Sarcoma European & Latin American Network (Selnet

SARCOMA EUROPEAN & LATIN AMERICAN NETWORK (SELNET) RECOMMENDATIONS ON PRIORITIZATION IN SARCOMA CARE DURING COVID-19 PANDEMIC

a,b a,b c d JAVIER MARTIN-BROTO,MDPHD , NADIA HINDI, MD, SAMUEL AGUIAR JR MD, RONALD BADILLA-GONZÁLEZ, MD, e f g h,i,j VICTOR CASTRO-OLIDEN, MD, MATIAS CHACÓN, MD, RAQUEL CORREA-GENEROSO, MD, ENRIQUE DE ALAVA,MDPHD, k l m n DAVIDE MARÍA DONATI, MD, MIKAEL ERIKSSON, MD, MARTIN FALLA-JIMENEZ, MD, GISELA GERMAN, MD, o p q e MARIA LETICIA GOBO SILVA, MD, FRANCOIS GOUIN, MD, ALESSANDRO GRONCHI, MD, JUAN CARLOS HARO-VARAS, MD, r s t u NATALIA JIMÉNEZ-BRENES, MD, BERND KASPER, MD, CELSO ABDON LOPES DE MELLO, MD, ROBERT MAKI,MDPHD, a v w x PAULA MARTÍNEZ-DELGADO,PHD, HECTOR MARTÍNEZ-SAID, MD, JORGE LUIS MARTINEZ-TLAHUEL, MD, JOSE MANUEL MORALES-PÉREZ, MD, y z aa FRANCISCO CRISTOBAL MUÑOZ-CASARES, MD, SUELY A. NAKAGAWA, MD, EDUARDO JOSE ORTIZ-CRUZ,MDPHD, bb cc a dd EMANUELA PALMERINI,MDPHD, SHREYASKUMAR PATEL, MD, DAVID S. MOURA,PHD, SILVIA STACCHIOTTI, MD, ee ff f gg MARIE PIERRE SUNYACH, MD, CLAUDIA M. VALVERDE, MD, FEDERICO WAISBERG, MD, JEAN-YVES BLAY,MDPHD aGroup of Advanced Therapies and Biomarkers in Sarcoma, Institute of Biomedicine of Seville (IBIS, HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain; bDepartment of medical oncology, University Hospital Virgen del Rocio, Seville, Spain; cDepartment of Pelvic Surgery, A.C. Camargo Cancer Center, S~ao Paulo, Brazil; dDepartment of medical oncology, Rafael Angel Calderón Guardia Hospital, San José, Costa Rica; eDepartment of medical oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru; fDepartment of medical oncology, Alexander Fleming Cancer Institute, Buenos Aires, Argentina; gRadiotherapy department, Virgen de la Victoria University Hospital, Málaga, Spain; hPathology department, University Hospital Virgen del Rocío, Seville, Spain; iCIBERONC, Madrid, Spain; jDepartment of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, Seville, Spain; kUnit of Orthopedic Pathology and Osteoarticular Tissue Regeneration, Rizzoli Orthopedic Institute, Bologna, Italy; lDepartment of medical oncology, Skane University Hospital-Lund, Lund, Sweden; mDepartment of breast and soft tissues surgery, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru; nDepartment of medical oncology, Hospital Oncológico Provincial, Córdoba, Argentina; oDepartment of radiation therapy, A.C. Camargo Cancer Center, S~ao Paulo, Brazil; pDepartment of orthopedic surgery, Centre León Bérard, Lyon, France; qDepartment of surgery, Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy; rDepartment of medical oncology,San Vicente de Paúl Hospital, Heredia, Costa Rica; sDepartment of medical oncology, Mannheim University Medical Center, Mannheim, Germany; tDepartment of medical oncology, A.C. Camargo Cancer Center, S~ao Paulo, Brazil; uDepartment of medical oncology, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA; vDepartment of medical oncology, Instituto Nacional de Cancerología, CDMX, Mexico; wDepartment of surgery, Instituto Nacional de Cancerología, CDMX, Mexico; xRadiology Department, University Hospital Virgen del Rocio, Seville, Spain; yDepartment of surgery, University Hospital Virgen del Rocio, Seville, Spain; zOrthopedic department, A.C. Camargo Cancer Center, S~ao Paulo, Brazil; aaOrthopedic surgery and traumatology department, La Paz University Hospital, Madrid, Spain; bbDepartment of medical oncology, Rizzoli Orthopedic Institute, Bologna, Italy; ccDepartment of Melanoma Medical Oncology University of Texas M. D. Anderson Cancer Center, Houston, TX, USA; ddDepartment of medical oncology, Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy; eeDepartment of radiation therapy, Centre León Bérard, Lyon, France; ffDepartment of medical oncology,Vall d’Hebron Hospital, Barcelona, Spain; and ggDepartment of medical oncology, Centre León Bérard, Lyon, France †FUNDING: No dedicated funding has been used for this work. Key Words. COVID-19 • Sarcoma • Guidelines • Patient care • Multidisciplinary

ABSTRACT

Background. COVID-19 outbreak has resulted in collision hospital capacity, especially in intensive care units, causing between SARS-CoV-2-infected patients and cancer patients a domino effect, displacing areas from their primary use. on different fronts. Serious SARS-CoV-2 cases overwhelmed Cancer patient has been impacted by deferral, modiﬁcation

CORRESPONDING AUTHOR Dr. Javier Martin-Broto Department of Medical Oncology, University Hospital Virgen del Rocío Instituto de Bio- medicina de Sevilla, LAB 214 C/Antonio Maura Montaner s/n 41013 – Sevilla Spain Telephone: +34 955923113 jmartin@mustbesevilla. org Received June 3, 2020; accepted for publication August 14, 2020. http://dx.doi.org/10.1634/theoncologist.2020-0516 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modiﬁcations or adapta- tions are made.

The Oncologist 2020;9999:•• www.TheOncologist.com © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. 2 SELNET recommendations in sarcoma during COVID-19 or even cessation of therapy. Adaptive measures to mini- Results. There were 80 SR, 35 R and 10 NC among the mize hospital exposure, following the precautionary princi- 125 recommendations issued and completed by 31 multi- ple have been proposed for cancer care during COVID-19 disciplinary sarcoma experts. The consensus was higher era. We present here a consensus on prioritizing recom- among the 75 higher-priority recommendations (85%, 12% mendations across the continuum of sarcoma patient care. and 3% for SR, R and NC, respectively) than in the 50 lower- Material and methods. A total of 125 recommendations priority recommendations (32%, 52% and 16% for SR, R and were proposed in soft-tissue, bone and visceral sarcoma NC, respectively). care. Recommendations were assigned as higher- or lower- Conclusion. The consensus on 115 of 125 recommendations priority if they cannot or can be postponed at least 2-3 indicates a high-level of convergence among experts. The months, respectively. The consensus level for each recom- SELNET consensus provides a tool for sarcoma multi- mendation was classiﬁed as “strongly recommended” (SR) if disciplinary treatment committees during the COVID-19 more than 90% of experts agreed, “recommended” (R) if outbreak. The details of different recommendations and 75-90% of experts agreed and “no consensus” (NC) if fewer the distinction between two priority levels enables a practi- than 75% agreed. Sarcoma experts from 11 countries within cal approach for both Latin-American and other health-care the SELNET consortium participated, including countries in providers, and sarcoma expert centres. The Oncologist the Americas and Europe. The ESMO-Magnitude of clinical 2020;9999:•• beneﬁt scale was applied to systemic-treatment recommendations to support prioritization.

Implications for Practice: SELNET consensus on sarcoma prioritization care during the COVID-19 era, issued 125 pragmatical recommendations distributed as higher or lower priority, to protect critical decisions on sarcoma care during COVID-19 pandemic. A multidisciplinary team from 11 countries, including countries in the Americas and Europe, reached consensus on 115 recommendations. The consensus was lower among lower-priority recommendations, which shows reticence to postpone actions even in indolent tumors. The ESMO-magnitude of clinical beneﬁt scale was applied as support for prioritizing systemic treatment. Consensus on 115 of 125 recommendations indicates a high-level of convergence among experts. The SELNET consensus provides a practice tool for the guidance in the decisions of sarcoma multidisciplinary treatment committees during the COVID-19 outbreak.

INTRODUCTION immune cells, immune modulators, cytokines, and molecules expression towards the escape phase and the devel- Deferral, modification or even cessation of therapy consti- opment of an immunosuppressive tumor tute hindrances that cancer patients have been impacted microenvironment.[3] Both specific diagnoses and their with during the current COVID-19 outbreak. The balance treatment with chemotherapy, surgical resection, and between adapting measures to minimize hospital exposure, newer treatments variably compromise immune function, following the precautionary principle, and offering a more and render some cancer patients more susceptible to infec- relaxed diagnostic or therapeutic management while pre- tions.[4] serving the patient’s survival options, is not easy at all. As with other infections, the innate and adaptive arms More than 80 reports, often short reports and letters, of the immune system play different key roles in the have addressed the intersection of cancer and COVID-19 COVID-19 infection and evolution. SARS-CoV-2 causes an care. Even when the risk of morbidity and mortality is overwhelming persistent innate-induced inflammation that almost ever higher in cancer patient that in COVID-19 can lead to a cytokine storm, cytokine-associated lung infected patients (i.e. risk of death for pancreatic cancer is injury, and diffuse organ involvement.[5] Alterations of the over 90% while for COVID-19 infected patient is usually CD4+ and CD8+ T cells subsets have been observed, with lower than 5%)[1], the truth is that precautionary principle loss of functional diversity in CD4+ T cells, and increased has prevailed over the cancer care continuation in many expression of regulatory molecules in CD8+ T cells.[6, 7] cases.[2] Elective surgeries were largely suspended, in some Hence, it can be assumed that the systemic immunosup- instances, due to shortage of ventilators, and thus the oper- pressive state of at least cancer patients might result in an ating theatres became extemporaneous intensive care increased risk of COVID-19 infection and poorer prognosis units. Some reports are already appearing focusing on the for this group of patients. real impact (direct and indirect) of COVID-19 outbreak in Epidemiological statistics of the cases in China cancer patients. In some locales where the admissions for suggested that cancer patients were at greater risk than the SARS-CoV-2 far exceeded the hospital capacity, it is com- general population, data which appear to be borne out mon sense that cancer care was compromised in a variety more for hematologic malignancies than solid tumors, of ways. though there still appears to be greater risk even for solid Patients with cancer constitute a large population with tumor patients for fatal outcomes from SARS-CoV2.[8] a spectrum of risk with respect to immunosuppression. Can- Noteworthy, it has been reported that COVID-19-related cer immunoediting, which represents the interplay between deaths were strongly associated with: being male, older age tumor and immune system, leads ultimately to changes in

© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. 3 and deprivation; severe asthma; uncontrolled diabetes; can- METHODS cer and several other previous clinical conditions.[9] The recommendations have been divided into two scenar- Importantly, a recent epidemiological report from UK ios, higher and lower priority, in order to make them simple based on 800 cancer patients with COVID-19 infection and replicable. Higher priority is defined as an undelayable observed a mortality rate of 28%, being older age, male procedure, since the inherent risk of the tumor, affecting fi gender and comorbidities as cardiovascular disease, signi - survival or morbidity, would likely exceed the risk of COVID- cant prognostic factors related to higher mortality. Remark- 19 infection if this procedure had not been performed. By ably, chemotherapy or other systemic therapy administered contrast, lower priority is defined as a delayable procedure within 4 weeks from testing positive for COVID-19 did not (at least 2-3 months), since the inherent risk of the tumor, fi have signi cant effect on mortality from COVID-19 dis- affecting survival or morbidity, would be lower enough so ease.[10] that the patient could minimize or avoid the hospital fre- Taken together, rapidly evolving data indicate that onco- quentation, and consequently to reduce the risk of infection logic patients, as sarcoma patients, constitute a high-risk by COVID-19. A total of 125 recommendations have been group to suffer higher mortality and morbidities than in proposed in soft tissue, bone and visceral sarcomas, to thor- general population if infected by SARS-CoV-2. oughly cover details for diagnosis, surgery, radiation ther- Additionally, in this COVID-19 outbreak, the major risk apy, systemic treatments, follow-up and clinical research. for patients with cancer is the inability to receive necessary These recommendations were proposed by the SELNET medical services. Decisions on whether or not to postpone coordinator team and shared with the official partners of cancer treatment and clinical trials need to made on a SELNET network. Associated partners were not involved in patient by patient basis and according to the inherent this consensus. Each point derived from MDT expertise dis- tumor risk in each patient and the prevailing situation, cussion from the SELNET coordination, aimed to be prag- because delays could lead to tumor progression and ulti- matic, detailed and patient-oriented for each ’ mately poorer outcomes.[11] In this sense, patients voice recommendation. has warned that in up to 30% of oncologic patients, Official partners had the competence to give their own changes in their treatment or in the follow-up, have opinion if this was clear enough for them or to give the occurred during COVID-19 pandemic.[12] Beyond the opinion of their MDT on certain recommendations. increased risk of requiring mechanical ventilation and death In this consensus, multidisciplinary (MDT) experts par- that should be prospectively analyzed in oncologic patients ticipated from AC Camargo Cancer Center (Sao Paulo, Bra- with COVID infection, it is also relevant to take into account zil), Instituto Alexander Fleming (Buenos Aires, Argentina), the impact of the precautionary principle that is Instituto Nacional de Enfermedades Neoplasicas (Lima, implemented in our patients.[13] This latter implies that Peru), Instituto Nacional de Cancerologia (Mexico DF, Mex- cancer patients have suffered delays or cancellation diag- ico), Hospital Calderon Guardia (San José, Costa Rica), Cen- nostic tests, or surgeries, on radiation therapies or systemic tre Leon Berard (Lyon, France), Istituto Nazionale dei treatments. Tumori (Milan, Italy), IRCCS Istituto Ortopedico Rizzoli The aim of this paper is to build a consensus on prioriti- (Bologna, Italy), Abramson Cancer Center (Pennsylvania, zation aspects in the sarcoma care during the current or USA), University Hospital Lund (Lund, Sweden), Mannheim future COVID-19 outbreak, that could appropriately balance University Medical Center (Mannheim, Germany), MD the precautionary principle while preserving the highest Anderson Cancer Center (Houston, USA), Spanish group for survival probabilities in sarcoma patients. Research on Sarcomas (GEIS) and University Hospital Virgen This consensus has been developed within Sarcoma del Rocio (Sevilla, Spain). Besides that, a European patient European-Latin American Network (SELNET). This is a con- advocacy group (SPAEN) was also involved in this consensus sortium granted by European Commission within the Hori- as well as the external scientific and ethic committees of zon 2020 Call, within the program H2020-SC1-BHC- SELNET. 2018-2020 (Better Health and care, economic growth and Among 31 participating experts in the consensus, there sustainable health systems). The aim of SELNET consortium were 18 oncologists (15 for adults and 3 also for pediatrics); is to improve clinical outcome in sarcoma care, through a 4 orthopedic surgeons; 4 surgical oncologists; 2 radiation network of reference centres in sarcoma.[14] oncologists, 1 pathologist and 1 radiologist. As SELNET These guidelines intend to add value over and above mainly focusses on adult-type sarcomas, no exclusive pedi- other clinical practice guidelines (CPG) reported for onco- atric oncologist participated in the consensus. Fourteen logic patients in the context of COVID-19 outbreak. Thus, Latin-American sarcoma experts participated in the consen- fi our guidance focusses speci cally on sarcoma patients and sus, 9 oncologists, 4 surgeons and 1 radiation therapist. Cor- thoroughly provides precise details on prioritization on relations between Latin-American and EU-US expert 125 clinical sarcoma situations, while NICE offers a general recommendations were evaluated using Pearson’s chi- recommendation for any oncologic patient [15] and ESMO squared test for bivariate options (agreement or disagree- offers a more general recommendation of prioritization for ment) and Mann-Whitney U test for multivariate options sarcoma patients. [16] (strongly agree, agree, disagree and strongly disagree). For each recommendation, every participant has chosen among the following options: strongly agree, agree,

www.TheOncologist.com © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. 4 SELNET recommendations in sarcoma during COVID-19 disagree, and strongly disagree. The neutral option was not American, North-America and Europe. This consensus has offered in order to avoid ambiguity. been developed within SELNET consortium as a guide to Those recommendations with ≥90% of consensus protect cancer care in the complex and heterogeneous field (at least strongly agree plus agree obtained in ≥90% of par- of sarcoma and amid COVID-19 outbreak. This consensus ticipants) will be considered as strongly recommended. intends to offer precise advises on different clinical sarcoma Those with ≥75% but <90% will be considered as rec- scenarios that oncology community could face with, with ommended and the remaining recommendations as “no- the aim of prioritize or not (to postpone) different clinical consensus was obtained”. The cut-off of 75 % has been the decisions in sarcoma patients. To this end percentage of median threshold to define consensus in Delphi studies consensus have issued for every high and low priority [17], while the demanding 90% cut-off was arbitrarily cho- across different procedures involving committee discussion, sen to indicate the highest consensus range if at least this diagnosis, treatments and follow-up. General oncology com- percentage was reached. munity should network with expert centers from sarcoma In order to mitigate the subjectiveness, the ESMO- suspicion, and these guidelines constitute a support on Magnitude of Clinical Benefit Scale (MCBS) V1.1 was applied what actions should be postponed and what others no in to recommendations involving systemic treatments to sup- the time of COVID-19 outbreak in the management of sar- port this prioritization strategy [Online Supplemental Mate- coma patients. rial 1].[18, 19] Though MCBS has not been formally Several oncology societies and health care providers evaluated for sarcoma therapies, MCBS methodology was issued recommendations, most often on their websites, followed for the estimation of the benefit obtained with dif- regarding adaptive strategies for emergent standards of ferent sarcoma systemic treatments [Online Supplemental care in cancer patients during COVID-19 pandemic.[28] The Material 2]. Cancer Core Europe, which encompasses 7 cancer centres and oncologic institutes in 7 European countries, published a general consensus on the adapting measures to minimize RESULTS the number of hospital visits and to prevent anticancer From a total of 31 fulfilled questionnaires analyzed, the rec- treatment that could induce complications of COVID-19 ommendations were distributed as strongly recommended infections. The methodology for these recommendations (SR) in 80, recommended (R) in 35 and no consensus was not defined, however.[29] (NC) in 10. The consensus was higher among the 75 higher- The National Institute for Health and Care Excellence priority recommendations (85%, 12% and 3% for SR, R and (NICE) issued prioritization guidelines on the use of systemic NC respectively) than in the 50 lower-priority recommenda- and radiation treatments for cancer. This guide established tions (32%, 52% and 16% for SR, R and NC respectively). 6 prioritization levels from the first for curative treatments Table 1 describes the consensus level for each recom- offering more than 50% of success or adjuvant neoadjuvant mendation and indicates the MCBS in most contexts of sys- treatment which adds at least 50% of cure to surgery or temic treatments. The statistical distribution for each radiation therapy alone, while the last level is defined as recommendation is presented in Online Supplemental non-curative regimen with a 15-50% of chance of palliation Material 1. or temporary tumor control and less than 1 year expected Of note, statistically significant differences between extension to life.[30] Similarly, a radiotherapy prioritization Latin-American and EU-US expert recommendations were guide was issued with 5 levels. The general modifications only detected by Pearson’s chi-squared and Mann-Whitney are based on postponing or avoiding radiation therapy in U test in 3 out of 125 recommendations (Table 2). EU-US cases of little added value, or changing treatment plans to experts showed to be more conservative for the advice of shorten the number of visits to a health care facility.[15] adjuvant chemotherapy in high grade chondrosarcoma, the European Society for Medical Oncology (ESMO) issued sev- advice of adjuvant radiotherapy in low grade, deep STS eral guidelines on each tumor for prioritizing the care into larger than 5 cm and for the advice of adjuvant radiother- 3 or 4 categories. In the case of sarcoma, the low priority apy in superficial STS larger than 5 cm. profile is typified by a stable patient who can safely have delays in treatment for the duration of the COVID-19 pandemic. The intermediate profile is exemplified by a patient DISCUSSION with a non-critical situation, but one in which delay beyond Since sarcoma multidisciplinary committees are so critical 6 weeks could impair clinical outcomes.[16] The Society of to patient outcomes,[20-27] we emphasize the message Surgical Oncology (SSO) has joined individual sarcoma that these meetings should continue, at least in tele- expert opinions and has issued 6 recommendation points committee format, in the COVID-19 era. Tele-committees based on prioritizing actions considering several sarcoma should be scheduled on a regular basis (e.g. weekly), and contexts.[31] the following specialists should participate: pathologists, Certainly, this prioritization does not just focus on indi- radiologists, surgeons, radiation oncologists and medical vidual patient risk, but also highlights the community risks oncologists. and benefit: the reduction of people in transit and the isola- In this paper, a prioritization of diagnostic, care and tion of patients in general decreases contagion risk in the follow-up procedures across different sarcoma contexts has community, leaving more resources to treat the impact of been reached by consensus among sarcoma experts from COVID-19 pandemic. However, the other side of the coin different disciplines and from 11 countries among Latin- starts to show consequences in other group of patients, as

© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. 5 cancer patients. In the Netherlands, a remarkable drop in then on, once per year. This strategy is based on the higher the cancer diagnosis was noticed from pandemic initiation risk of recurrence observed in the 3 first years after treat- according to a nationwide cancer registry.[32] ment for localized disease, and to the fact that the asymp- There are three principal approaches to conducting con- tomatic recurrence, detected by CT scan for instance, could sensus methodology research, the consensus development potentially have higher curative options. There are some panel, the nominal group process and the Delphi technique. reports addressing the relevance of smaller size as indepen- [33] The two latter requires at least 2 sessions or rounds, dent prognostic relevance, at the time of metastatic dis- being more complex. The consensus development panel is ease, for longer survival.[36-38] Nevertheless, the truth is the commonest used in health care research. This consists that convincing evidence that determined strategy is related in organized meetings of experts in a given field, and usu- with better survival is lacking, and a lead-time bias can ally requires experts in different disciplines to make a multi- occur in highly interventionist follow-up. disciplinary consensus. Usually this approach is supported In conclusion, this SELNET consensus provides a tool for by the literature evidence and there are dome face-to-face the multidisciplinary sarcoma committees during the discussions. In sarcoma oncology, ESMO guidelines follow COVID-19 outbreak. The detail of different recommenda- this consensus development panel approach.[25, 27, 34] tions and the distinction between two levels of prioritiza- The consensus we present here has two main differences in tion enables a practical approach for Latin-American health- comparison with the consensus development panel. Despite care providers and sarcoma expert centres. the proposed prioritizing recommendations are based on the published evidence, there are no comparative studies analyzing for instance the delay of some treatments in sar- ACKNOWLEDGMENTS coma patients. Besides, no formal face-to-face meeting was The authors would like to thank also SELNET project. organized due to inherent confinement constraints. In con- SELNET has received funding from the European Union’s trast, the fact that all expert participants provided their Horizon 2020 research and innovation programme under own opinion on each recommendation ensures more inde- grant agreement N 825806. pendence and the quality of the conclusions, avoiding inter- ferences that could arise in a face-to-face discussion. On the other hand, with the aim to minimize the subjec- tivity in the recommendation process, the ESMO-MCBS was DISCLOSURE fulfilled, at least for systemic therapies applied in sarcoma. Javier Martin-Broto reports research grants from Pharma- We tried to adopt the grade 3 or higher and grades A or B Mar, Eisai, Immix BioPharma and Novartis outside the sub- scores, in the systemic treatment, as the cut-off for preserv- mitted work; honoraria for advisory board participation and ing the use of such treatments in the COVID-19 pandemic expert testimony from PharmaMar, honoraria for advisory era. The ESMO-MCBS v1.1 is a validated scale measuring board participation from Eli Lilly and Company, Bayer and the magnitude of clinical benefit, and adds value regarding Eisai; and research funding for clinical studies (institutional) with just the statistical significance focus.[18] Even when from PharmaMar, Eli Lilly and Company, AROG, Bayer, Eisai, there is not yet an ESMO-MCBS in sarcoma, our exercise Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, has followed the rules of the scale and this has been an Nektar, Forma, Amgen and Daiichi-Sankyo. Nadia Hindi additional support for this consensus. reports grants, personal fees and non-financial support The fact that 80 over 125 recommendations were from PharmaMar, personal fees from Lilly, grants from Eisai, “strongly recommended” and only 10 had been “no consen- and grants from Novartis, outside the submitted work. sus” indicates a high grade of accord among sarcoma Enrique de Alava reports personal fees and non-financial experts in this consensus on prioritization. The fact that support from Roche, personal fees and non-financial sup- lower consensus had been obtained in the low priority port from BMS, personal fees and non-financial support group, might indicate the reticence of sarcoma experts in from PharmaMar, personal fees from Bayer, outside the postpone treatment, even in indolent or low-risk cases. submitted work. Jorge Luis Martinez-Tlahuel reports per- This consensus has been mainly addressed keeping in sonal fees from Elli Lilly and Amgen, outside the submitted mind Latin-American communities, and thus it has pursued work. David S. Moura reports institutional research grants the simplicity and concision, taking into consideration that from PharmaMar, Eisai, Immix BioPharma and Novartis out- there are many health-care providers in each country. side the submitted work; travel support from PharmaMar, Hence, assigning higher or lower priority to those Eisai, Celgene, Bayer and Pfizer. Silvia Stacchiotti reports undelayable or delayable treatments, respectively, facili- grants and personal fees from Bayer, grants and personal tates the decision-making process in sarcoma patients. fees from Lilly, grants and personal fees from PharmaMar, Additionally, this SELNET consensus issues 125 recommenda- grants from Glaxo smith kline, grants from Novartis, grants tions, which indicates the level of thoroughness is high cov- from Pfizer, outside the submitted work. Claudia Valverde ering a substantial spectrum of sarcoma care. reports honoraria from PharmaMar, Lilly, Pfizer, Bayer and Follow-up recommendations in the context of sarcoma Novartis, institutional grants from PharmaMar, Lilly, Pfizer, remains largely unstudied,[35] and, usually is based on con- Novartis, Incyte, Bayer and Eisai and non-financial interests ventions and, thus in high risk patients, for example, the from PharmaMar and Lilly, outside the submitted work. imaging tests are performed every 3-4 months for the first Jean-Yves Blay declares research support and honoraria 3 years, then every 6 months for the 4th and 5th years and from GSK, Novartis and Bayer. www.TheOncologist.com © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. 6 SELNET recommendations in sarcoma during COVID-19

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TABLE 1. Prioritising recommendations classified in higher and lower priority with consensus results for each recommendation (percentage agreeing with the recommendation). Multidisciplinary sarcoma tele-committees Higher priority Lower priority a) Soft-tissue, bone or visceral sarcoma a) Soft-tissue, bone or visceral sarcoma • Localized and advanced disease • Localized and advanced disease 1. Every new suspicion of sarcoma (soft tissue, bone or visceral) 4. Cases with diagnostic suspicion of: diagnosis. The only exceptions being the cases likely to be - Bone lesions likely to be benign. well-differentiated liposarcoma or low risk gastric GIST. - Desmoid tumours; [Strongly recommended, 97%] - Lipomas; 2. Therapeutic plan for patients previously diagnosed with: - Tenosynovial giant cell tumour (TGCT). - Any sarcoma with metastatic life-threatening lesions. [Strongly recommended, 97%] - Ewing sarcoma; 5. Indolent tumours for which the committee discussion can be - High grade recurrent resectable tumours; delayed, at physician discretion. (i.e. those in follow-up with - High risk localized sarcoma; length intervals of 6 months or longer) - Osteosarcoma; [Strongly recommended, 94%] -Rhabdomyosarcoma (embryonal, alveolar and sclerosing) [Strongly recommended, 100%] 3. Therapeutic plan for recurrent or progressing sarcomas. [Strongly recommended, 97%] Diagnostic process Higher priority Lower priority a) Soft-tissue sarcoma a) Soft-tissue sarcoma • Localized disease • Localized disease • Deep lesions larger than 3 cm or any tumour larger than 5 • Lesions not fitting with the points 1 or 2 of the higher cm in limbs or trunk-wall with no lipoma aspect. priority. [Strongly recommended, 100%] [Strongly recommended, 97%] Any lump that even not fitting with point 1 had experienced a Retroperitoneal mass with the appearance of well recent fast growth. differentiated liposarcoma. [Strongly recommended, 97%] [No consensus, only 74% agreed] Lesions with suspicion of local recurrence Lesions with appearance of desmoid tumours, or [Strongly recommended, 97%] oligosymptomatic lesions with appearance of TGCT. Local neurofibroma or TGCT with suspicion of malignant [No consensus, 74%] transformation[Strongly recommended, 97%] • Advanced disease • Advanced disease • Lung micronodules (less than 1 cm) • Any new tumoral lesion in somatic tissues with apparent [Recommended, 81%] metastatic spread. Appearance of metastatic spread in the context of indolent [Strongly recommended, 100%] tumours (i.e. EMCh, or ASPS). Any new metastatic recurrence with unexpected behaviour for [No consensus, only 74% agreed] the tumour context. [Strongly recommended, 94%] b) Bone sarcoma b) Bone sarcoma • Localized disease • Localized disease • Any new tumoral lesion with suspicion of malignancy. • Bone lesions likely to be benign without symptoms or [Strongly recommended, 100%] complication risks. Bone tumours without suspicion of malignancy but with risk of [Recommended, 87%] fracture. • Advanced disease [Strongly recommended, 100%] • Lung micronodules (less than 1 cm) Osteochondromas or GCTB with suspicion of malignant [Recommended, 77%] transformation. Indolent metastatic disease (i.e. adamantinoma, periosteal [Strongly recommended, 97%] osteosarcoma) Any suspicion of local recurrence. [Recommended, 87%] [Strongly recommended, 100%] • Advanced disease • Any new bone tumour with metastatic spread [Strongly recommended, 97%] Any new metastatic recurrence with unexpected behaviour for the tumour context. [Strongly recommended, 97%] c) GIST or other visceral sarcomas c) GIST or other visceral sarcomas • Localized disease • Localized disease • Clinically evident intramural gastrointestinal lesion. • Intramural lesions less than 1-2 cm in the gastrointestinal [Strongly recommended, 97%] tract. Clinical and radiological suspicion of uterine leiomyosarcoma [Strongly recommended, 90%] (subserosal mass, with recent symptoms). Uterine mass predominantly intramural, no recent history of [Strongly recommended, 97%] symptoms/signs, more likely to be myofibromas. • Advanced disease [Recommended, 87%] • Any appearance of new nodules suspected of metastatic • Advanced disease spread (except for micronodules or indolent). Biopsy of • Appearance of metastatic spread in the context of indolent GIST (PDGFRA mutant, KIT/PDGFRA wild type) (continued)

TABLE 1. (continued) Multidisciplinary sarcoma tele-committees Higher priority Lower priority metastatic nodules will be not necessary in the context of [Recommended, 81%] consistent natural history. [Recommended, 84%] Surgery Higher priority Lower priority a) Soft-tissue sarcoma a) Soft-tissue sarcoma • Localized disease • Localized disease • High-risk (≥ 40% of death risk by sarculator) localized STS of • Low-risk tumours (less than 20% of death risk) (well limbs/trunk wall (after neoadjuvant treatment if indicated) differentiated liposarcoma; atypical liposarcoma; low [Strongly recommended, 100%] risk SFT) Intermediate-risk STS (20-40% of death risk by Sarculator). [Recommended, 81%] [Strongly recommended, 97%] Local recurrence of low-risk tumour Any local recurrence of grade 2 or 3 STS of limbs/trunk wall [Recommended, 87%] [Strongly recommended, 100%] Retroperitoneal sarcoma (well-differentiated liposarcoma, low Local therapy for extraskeletal Ewing sarcoma, or grade SFT, desmoid tumours) rhabdomyosarcoma (embryonal, alveolar and sclerosing) [Recommended, 84%] [Strongly recommended, 97%] • Advanced disease Any surgical complication entailing risk for the patient. • Indicate metastasectomy but due to indolent behaviour of [Recommended, 87%] STS, this can be postponed (i.e. EMCh, ASPS) Retroperitoneal sarcoma (dedifferentiated liposarcoma, [Recommended, 87%] leiomyosarcoma, other high/intermediated grade sarcomas) Synchronous metastatic STS or metachronous metastatic STS [Strongly recommended, 100%] with a short relapse interval, where systemic therapy could be • Advanced disease tried ﬁrst. • Metastasectomies in oligometastatic patients with an [Recommended, 87%] adequate time interval without progression. Pulmonary micronodules with uncertain malignant nature. [Strongly recommended, 94%] [Recommended, 84%] Any life-threatening resectable metastatic spread in adequate MDT discussion. [Strongly recommended, 97%] b) Bone sarcoma b) Bone sarcoma • Localized disease • Localized disease • High-grade conventional osteosarcoma and skeletal Ewing • Low-grade osteosarcoma (parosteal and other variants). sarcoma after neoadjuvant chemotherapy. [Recommended, 84%] [Strongly recommended, 97%] Low-grade chondrosarcoma High grade conventional chondrosarcoma. [Strongly recommended, 90.32%] [Strongly recommended, 100%] Adamantinoma Mesenchymal chondrosarcoma (upfront or after neoadjuvant [Recommended, 87%] chemotherapy, following MDT decision) GCTB without suspicion of malignant transformation (consider [Strongly recommended, 100%] induction with denosumab) Other high-grade primary bone tumours [Recommended, 87%] [Strongly recommended, 97%] Any other low-grade bone sarcoma High-grade/Intermediate grade in local recurrence. [Recommended, 84%] [Strongly recommended, 97%] • Advanced disease Any surgical complication that would be solved by surgery. • Indicated metastasectomy but due to indolent behaviour, [Strongly recommended, 100%] this can be postponed (i.e. adamantinoma, low-grade • Advanced disease bone tumours) • Metastasectomies as part of multimodality treatment in [Strongly recommended, 90%] osteosarcoma or Ewing sarcoma. Metastatic GCTB (denosumab can be a therapeutic option). [Strongly recommended, 94%] [Strongly recommended, 90%] Oligometastatic chondrosarcoma without evidence of local Pulmonary micronodules with uncertain malignant nature recurrence. [Strongly recommended, 90%] [Strongly recommended, 97%] Oligometastatic high grade bone sarcoma without evidence of local recurrence. [Strongly recommended, 97%] c) GIST/ other visceral sarcomas c) GIST/ other visceral sarcomas • Localized disease • Localized disease • Clinically evident GIST (consider neoadjuvant imatinib for • Low-risk or very-low risk GIST without clinical complications. gastroesophageal junction or gastric antrum or duodenal [Recommended, 87%] or rectal GIST or any bulky GIST in order to facilitate In the context of indolent GISTs (i.e. PDGFRA mutants or KIT/ surgery). PDGFRA wild type) consider postponing surgery based on other [Strongly recommended, 100%] relevant factors. Symptomatic GIST not suitable for neoadjuvant imatinib (i.e. [Strongly recommended, 100%] imatinib intolerant or genotype resistant to imatinib) Any low-grade visceral sarcoma without relevant symptoms or [Strongly recommended, 97%] other complications. Any other visceral grade 2 or grade 3 sarcomas or symptomatic [Recommended, 87%] low-grade. • Advanced disease [Strongly recommended, 100%] (continued) www.TheOncologist.com © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. 10 SELNET recommendations in sarcoma during COVID-19

TABLE 1. (continued) Multidisciplinary sarcoma tele-committees Higher priority Lower priority • Advanced disease • Nodule within mass as GIST progression that could be • In the context of unique or oligometastatic responding postponed or managed with radiofrequency. patients for whom extending 3-months imatinib could be [Strongly recommended, 97%] difficult. Metastatic indolent GIST (even oligometastatic) (i.e. PDGFRA) [Strongly recommended, 90%] that could be postponed. Multicentric GIST or with nodal involvement (i.e. KIT/PDGFRA [Strongly recommended, 97%] wild type GIST). [Strongly recommended, 94%] Metastatic lesion causing symptomatic or other serious effect not amenable with imatinib. [Strongly recommended, 97%] Medical Oncology# Higher priority Lower priority a) Soft-tissue sarcoma a) Soft-tissue sarcoma • Localized disease • Localized disease • Neoadjuvant chemotherapy for extraskeletal Ewing • Perioperative chemotherapy in localized STS of limbs/trunk sarcoma*1,2 and paediatric-type rhabdomyosarcoma*3 wall larger than 5 cm, grade 3 and deep tumours but with (embryonal, alveolar and sclerosing) risk of death less than 40% based on sarculator would be [Strongly recommended, 97%] postponed or not recommended. Perioperative chemotherapy in high-risk STS of limbs/trunk wall [Strongly recommended, 90%] (> 40% death-risk based on sarculator) (3 cycles of epirubicin + • Advanced disease ifosfamide) in selected patients.*4 • Newly diagnosed metastatic disease with micronodules [Strongly recommended, 97%] [Recommended, 84%] Potentially resectable localized STS Indolent STS or slow progressive STS with barely or no [No consensus, only 74% agreed] symptomatic impact. • Advanced disease*5 [Strongly recommended, 90%] • Overtly disease progression Progressive disease beyond 2nd with low probability of clinical [Strongly recommended, 94%] benefit. Newly diagnosed metastatic disease (other than doubtful [Recommended, 84%] micronodules) [Strongly recommended, 97%] Symptomatic patients in relation to their tumour volume. [Strongly recommended, 94%] Patients with already initiated chemotherapy, or other systemic treatment with clinical or radiological benefit. [Strongly recommended, 100%] Potentially resectable advanced STS. [Strongly recommended, 90%] b) Bone sarcoma b) Bone sarcoma • Localized disease • Localized disease • Neoadjuvant chemotherapy in osteosarcoma*6,7 or Ewing • Perioperative chemotherapy in high-grade bone sarcoma skeletal sarcoma.*1,2 (i.e. Undifferentiated high-grade pleomorphic bone [Strongly recommended, 94%] sarcoma). Neoadjuvant chemotherapy in mesenchymal chondrosarcoma [No consensus, only 68% agreed] potentially resectable. Perioperative chemotherapy in high-grade chondrosarcoma. [Recommended, 87%] [Recommended, 81%] • Advanced disease • Advanced disease • Upfront chemotherapy in metastatic osteosarcoma or Ewing • Systemic treatment beyond second line of metastatic sarcoma.*2 disease in osteosarcoma or beyond third line in Ewing [Strongly recommended, 100%] sarcoma Chemotherapy in recurrent advanced osteosarcoma no suitable [Recommended, 81%] for surgery.*8 Any chemotherapy line in chondrosarcoma [Strongly recommended, 100%] [Recommended, 87%] Chemotherapy in recurrent advanced Ewing sarcoma.*9 Imatinib in advanced/recurrent asymptomatic chordoma. [Strongly recommended, 100%] [Strongly recommended, 94%] Metastatic undifferentiated high-grade bone sarcoma. [Strongly recommended, 94%] c) GIST/ other visceral sarcomas c) GIST/ other visceral sarcomas • Localized disease*10 • Localized disease • Neoadjuvant imatinib in locally advanced GIST with sensitive • Adjuvant imatinib with < 40% of recurrence risk (heat maps) genotype (to facilitate posterior surgery) [Recommended, 81%] [Strongly recommended, 94%] • Advanced disease Neoadjuvant imatinib in gastro-oesophageal junction, or gastric • Metastatic indolent disease (i.e. PDGFRA mutant) antrum or rectal GIST (to minimize morbidity) with sensitive [Recommended, 87%] genotype. Radiological progression without clinical impact. [Strongly recommended, 100%] [No consensus, 68%] Adjuvant imatinib in patients with > 40% of recurrence risk (heat maps) (continued)

TABLE 1. (continued) Multidisciplinary sarcoma tele-committees Higher priority Lower priority [Strongly recommended, 100%] • Advanced disease*11 • TKI for first, second and third line in metastatic disease with imatinib, sunitinib and regorafenib respectively. [Strongly recommended, 94%] Radiation Oncology Higher priority Lower priority a) Soft-tissue sarcoma a) Soft-tissue sarcoma • Localized disease • Localized disease • Perioperative radiation therapy (preferably postoperative • Postoperative radiation therapy in low grade, > 5 cm and during COVID-19 outbreak) in grade 2-3, > 5 cm and deep deep STS of limbs or trunk-wall. STS of limbs/trunk wall. [No consensus, 71%] [Strongly recommended, 97%] • Advanced disease Perioperative radiation therapy (preferably postoperative • Radiation therapy for local control of asymptomatic primary during COVID-19 outbreak) in > 5 cm and superficial STS of any tumour in the context of metastatic STS. grade in limbs/trunk wall. [Recommended, 84%] [Recommended, 77%] Perioperative radiation therapy (preferably postoperative during COVID-19 outbreak) in < 5 cm and deep STS of any grade in limbs/trunk wall. [No consensus, only 61% agreed] Radiation therapy in cases of head and neck sarcomas. [Strongly recommended, 90%] Radiation therapy in rhabdomyosarcomas (embryonal, alveolar and sclerosing) and extraskeletal Ewing sarcoma [Strongly recommended, 100%] • Advanced disease • Any symptomatic metastatic lesion that could be alleviate with radiation therapy, balancing risk/benefit. [Strongly recommended, 97%] Radiation therapy for symptomatic primary tumour in the context of metastasis. [Strongly recommended, 100%] b) Bone sarcoma • Localized disease • Radiation therapy is skeletal Ewing sarcoma according to CPG. [Strongly recommended, 100%] Unresectable osteosarcoma after induction chemotherapy. [Strongly recommended, 94%] Definitive radiation therapy for grade 3 chondrosarcoma. [Recommended, 87%] • Advanced disease • Any symptomatic metastatic lesion that could be alleviate with radiation therapy, balancing risk/benefit. [Strongly recommended, 97%] c) GIST/ other visceral sarcomas c) GIST/ other visceral sarcomas • Localized disease • Localized disease • Radiation therapy for unresectable breast or uterine • Postoperative radiation therapy in breast sarcoma larger sarcoma. than 5 cm or high grade. [Strongly recommended, 97%] [No consensus, only 65% agreed] • Advanced disease • Advanced disease • Any symptomatic metastatic lesion that could be alleviate • Radiation therapy for unresectable breast or uterine with radiation therapy, balancing risk/benefit. sarcoma with metastatic spread. [Strongly recommended, 100%] [No consensus, only 74% agreed] Follow-up Higher priority Lower priority a) Soft-tissue, bone or visceral sarcoma a) Soft-tissue, bone or visceral sarcoma • Localized and advanced disease • Localized and advanced disease • The follow-up recommendation for high risk STS, • The follow-up recommendation for low-intermediate risk of conventional osteosarcoma, Ewing sarcoma, STS, Low grade osteosarcoma, high-risk GIST under rhabdomyosarcoma (embryonal, alveolar or sclerosing), adjuvant imatinib, intermediate-low risk of localized GIST high risk GIST after completion of adjuvant imatinib is to is to schedule CT scans or chest X-ray (in some cases): schedule CT scans or chest X-ray (in some cases): - Every 5-6 months for the first 5 years; - Every 3-4 months for the first 3 years; - Every year after the 5th year. - Every 6 months in 4th or 5th years; [Strongly recommended, 97%] (continued) www.TheOncologist.com © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. 12 SELNET recommendations in sarcoma during COVID-19

TABLE 1. (continued) Multidisciplinary sarcoma tele-committees Higher priority Lower priority - Every year after the 5th year. Consider, in the appropriate context, to prolong the interval 2-3 [Strongly recommended, 97%] months if the patient is beyond the first 3 years of follow-up. Being the objective to minimize the contact of the patient with the hospital during the COVID-19 outbreak, it is desirable to have, as much as possible, teleconsultation during follow-up. Clinical Trials Higher priority Lower priority a) Soft-tissue, bone or visceral sarcoma a) Soft-tissue, bone or visceral sarcoma • Localized and advanced disease • Localized and advanced disease • To new enrolment: • To new enrolment: Therapies likely to improve clinical outcome: (drugs with strong Therapies for indolent entities (TGCT, GCTB, Desmoid tumours) preclinical rationale, drugs showing promising results in for which the enrolment can be postponed, phase I trials previous clinical trials, drugs with robust predictive with substantial number of procedures, serious logistic biomarker, therapy targeting addictive signalling pathway in difficulties due to the pandemic situation, CAR-T cells based some tumours, therapy targeting relevant signalling in trials (it could require intensive care support), orphan diseases). immunomodulation therapies that could exacerbate the [Strongly recommended, 97%] inflammatory response to SARS-CoV-2. To maintain the treatment under trial: [Strongly recommended, 90%] Patients with clinical or radiological benefit, patients still not assessed for efficacy without relevant toxicity. [Strongly recommended, 100%] Consider adapting procedures in agreement with the trial sponsor as relax the interval of clinical visits, to minimize as much as possible hospital frequentation. #In the section of medical oncology, asterisks indicate the ESMO-MCBS applications for most relevant papers. Acronyms: EMCh extraskeletal myxoid chondrosarcoma; ASPS alveolar soft part sarcoma; GCTB giant cell tumour of bone; GIST gastro intestinal stromal tumour. Soft Tissue Sarcomas (Localized disease) *1 The benefit from VDC/IE over VDC chemotherapy in Ewing Sarcoma[39] shows level A of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 1. *2 The benefit from VDC/IE over VIDE chemotherapy in Ewing Sarcoma[40] shows level B of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 1. *3 The benefit from IVA when compared with other regiments with more drugs (IVA+Carbo-etoposide-epirrubicin and IVADo) in rhabdomyosarcoma [41, 42] shows level B of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1.- Form 1 (IVA is the recommended option as resulted in less toxicity with the same survival outcome). *4 The benefit from 3 cycles of epirubicin and ifosfamide in the perioperative setting in high risk STS patients[43-45] shows level A of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1.- Form 1. (Advanced disease) *5 The benefit from eribulin in liposarcoma[46] shows level 4 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1.- Form 2A (benefit in OS). The benefit from eribulin in L- sarcoma (liposarcoma and leiomyosarcoma)[46] shows level 3 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1.- Form 2A. The benefit from trabectedin in L-sarcoma (liposarcoma and leiomyosarcoma)[47] shows level 3 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 2B. The benefit from trabectedin in translocation-related sarcoma[48] shows level 4 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 2A (benefit in OS). The benefit from pazopanib in pre-treated STS excluding liposarcoma[49] shows level 3 of recommendation when applying the ESMO-Magnitude of Clinical Bene- fit Scale (MCBS) V1Á1- Form 2B. The benefit from the combination of gemcitabine and dacarbazine in pre-treated STS[50] shows level 4 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 2A (benefit in OS). The benefitfromthe combination of gemcitabine and docetaxel in advanced STS[51] and in advanced leiomyosarcoma[52] shows level 1 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 2C. The benefit from high-dose ifosfamide in advanced STS[53] shows level 4 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 3. The benefit from doxorubicin in advanced STS[54] shows level 4 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 3. Bone sarcoma-Osteosarcoma (Localized disease) *6 The benefit from adjuvant chemotherapy in resected conventional osteosarcoma[55, 56] shows level A of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 1. *7 The benefit from the addition of Mifamurtide to adjuvant chemotherapy in resected conventional osteosarcoma[57] shows level A of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 1. (Advanced disease) *8 The benefit from cisplatin in advanced osteosarcoma[58] shows level 4 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form C. The benefit from cisplatin + doxorubicin + ifosfamide in advanced osteosarcoma[59] shows level 4 of recommendation when applying the ESMO-Magnitude of Clinical Ben- efit Scale (MCBS) V1Á1- Form C. The benefit from ifosfamide-etoposide in advanced osteosarcoma[60] shows level 3 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form C. The benefit from high-dose ifosfamide in advanced osteosarcoma [61] shows level 4 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form C. The benefit from sorafenib plus everolimus[62] and regorafenib[63] in advanced osteosarcoma shows level 2 of recommendation when applying the ESMO- Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form C. Bone sarcoma- Ewing’s sarcoma (Localized disease) *1 The benefit from VDC/IE over VDC chemotherapy in Ewing Sarcoma[39] shows level A of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 1. *2 The benefit from VDC/IE over VIDE chemotherapy in Ewing Sarcoma[40] shows level B of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 1. (Advanced disease) *9 The benefit from gemcitabine and docetaxel in Ewing Sarcoma[64, 65] shows level 2 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form C. The benefit from Cyclophosphamide-topotecan cannot be properly assessed with the currently available evidence. The benefit from high-dose ifosfamide in Ewing Sarcoma[66] shows level 3 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form C. GIST (Localized disease) *10 The benefit from 3 years of adjuvant imatinib in localized GIST[67] shows level A of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 1. (Advanced disease) *11 The benefit from imatinib in advanced GIST[68] shows level 4 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 3. The benefitfrom sunitinib in advanced GIST[69, 70] shows level 4 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 2B and Form 2A respectively. The benefit from Regorafenib in advanced GIST[71] shows level 3 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 2B. The benefit from Ripretinib in advanced GIST[72] shows level 4 of recommendation when applying the ESMO-Magnitude of Clinical Benefit Scale (MCBS) V1Á1- Form 2B and Form 2A respectively.

Table 2. Mann-Whitney U and Pearson’s chi-squared test for those recommendations with statistical differences between Latin-American (LATAM) and Europe-United States of America (EU-US) experts. R #93 collects agreement as a low priority for adjuvant chemotherapy in high grade localized chondrosarcoma. R #105 collects agreement as a high priority for perioperative radiation therapy in superﬁcial STS larger than 5 cm and R #114 collects agreement as a lower priority for low grade, deep STS and larger than 5 cm. Mann-Whitney test Pearson’s chi-squared test LATAM EU-US p LATAM EU-US p Recommendation #93 38% 7% 0.001 Recommendation #93 57% 100% 0.009 Strongly agree 31% 64% Agree 43% 0% Agree 31% 22% Disagree Disagree 0% 7% Strongly disagree Recommendation #105 25% 64% 0.008 Recommendation #105 100% 63% 0.01 Strongly agree 38% 36% Agree 0% 37% Agree 31% 0% Disagree Disagree 6% 0% Strongly disagree Recommendation #111 41% 21% 0,021 Recommendation #111 43% 94% 0.002 Strongly agree 53% 21% Agree 57% 6% Agree 6% 58% Disagree Disagree 0% 0% Strongly disagree