis. J Bone JtSurg. a national multidisciplinary team meeting for a rare cancer. Eur J Cancer 2008;90:1265–71. https ://doi.org/10.2106/JBJS.F.01324 . Care (Engl). 2019. https ://doi.org/10.1111/ecc.12971 .n 31. Haeusler J, Ranft A, Boelling T, Gosheger G, Braun-Munzinger G, Vieth V, 12. Ladenstein R, Pötschger U, Le Deley MC, Whelan J, Paulussen M, Oberlin et al. The value of local treatment in patients with primary, disseminated, O, et al. Primary disseminated multifocal Ewing sarcoma: results of the multifocal ewing sarcoma (PDMES). Cancer. 2010;116:443–50. Euro-EWING 99 trial. J ClinOncol. 2010;28:3284–91. 13. Albergo JI, Gaston CL, Laitinen M, Darbyshire A, Jeys LM, Sumathi V, et al. Ewings sarcoma: only patients with 100% of necrosis after chemo- Publisher’s Note therapy should be classified as having a good response. Bone Joint J. Springer Nature remains neutral with regard to jurisdictional claims in pub- 2016;98-B:1138–44. lished maps and institutional affiliations.

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