Sarcomas of Bone and Soft Tissues in Children and Adolescents [1st ed.] 9783030511586, 9783030511609

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Pediatric Oncology Series Editors: Gregory H. Reaman · Franklin O. Smith

Carola A. S. Arndt   Editor

Sarcomas of Bone and Soft Tissues in Children and Adolescents

Pediatric Oncology Series Editors Gregory H. Reaman Center for Drug Evaluation and Research U.S. Food and Drug Administration Center for Drug Evaluation and Research Silver Spring, MD, USA Franklin O. Smith Medpace CINCINNATI, OH, USA

More information about this series at http://www.springer.com/series/5421

Carola A. S. Arndt Editor

Sarcomas of Bone and Soft Tissues in Children and Adolescents

Editor Carola A. S. Arndt Department of Pediatric and Adolescent Medicine Mayo Clinic Rochester, MN USA

ISSN 1613-5318     ISSN 2191-0812 (electronic) Pediatric Oncology ISBN 978-3-030-51158-6    ISBN 978-3-030-51160-9 (eBook) https://doi.org/10.1007/978-3-030-51160-9 © Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Contents

1 Epidemiology of Bone and Soft Tissue Sarcomas ������������������������   1 Philip J. Lupo, Logan G. Spector, Schuyler O’Brien, Joshua D. Schiffman, and Simone Hettmer 2 Sarcoma Pathology and Biology ����������������������������������������������������  17 Marielle Yohe, Javed Khan, and Erin Rudzinski 3 Staging and Imaging of Sarcoma����������������������������������������������������  37 Carola A. S. Arndt and Andrea Ferrari 4 Multi-institutional Trials for Patients with Rhabdomyosarcoma: Lessons from North American Studies from 1967 Through 1997����������������������  47 R. Beverly Raney, Carola A. S. Arndt, and Harold M. Maurer 5 Treatment of Rhabdomyosarcoma ������������������������������������������������  53 Carola A. S. Arndt, Ewa Koscielniak, and Gianni Bisogno 6 Current Approaches to Therapy: Soft Tissue Sarcomas Other than Rhabdomyosarcoma in Children and Adolescents�����  65 Daniel Orbach, Sheri L. Spunt, and Andrea Ferrari 7 Osteosarcoma: History of Therapy������������������������������������������������  87 Paul Meyers 8 Osteosarcoma-Approach to Therapy ��������������������������������������������  91 Stefan Bielack, Matthew G. Cable, Richard Gorlick, Stefanie Hecker-Nolting, Leo Kager, Neyssa Marina, R. Lor Randall, and Jeremy Whelan 9 Contemporary Approach to Therapy for Ewing Sarcoma���������� 111 Steven G. DuBois and Uta Dirksen 10 Experimental Models���������������������������������������������������������������������� 129 Susanne A. Gatz, Janet Shipley, Charles Keller, and Corinne M. Linardic 11 Strategies for New Agent Development in Pediatric Sarcomas������ 149 Emily G. Greengard and Brenda J. Weigel 12 Immunotherapy for Pediatric Sarcomas �������������������������������������� 165 Allison Pribnow, Karin Straathof, and Robbie G. Majzner v

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Epidemiology of Bone and Soft Tissue Sarcomas Philip J. Lupo, Logan G. Spector, Schuyler O’Brien, Joshua D. Schiffman, and Simone Hettmer

1.1

Introduction

Bone and soft tissue sarcomas are relatively rare cancers that collectively account for approximately 1% of adult solid tumors and 12% of all pediatric malignancies (Burningham et al. 2012; Ries et  al. 1999). Major bone tumors include osteosarcoma and Ewing sarcoma, whereas soft tissue sarcomas are largely categorized by rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcomas. In spite of their relative infrequency, these tumors remain a leading cause of cancer death in individuals 10  years of age significantly improved their outcome, whereas it had no effect on boys under 10. Therefore, on COG studies ipsilateral lymph node dissection is required for boys over 10 with paratestis primaries, and for boys under 10 with imaging findings concerning for nodal involvement. The European MMT group has taken a different approach, preferring more intensive therapy for paratestis pri-

mary tumors over node sampling (Stewart et  al. 2003). The Italian and German study compared the clinical and surgical/pathologic stages in 95 children with paratesticular rhabdomyosarcoma: among 72 patients with negative radiologic findings (cN0), surgical/pathological assessment detected nodal involvement in only one case (pN1). This finding suggested that CT accurately evaluates the retroperitoneum. In analyses of only those patients older than 10 years, results did not seem different, even if the number of cases was substantially lower (13 of 13 cN0 patients were pN0 too) (Ferrari et al. 2002). On the basis of these results, the EpSSG protocol considered retroperitoneal lymphadenectomy or nodal sampling at diagnosis as not recommended unless there is uncertainty on imaging. The planned COG intermediate risk study will require pathologic evaluation of nodes in all patients with extremity tumors and strongly

3  Staging and Imaging of Sarcoma

encourages it for patients with ARMS or clinically involved nodes regardless of histology. The preferred method of nodal evaluation is sentinel node sampling since this has been shown to be useful and feasible in pediatric patients with soft tissue sarcomas, even in a case reported with parameningeal RMS (De Corti et al. 2009; Weiss et al. 2011). FDG-PET is being used more commonly in initial staging evaluation of sarcomas and is also being evaluated for response assessment. A small study of 13 children and adolescents with histologically proven RMS found FDG-PET scanning to be more sensitive than conventional imaging in detection of lymph nodes and bone metastases; however subcentimeter pulmonary nodules may not consistently be detected (Ricard et al. 2011). Moreover in one patient FDG-PET scan was positive in lymph nodes due to concurrent infection. In this series, FDG PET modified lymph node staging in four of 13 patients, bone involvement in two patients, and led to treatment alteration in two patients. A prospective study of 46 pediatric sarcoma patients, of whom 12 had RMS, found similar results in the superiority of FDG-PET scan in detection of lymph node and bone metastases, but not subcentimeter lung nodules (Volker et al. 2007). A limitation of both studies was that positive imaging was not consistently confirmed pathologically. Klem and colleagues also evaluated FDG-PET for initial staging in 24 patients with RMS and determined it to be 77% sensitive and 95% specific when compared with the final clinical determination of disease but still concluded that although “PET is a helpful adjunct… is not accurate enough to replace biopsy of suspicious nodes” (Klem et  al. 2007). Federico and colleagues had similar conclusions in terms of high sensitivity for detection of nodal disease but low sensitivity in detection of lung disease (Federico et al. 2013). Mody et al. retrospectively evaluated 25 children with Ewing sarcoma family of tumors and rhabdomyosarcoma who had PET scans at various time points during therapy and found sensitivity of the PET scan was 86%, specificity was 80%, positive predictive value was 89%, and negative predictive value was 67%

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(Mody et al. 2010). Wegner and colleagues found PET scans to result in a change in management or be helpful in determining management of a wide variety of pediatric malignancies (Wegner et  al. 2005). Gerth and colleagues found combining PET and CT to be significantly more accurate than PET alone in  localization and detection of lesions in patients with Ewings sarcoma, and most PET imaging is now fused with CT imaging (Gerth et  al. 2007). Eugene et  al. evaluated 23 patients with RMS with PET/CT and conventional imaging and confirmed again that PET/CT provides important additional staging information as well as being prognostic for tumor response, but effect of PET response on outcome was not evaluated (Eugene et  al. 2012). On the planned next intermediate risk Children’s Oncology Group RMS study, data will be collected on results of FDG-PET scan and nodal biopsy to determine rates of false positivity and negativity for FDG-PET scans. Surprisingly, tumor response by conventional anatomic imaging in patients with RMS does not correlate with outcome in two COG studies (Burke et al. 2007; Rosenberg et al. 2014). This is in contrast to the findings of two European groups, the Italian and German CWS group which found a correlation between the degree of shrinkage after induction chemotherapy (assessed radiologically after three courses of therapy) and final outcome, leading to subsequent European trials using radiologic response to tailor subsequent treatment (Koscielniak et al. 1999; Ferrari et al. 2010). Two recent studies from Memorial Sloan Kettering Cancer Center suggest that functional imaging with FDG-PET scan after local control with radiation as well as after up front chemo were predictive of EFS, overall survival, as well as local control (Casey et  al. 2014; Dharmarajan et al. 2012). A small study of adults with high-grade sarcomas by Tateishi et al. suggested that metabolic reduction after neoadjuvant chemotherapy evaluated by FDG PET can be used for stratification of histopathologic response in patients with high-grade sarcoma and that percentage of SUV2 reduction as well as histopatho-

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logic response were independent predictors of outcome (Tateishi et  al. 2011). Correlation of PET response with outcome and histopathologic response in soft tissue sarcomas will require further evaluation and confirmation. A number of investigators have investigated correlation of PET response with outcome and histopathologic response in Ewing sarcoma and osteosarcoma. Hawkins et  al. evaluated 36 patients with Ewing sarcoma family of tumors and reported that not only did PET imaging corerlate with histologic response, but SUV2 less than 2.5 was predictive of progression-free survival (PFS) independent of initial stage (Hawkins et  al. 2005). The same investigators found that PET response was only partially correlated with histopathologic response to chemotherapy in osteosarcoma, although an SUV2