Chemotherapy-induced Necrosis in Ewing Sarcoma: Which is the Best Scoring Tool
Conditions: Ewing Sarcoma of Bone
Sponsor: Istituto Ortopedico Rizzoli

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“Chemotherapy-induced necrosis in Ewing sarcoma: which is the best 
scoring tool?” 
 
Study code EW-score 
Sponsor’s Name and 
Address: 
Istituto Ortopedico Rizzoli 
Via di Barbiano 1/10 
40136 Bologna 
Italy 
Study 
Number/Version/Date: 
Vers 1.0  
08 Mar 2019 
Coordinating Center: IRCCS Istituto Ortopedico Rizzoli 
Pathology Unit 
Via Pupilli 1 
40136 Bologna, Italy 
Coordinating 
Investigator and 
address: 
Alberto Righi MD 
Phone: 051-6366.665 
Email: alberto.righi@ior.it 
Scientific/Medical study 
responsible and 
developer 
Alberto Righi MD 
 
Methodology: Retrospective study 
(Single insitution case series review of clinical data) 
Type: Academic 
 
Founding: None 
 
Principal Investigator 
Signature 
I confirm that I’ve read this protocol and I accept to run the study 
in compliance with what is stated in the protocol and with the 
ICh-GCP and all applicable law 
 
Alberto Righi MD 
 
Firma 
 
_________________________ 
 
 

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TABLE of CONTENTS 
Background 
 
 
 
 
 
 
 
 
 
pg. 3 
Objective of the study 
 
 
 
 
 
 
 
pg.  3 
Study design   
 
 
 
 
 
 
 
 
pg. 3 
Population     
 
 
 
 
 
 
 
 
pg.  3 
Material and Methods   
 
 
 
 
 
 
 
pg.  4 
Statistics 
 
   
 
 
 
 
 
 
 
pg.  4 
Data Collection            
  
 
 
 
 
 
 
pg.  4 
Ethic and quality assurance  
 
  
 
 
 
 
pg. 4 
Informed Consent   
  
 
 
 
 
 
 
             pg.  5 
Confidentiality                                                                                       
 
 
pg.  5 
Publication of results                                                        
 
 
             pg.  5 
Sponsor Role and Responsibility                                                                                   pg.  6 
References 
                                                                                       
 
 
pg.  6 
 
 

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BACKGROUND 
Ewing sarcoma, commonly bearing a pathognomonic EWS-FL1 translocation, is the second most 
common bone malignancy in children and adolescents, with an annual incidence of 200–500 cases 
in the United States and of 120-150 cases in Italy [1,2]. With advances in multidisciplinary care, 5-
year survival rates for pediatric Ewing sarcoma patients have improved from 50% during the 
period from 1983–1990 to 70% during the period from 2004–2016 [1-3]. Prolonged disease-free 
survival is achieved in the majority of patients with localized Ewing sarcoma after treatment with 
multiagent chemotherapy and primary tumor control [3]. The best predictive factor is 
histologically determined chemotherapy-induced necrosis assessed in resected primary tumors, 
that has allowed to identify patients who are candidates for more intensive or novel therapies [3-
6]. The good and poor responder patients to neo-adjuvant chemotherapy has been defined to 
different systems published in literature: true Percentage, Huvos System and Bologna System [4-
7]. 
  
OBJECTIVE OF THE STUDY  
The aim of the present study is to evaluate which is the best scoring tool to determine the 
histological response to chemotherapy in localized Ewing sarcoma of bone. 
The study will exam all the different systems to evaluate the histological necrosis after neo-
adjuvant chemotherapy in all patients with localized Ewing sarcomas of bone surgically treated 
between 1982 and 2012.  
 
STUDY DESIGN 
This is single institution cases series review of histological and clinical data 
 
POPULATION 
Inclusion criteria 
1) Male and female patients surgically treated at Rizzoli Institute from 01 Jan 1982 to 31 
Dic 2012 
2) Patients with diagnosis of Ewing sarcoma of bone who have had neo-adjuvant 
chemotherapy 
3) Diagnosis of Ewing sarcoma localized  
 

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Exclusion criteria 
1. Metastatic disease at presentation 
2. Soft tissue origin 
3. Radiotherapy before surgery 
 
The study will include male and female patients without limit of age 
 
MATERIAL AND METHODS 
We will retrieve from the database of the Rizzoli institute all the cases with a histological diagnosis 
of Ewing sarcoma from 01 Jan 1982 to 31 Dic 2012.  
We aspect to find approximately 500 cases.  
We will review all the medical records, and histological data of these cases.  
 
STATISTICS 
To the case series will be applied a descriptive statistic. 
 
 
DATA COLLECTION 
Clinical data will be retrieved by patient charts. 
A protocol-specific CRF reporting the results of the review will be provided. 
A CRF is required and should be completed for each included subject. 
 
ETHICS AND QUALITY ASSURANCE 
The clinical trial protocol and its documents will be sent before initiating the study to the 
competent Authorities and Ethics Committees of each participating country for its approval. 
The responsible investigator will ensure that this study is conducted in agreement with either the 
most updated Declaration of Helsinki and all the international and local laws that apply to clinical 
trials and to patient protection.  

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The protocol has been written, and the study will be conducted according to the principles of the 
ICH Harmonized Tripartite Guideline for Good Clinical Practice  
(ref: http://www.emea.eu.int/pdfs/human/ich/013595en.pdf).  
 
INFORMED CONSENT 
For Scientific Institute for Research and Healthcare (IRCCS) informed consent form to the 
processing of personal data is not applicable as for the Article 110 bis, paragraph 4 of the New 
Privacy Code (GDPR) regarding the use of clinical activity data collected for research purposes  
 
 
CONFIDENTIALITY 
In order to ensure confidentiality of clinical trial data as disposed the national and European 
applicable regulation, data will be only accessible for the trial Sponsor and its designees, for 
monitoring/auditing procedures, the Investigator and collaborators, the Ethics Committee of each 
corresponding site and the Health Authority. 
Investigator and the Institution will allow access to data and source documentation for 
monitoring, auditing, Ethic Committee revision and inspections of Health Authority, but 
maintaining at all times subject personal data confidentiality as specified in the “Directive 
95/46/EC of the European Parliament and of the Council of 24 October 1995”.  
 The Investigator must guarantee that patient anonymity is kept at all times and their identity 
must be protected from unauthorized persons and institutions.  
All patients included in the study will be identified with a numeric code, so that no identifiable 
personal data will be collected (pseudo anonymization) 
The Investigator must have and conserve a patients’ inclusion registry where it figures the 
personal data of the patient: name, surname, address and corresponding identification code into 
the study, this register will be kept on the Investigator File. 
 
PUBBLICATION OF RESULTS  
The results from this study will be published or shown at scientific conferences.  
The final publication of the study results will be written by the Principal Investigator. 
 
 

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SPONSOR ROLE AND RESPONSIBILITY 
The sponsor is the sole owner of the data and is responsible of all the clinical trial activities from 
study design, development, data collection, management, analysis, interpretation of data, writing 
and the decision to submit the report for publication written by the Principal Investigator,  
 
REFERENCES 
[1] Esiashvili N, Goodman M, Marcus RB Jr. Changes in incidence and survival of ewing sarcoma 
patients over the past 3 decades: Surveillance epidemiology and end results data. J Pediatr 
Hematol Oncol. 2008; 30:425–430.  
[2] Smith MA, Seibel NL, Altekruse SF, et al. Outcomes for children and adolescents with cancer: 
Challenges for the twenty-first century. J Clin Oncol. 2010; 28:2625–2634. 
[3] Whelan J, Le Deley MC, Dirksen U, Le Teuff G, Brennan B, Gaspar N, Hawkins DS, Amler S, Bauer 
S, Bielack S, Blay JY, Burdach S, Castex MP, Dilloo D, Eggert A, Gelderblom H, Gentet JC, Hartmann 
W, Hassenpflug WA, Hjorth L, Jimenez M, Klingebiel T, Kontny U, Kruseova J, Ladenstein R, 
Laurence V, Lervat C, Marec-Berard P, Marreaud S, Michon J, Morland B, Paulussen M, Ranft A, 
Reichardt P, van den Berg H, Wheatley K, Judson I, Lewis I, Craft A, Juergens H, Oberlin O; Euro-
E.W.I.N.G.99 and EWING-2008 Investigators. High-Dose Chemotherapy and Blood Autologous 
Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: 
Results of Euro-E.W.I.N.G.99 and Ewing-2008. J Clin Oncol. 2018 Sep 6: JCO2018782516. doi: 
10.1200/JCO.2018.78.2516. 
[4] Picci P, Böhling T, Bacci G, Ferrari S, Sangiorgi L, Mercuri M, Ruggieri P, Manfrini M, Ferraro A, 
Casadei R, Benassi MS, Mancini AF, Rosito P, Cazzola A, Barbieri E, Tienghi A, Brach del Prever A, 
Comandone A, Bacchini P, Bertoni F. Chemotherapy-induced tumor necrosis as a prognostic factor 
in localized Ewing's sarcoma of the extremities. J Clin Oncol. 1997 Apr;15(4):1553-9. 
[5] Picci P, Rougraff BT, Bacci G, Neff JR, Sangiorgi L, Cazzola A, Baldini N, Ferrari S, Mercuri M, 
Ruggieri P, et al. Prognostic significance of histopathologic response to chemotherapy in 
nonmetastatic Ewing's sarcoma of the extremities. J Clin Oncol. 1993 Sep;11(9):1763-9. 

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[6] Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, 
Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, 
Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma 
Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--
cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit 
of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 
20;26(27):4385-93.  
[7] Huvos A: Osteogenic sarcoma. Pathological assessment of pre-operative (neoadjuvant) 
chemotherapy. In Bone Tumors. Diagnosis, Treatment, and Prognosis, 2° edn, Philadelphia, WB 
Saunders Co, 1991, pp. 122-128.