Cooperative Weichteilsarkom Studiengruppe Research Articles

Importance of Adequate Surgical Local Control in Fusion-Negative Para-Testicular Rhabdomyosarcoma: Data From the Cooperative Weichteilsarkom Studiengruppe Trials (CWS-96 and CWS-2002P) and the European Soft Tissue Sarcoma Registry (SoTiSaR)

BackgroundThis study aimed to assess the impact that the quality of primary and subsequent surgeries has on the survival of patients with para-testicular rhabdomyosarcoma (PTRMS).MethodsPatients with localized (IRS I–III) and metastatic (IRS IV) PTRMS were enrolled in the two Cooperative Weichteilsarkom Studiengruppe (CWS) trials (CWS-96, CWS-2002P) and the Soft Tissue Sarcoma Registry (SoTiSaR).ResultsAmong 196 patients (median age, 8.4 years), 106 (54.1%) had primary complete resection. Image-defined lymph node (LN) disease was detected in 21 (11.5%) patients in the localized cohort and 12 (92.3%) patients in the metastatic cohort. The 5-year event-free survival (EFS) and overall survival (OS) were respectively 87.3% and 94.0% for the patients with localized PTRMS and 46.2% and 42.2% for the patients with metastatic PTRMS. Protocol violations during the primary surgery (PV-PS) were observed in 70 (42%) of the IRS I–III patients. This resulted in higher rates of R1/R2 resections (n = 53 [76%] vs n = 20 [21%]; p < 0.001) with a need for pretreatment re-excision (PRE) (n = 50 [83%] vs n = 10 [17%]; p < 0.001) compared with the patients undergoing correct primary surgery. Protocol violations during PRE occurred for 13 (20%) patients. Although PV-PS did not influence the 5-year EFS or OS in the localized PTRMS cohort, the unadjusted log-rank test showed that R status after PRE is a prognostic factor for 5-year OS (R1 vs R0 [81.8% vs 97.6%]; p = 0.02).ConclusionsThe quality of surgical local control in PTRMS is unsatisfactory. Emphasis should be placed on evaluating the resection status after PRE in further clinical trials.

Angiosarcoma in children: the experience of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology and literature review

Angiosarcoma is a rare and highly malignant endothelial tumor, which occurs mainly in adults and is extremely rare in children and adolescents. The German guidelines for the treatment of soft tissue sarcomas provided by the Cooperative Weichteilsarkom Studiengruppe in 2012 included a separate therapeutic regimen for pediatric angiosarcoma consisting of a combination of vincristine/doxorubicin/cyclophosphamide (VDC) and paclitaxel. The aim of this article was to describe the epidemiological, clinical, and morphological characteristics of angiosarcoma, to review treatment approaches, and to present the experience of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation in the treatment of children with angiosarcoma. Our study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. The study included 5 patients diagnosed with angiosarcoma who had received treatment between 2012 and 2022. The patients’ parents gave consent to the use of their child's data, including photographs, for research purposes and in publications. Data on the patients’ age, gender, tumor location and extension, performed treatment and outcomes of the disease were analyzed. The male:female ratio was 0.66:1 and the median age was 5.2 years. Tumors were located in the soft tissues (n = 3) and in the bones (n = 2). In all the cases, invasion of the surrounding tissues was observed. There were no distant metastases at the time of diagnosis. Two (40%) patients underwent primary resection (R1) and 3 (60%) patients had tumor biopsy. Four patients received therapy according to the German guidelines for the treatment of angiosarcoma (VDC/paclitaxel courses), and 1 patient received treatment according to the guidelines for the management of non-rhabdomyosarcoma soft-tissue sarcomas (courses with vincristine, ifosfamide, doxorubicin/ vincristine, ifosfamide, actinomycin D). Objective response to treatment was achieved in 3 (60%) cases. Local control treatment of these 3 patients consisted of radiation therapy with a total dose of 50.4 Gy after R1 resection in 2 cases and biopsy in 1 case. After a median follow-up of 32 months, 2 patients who had received VDC/paclitaxel were alive without events (with complete and partial response), 3 patients died of progressive disease. Our data confirm the aggressive behavior of angiosarcoma in children. Protocol therapy that includes multiagent chemotherapy based on paclitaxel and doxorubicin along with local control treatment makes it possible to achieve a long-term control of the disease in some patients. However, further research on molecular and genetic characteristics of angiosarcoma is required to find potential novel targets for molecular targeted therapy. Further studies investigating the effectiveness of checkpoint inhibitors in angiosarcoma are also needed.

Radiotherapy and long-term sequelae in pediatric patients with parameningeal rhabdomyosarcoma: Results of two Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

Parameningeal location of rhabdomyosarcoma (PM RMS) is known to be an unfavorable prognostic factor. Scarce data are available on radiotherapy (RT) concepts with regard to outcome. Treatment and outcome of 395 children with PM RMS registered within two Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry (1995-2021) were evaluated. Patients were IRS group II (n=15) and III (n=380) and received systemic treatment according to the enrolled protocols: I2VA (n=172), VAIA/CEVAIE (n=223). Delayed resection was performed in 88/395 (22%) patients, and RT was additionally given in 79/88 (90%) resected patients. RT was the predominant local treatment in 355/395 (90%) patients: hyperfractionated accelerated photon (HART; n=77), conventionally fractionated photon (n=91) or proton beam (n=126), brachytherapy (n=4), heavy ions (n=1), not available (n=56). In the subgroup of RT as only local treatment (n=278), no intracranial tumor extension and complete remission at end of treatment were significant positive prognostic factors. No significant difference on tumor outcome was seen between different radiotherapy concepts. Long-term toxicity with mostly endocrinological and visual deficiencies was reported in 161/279 (58%) surviving patients with a lower trend after proton beam RT (48%) when compared to HART or conventionally fractionated photon RT (71% and 72%, respectively). Ten-year event-free and overall survival in the overall group were 62% (±5, 95% confidence interval [CI]) and 67% (±5, 95% CI); in the RT-only group 67% (±6, 95% CI) and 71% (±6, 95% CI), respectively. CWS data confirm the recent RT concept in PM RMS. Long-term sequelae as endocrinological and visual deficiencies need to be addressed.

Significance of fusion status, Oberlin risk factors, local and maintenance treatment in pediatric and adolescent patients with metastatic rhabdomyosarcoma: Data of the European Soft Tissue Sarcoma Registry SoTiSaR.

Outcome of primary metastatic rhabdomyosarcoma (RMS) is poor. Certain risk factors as fusion status, Oberlin score, and local treatment of primary tumor are known to influence prognosis. Patients with metastatic RMS were treated according to Cooperative Weichteilsarkom Studiengruppe (CWS) guidance with chemotherapy (CHT), radiotherapy (RT) excluding total lung irradiation (TLI), complete resection of the primary tumor, and metastasectomy if possible. Kaplan-Meier estimators and Cox proportional hazard models were used to examine event-free survival (EFS) and overall survival (OS) involving also landmark analyses. In the European Soft Tissue Sarcoma Registry SoTiSaR (2009-2018), 211 patients were analyzed. Many patients had fusion-positive alveolar RMS (n=83; 39%). Median age was 9.4years [0.1-19.7years]. Treatment primarily consisted of CHT with CEVAIE (carboplatin, epirubicine, vincristine, actinomycin-D, ifosfamide, etoposide: 86%, other regimens: 14%), RT (71%), resection of primary tumor (37%), metastasectomy (19%), and lymph node sampling/dissection (21%). Maintenance treatment (MT) (oral trofosfamide, idarubicin, etoposide) was added in 74% of patients. Oberlin factors, fusion status, and MT were predictive for EFS and OS. MT with O-TIE was not improving outcome when adjusting for the immortal time bias. Local treatment of the primary tumor and radical irradiation (except TLI) improved EFS, not OS, when adjusting for the Oberlin score. Patients with fusion-negative alveolar RMS (n=9) had an excellent outcome with a 5-year EFS and OS of 100%, compared to patients with embryonal RMS (49%/62%), PAX7- (22%/47%) and PAX3/FOXO1-positive ARMS (10/13%), respectively (p<.001). Prognosis of metastatic RMS primarily depends on fusion status and Oberlin score. Fusion status needs to be considered in future trials to optimize treatment outcome. The role of radical irradiation needs further investigation.

Second-line treatment of pediatric patients with relapsed rhabdomyosarcoma adapted to initial risk stratification: Data of the European Soft Tissue Sarcoma Registry (SoTiSaR).

Outcome of relapsed disease of localized rhabdomyosarcoma remains poor. An individual treatment approach considering the initial systemic treatment and risk group was included in the Cooperative Weichteilsarkom Studiengruppe (CWS) Guidance. Second-line chemotherapy (sCHT) ACCTTIVE based on anthracyclines (adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, etoposide) was recommended for patients with initial low- (LR), standard- (SR), and high-risk (HR) group after initial treatment without anthracyclines. TECC (topotecan, etoposide, carboplatin, cyclophosphamide) was recommended after initial anthracycline-based regimen in the very high-risk (VHR) group. Data of patients with relapse (n=68) registered in the European Soft Tissue Sarcoma Registry SoTiSaR (2009-2018) were retrospectively analyzed. Patients of initial LR (n=2), SR (n=16), HR (n=41), and VHR (n=9) group relapsed. sCHT consisted of ACCTTIVE (n=36), TECC (n=12), or other (n=15). Resection was performed in 40/68 (59%) patients and/or radiotherapy in 47/68 (69%). Initial risk stratification, pattern/time to relapse, and achievement of second complete remission were significant prognostic factors. Microscopically incomplete resection with additional radiotherapy was not inferior to microscopically complete resection (p=.17). The 5-year event-free survival (EFS) and overall survival (OS) were 26% (±12%) and 31% (±14%). The 5-year OS of patients with relapse of SR, HR, and VHR groups was 80% (±21%), 20% (±16%), and 13% (±23%, p=.008), respectively. Adapted systemic treatment of relapsed disease considering the initial risk group and initial treatment is reasonable. New treatment options are needed for patients of initial HR and VHR groups.

Pediatric Patients with Stage IV Rhabdomyosarcoma Significantly Benefit from Long-Term Maintenance Therapy: Results of the CWS-IV 2002 and the CWS DOK IV 2004-Trials

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma (STS) in childhood. Whereas more than 90% of patients with localized low-risk RMS can be cured, metastatic RMS have a dismal outcome, with survival rates of less than 30%. The HD CWS-96 trial showed an improved outcome for patients receiving maintenance therapy after completing intensive chemotherapy. Consequently, the international clinical trials CWS-IV 2002 and CWS DOK IV 2004 on metastatic disease of STS of the Cooperative Weichteilsarkom Studiengruppe (CWS) were designed in addition to the CWS-2002P trial for localized RMS disease. All patients received a multimodal intensive treatment regimen. To maintain remission, three options were compared: long-term maintenance therapy (LTMT) versus allogeneic hematopoietic stem cell transplantation (alloHSCT) versus high-dose chemotherapy (HDCT). A total of 176 pediatric patients with a histologically confirmed diagnosis of metastatic RMS or RMS-like tumor were included. A total of 89 patients receiving LTML showed a significantly better outcome, with an event-free survival (EFS) of 41% and an overall survival (OS) of 53%, than alloHSCT (n = 21, EFS 19%, p = 0.02, OS 24%, p = 0.002). The outcome of LTML was slightly improved compared to HDCT (n = 13, EFS 35%, OS 34%). In conclusion, our data suggest that in patients suffering from metastatic RMS, long-term maintenance therapy is a superior strategy in terms of EFS and OS compared to alloHSCT. EFS and OS of HDCT are similar in these strategies; however, the therapeutic burden of LTMT is much lower.

Imaging in rhabdomyosarcoma: a patient journey

Rhabdomyosarcoma, although rare, is the most frequent soft tissue sarcoma in children and adolescents. It can present as a mass at nearly any site in the body, with most common presentations in the head and neck, genitourinary tract and extremities. The optimal diagnostic approach and management of rhabdomyosarcoma require a multidisciplinary team with multimodal treatment, including chemotherapy and local therapy. Survival has improved over the last decades; however, further improvement in management is essential with current 5-year overall survival ranging from 35% to 100%, depending on disease and patient characteristics. In the full patient journey, from diagnosis, staging, management to follow-up after therapy, the paediatric radiologist and nuclear physician are essential members of the multidisciplinary team. Recently, guidelines of the European paediatric Soft tissue sarcoma Study Group, the Cooperative Weichteilsarkom Studiengruppe and the Oncology Task Force of the European Society of Paediatric Radiology (ESPR), in an ongoing collaboration with the International Soft-Tissue Sarcoma Database Consortium, provided guidance for high-quality imaging. In this educational paper, given as a lecture during the 2022 postgraduate ESPR course, the multi-disciplinary team of our national paediatric oncology centre presents the journey of two patients with rhabdomyosarcoma and discusses the impact on and considerations for the clinical (paediatric) radiologist and nuclear physician. The key learning points of the guidelines and their implementation in clinical practice are highlighted and up-to-date insights provided for all aspects from clinical suspicion of rhabdomyosarcoma and its differential diagnosis, to biopsy, staging, risk stratification, treatment response assessment and follow-up.

The significance of margins in pediatric Non-Rhabdomyosarcoma soft tissue sarcomas: Consensus on surgical margin definition harmonization from the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT).

Margin status following surgery in children, adolescents, and young adults with soft tissue sarcomas is controversial and has been defined differently by various specialties, with definitions changing over time and by cooperative group. The International Soft Tissue Sarcoma Consortium (INSTRuCT) is a collaboration of the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee, European pediatric Soft Tissue sarcoma Study Group (EpSSG), and the European Cooperative Weichteilsarkom Studiengruppe (CWS) devoted to improving patient outcomes by pooling and mining cooperative group clinical trial data. The INSTRuCT non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) working group aimed to develop international harmonized recommendations regarding surgical margin assessment and definitions in children and adolescents with soft tissue tumors. This review addresses accepted principles and areas of controversy, including the perspectives of surgeons, pathologists, radiation oncologists, and pediatric oncologists, to develop a framework for building common guidelines for future research.

Local control of parameningeal rhabdomyosarcoma: An expert consensus guideline from the International Soft Tissue Sarcoma Consortium (INSTRuCT).

The International Soft Tissue Sarcoma Database Consortium (INSTRuCT) consists of a collaboration between the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee, the European pediatric Soft Tissue Sarcoma Study Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). As part of the larger initiative of INSTRuCT to provide consensus expert opinions for clinical treatment of pediatric soft tissue sarcoma, we sought to provide updated, evidenced-based consensus guidelines for local treatment of parameningeal rhabdomyosarcoma using both existing literature as well as recommendations from the relevant cooperative group clinical trials. Overall, parameningeal rhabdomyosarcoma represents a distinctly challenging disease to treat, given its location near many critical structures in the head and neck, frequently advanced local presentation, and predilection for local failure. Definitive chemoradiation remains the standard treatment approach for parameningeal rhabdomyosarcoma, with surgery often limited to biopsy or salvage therapy for recurrent disease. In this consensus paper, we specifically discuss consensus guidelines and evidence for definitive local management with radiotherapy, with a focus on imaging for radiotherapy planning, dose and timing of radiation, approach for nodal irradiation, various radiation techniques, including proton therapy, and the limited role of surgical resection.

Controversies and challenges in the management of paediatric non-rhabdomyosarcoma soft tissue sarcomas

Non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) is a heterogeneous group of mesenchymal tumours distinct from rhabdomyosarcoma that affects children and adolescents, with clinical presentation varying from relatively benign to highly malignant.1,2 To develop a consensus approach to NRSTS, the International Soft-Tissue Sarcoma Consortium (INSTRuCT)3 was founded by the leadership of three large cooperative groups—the Children's Oncology Group (COG), the Cooperative Weichteilsarkom Studiengruppe (CWS), and the European paediatric Soft tissue sarcoma Study Group (EpSSG)—to pool expertise and resources to improve knowledge of these tumours in children, adolescents, and young adults, and to improve patient outcomes.

Infantile myofibromatosis: Excellent prognosis but also rare fatal progressive disease. Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

Infantile myofibromatosis (IM) is a rare benign soft tissue tumor and often a self-limiting disease but rarely includes life-threatening complications. Little is known about optimal treatment of primary localized (LD) and multifocal disease (MFD). Treatment and outcome of 95 children with IM registered within five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry (1981-2016) were evaluated. LD was diagnosed in 71 patients at a median age of 0.4years (range 0.0-17.7). MFD was present in 24 patients. The mainstay of treatment was watch-and-wait strategy (w&w) after initial biopsy or resection. Low-dose chemotherapy (CHT) was administered to 16/71 (23%) patients with LD and eight of 24 (33%) patients with MFD, imatinib was added in two. A delayed resection was possible in eight of 71 (11%) and five of 24 (21%) patients with LD and MFD, respectively. Overall, patients were alive in complete remission (n=77) and partial remission (n=10) at a median follow-up time of 3.4years after diagnosis (range 0.01-19.4); no data available (n=5). Three patients died of progressive disease (PD) despite CHT. Gender, tumor size, and location correlated with a favorable event-free survival (EFS) in patients with LD. The 5-year EFS and overall survival of patients with LD were 73% (±12, confidence interval [CI] 95%) and 95% (±6, CI 95%), respectively; for MFD 51% (±22, CI 95%) and 95% (±10, CI 95%). Prognosis is excellent in patients with LD and MFD. Targeted treatment needs to be evaluated for rare fatal PD.

Semi-Automatic Volumetric and Standard Three-Dimensional Measurements for Primary Tumor Evaluation and Response to Treatment Assessment in Pediatric Rhabdomyosarcoma.

Current prognostic classification of rhabdomyosarcoma in children requires precise measurements of the tumor. The purpose of the study was to compare the standard three-dimensional (3D) measurements with semi-automatic tumor volume measurement method concerning assessment of the primary tumor size and the degree of response to treatment for rhabdomyosarcoma in children. Magnetic Resonance Imaging data on 31 children with treated rhabdomyosarcoma based on the Cooperative Weichteilsarkom Studiengruppe (CWS) guidance was evaluated. Tumor sizes were measured by two methods: 3D standard measurements and semi-automatic tumor volume measurement (VOI) at diagnosis, and after 9 and 17/18 weeks of the induction chemotherapy. Response to treatment and prediction values were assessed. The tumor volume medians calculated using VOI were significantly higher in comparison with those calculated using the 3D method both during the diagnosis as well as after 9 weeks of the chemotherapy and during the 17–18th week of the treatment. The volume measurements based on the generalized estimating equations on the VOI method were significantly better than the 3D method (p = 0.037). The volumetric measurements alone can hardly be considered an unequivocal marker used to make decisions on modification of the therapy in patients with rhabdomyosarcoma.

European guideline for imaging in paediatric and adolescent rhabdomyosarcoma \u2014 joint statement by the European Paediatric Soft Tissue Sarcoma Study Group, the Cooperative Weichteilsarkom Studiengruppe and the Oncology Task Force of the European Society of Paediatric Radiology

Appropriate imaging is essential in the treatment of children and adolescents with rhabdomyosarcoma. For adequate stratification and optimal individualised local treatment utilising surgery and radiotherapy, high-quality imaging is crucial. The paediatric radiologist, therefore, is an essential member of the multi-disciplinary team providing clinical care and research. This manuscript presents the European rhabdomyosarcoma imaging guideline, based on the recently developed guideline of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) Imaging Committee. This guideline was developed in collaboration between the EpSSG Imaging Committee, the Cooperative Weichteilsarkom Studiengruppe (CWS) Imaging Group, and the Oncology Task Force of the European Society of Paediatric Radiology (ESPR). MRI is recommended, at diagnosis and follow-up, for the evaluation of the primary tumour and its relationship to surrounding tissues, including assessment of neurovascular structures and loco-regional lymphadenopathy. Chest CT along with [F-18]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)/CT or PET/MRI are recommended for the detection and evaluation of loco-regional and distant metastatic disease. Guidance on the estimation of treatment response, optimal long-term follow-up, technical imaging settings and standardised reporting are described. This European imaging guideline outlines the recommendations for imaging in children and adolescents with rhabdomyosarcoma, with the aim to harmonise imaging and to advance patient care.

Extraskeletal Ewing sarcoma in children, adolescents, and young adults. An analysis of three prospective studies of the Cooperative Weichteilsarkomstudiengruppe (CWS).

We have analyzed the outcome of patients with localized extraskeletal Ewing sarcoma (EES) treated in three consecutive Cooperative Weichteilsarkomstudiengruppe (CWS) soft tissue sarcoma (STS) studies: CWS-91, CWS-96, and CWS-2002P. Patients were treated in CWS-91 with four- (vincristine, dactinomycin, doxorubicin, and ifosfamide [VAIA] or cyclophosphamide [VACA II]) or five-drug (+etoposide [EVAIA]) cycles, in CWS-96 they were randomly assigned to receive VAIA or CEVAIE (+carboplatin and etoposide), and in CWS-2002P with VAIA III plus optional maintenance therapy (MT) with cyclophosphamide and vinblastine. Local therapy consisted of resection and/or radiotherapy (RT). Two hundred forty-three patients fulfilled the eligibility criteria. The 5-year event-free survival (EFS) and overall survival (OS) were 63% (95% confidence interval [CI] 57-69) and 73% (95% CI 67-79), respectively. The 5-year EFS by study was 64% (95% CI 54-74) in CWS-91, 57% (95% CI 48-66) in CWS-96, and 79% (95% CI 67-91) in CWS-2002P (n.s.). The 5-year OS was 72% (95% CI 62-82) in CWS-91, 70% (95% CI 61-79) in CWS-96, and 86% (95% CI 76-96) in CWS-2002P (n.s.). In CWS-96, 5-year EFS and OS in the VAIA arm versus the CEVAIE were 65% (95% CI 52-81) versus 55% (95% CI 39-76) log-rank p=.13, and 85% (95% CI 75-96) versus 61% (95% CI 45-82), log-rank p=.09. Our analysis provides interesting information on the treatment and specificities of EES, which can be useful for a better understanding of this rare entity and should be considered in the development of future clinical trials for Ewing sarcoma defined as FET-ETS fusion positive tumors.

Surgical management of paratesticular rhabdomyosarcoma: A consensus opinion from the Children's Oncology Group, European paediatric Soft tissue sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe.

The treatment of paratesticular rhabdomyosarcoma (PT-RMS) has varied over time and by cooperative group. The International Soft Tissue Sarcoma Database Consortium (INSTRuCT) is a collaboration of the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee, European pediatric Soft tissue sarcoma Study Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). The INSTRuCT surgical committee has been given charge of the development of internationally applicable consensus guidelines for the surgical treatment of rhabdomyosarcoma. This clinical consensus opinion document addresses accepted principles and areas of controversy, such as scrotal violation and retroperitoneal nodal evaluation, providing an evidence-based guideline for the surgical treatment for PT-RMS.

Infant malignant ectomesenchymoma masquerading as inguinal hernia in two patients

Infant malignant ectomesenchymoma masquerading as inguinal hernia in two patients

Pathology of childhood rhabdomyosarcoma: A consensus opinion document from the Children's Oncology Group, European Paediatric Soft Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe.

The diagnosis and classification of rhabdomyosarcoma (RMS) has undergone several shifts over the last 30years. While the main diagnostic categories remained the same, changes in the histologic criteria necessary for diagnosis, as well as varied reliance on immunohistochemical and molecular data over time, have created confusion, particularly regarding how these shifts impacted risk stratification and enrollment onto clinical trials. The goal of this report is to review the evolution and current status of RMS diagnosis, focusing on diagnostic criteria in the Children's Oncology Group (COG), the European Paediatric Soft Tissue Sarcoma Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). In addition, we emphasize research tools used to classify RMS and address biological questions within current clinical trials run by each group. The INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT) initiative will maximize potential to optimize risk stratification by recognizing and accounting for differences in historical data and current practices.

Introducing INSTRuCT: An international effort to promote cooperation and data sharing.

Pediatric oncology is justifiably proud of its long tradition of multi-institutional collaboration in clinical research. Perhaps no other field of medicine has more effectively shown what can be achieved by pooling talent and resources to study challenging diseases. Historically, most collaborative projects were limited to a single country or continent. However, more progress comes from even broader international cooperation. With rare cancers, this may be the only way to gather sufficient patient numbers to address key questions. Sharing national experiences can also lead to a deeper understanding of the advantages and risks associated with different therapeutic approaches. The first steps to increased global cooperation, however, is agreeing on a common language to describe patient cohorts and consensus standards to guide diagnosis, evaluation, and treatment. Applying these lofting goals to pediatric soft tissue sarcomas, the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT) was born.From its initial formative meeting in May 2017, INSTRuCT has patterned its structure and purpose on the successful model of the International Neuroblastoma Risk Group (INRG).1,2 The membership of INSTRuCT is composed of three large cooperative clinical trials organizations: Children’s Oncology Group (COG), Cooperative Weichteilsarkom Studiengruppe (CWS), and European paediatric Soft tissue sarcoma Study Group (EpSSG). The first goal for INSTRuCT is to develop an international risk stratification system for rhabdomyosarcoma (RMS) to replace competing systems used in Europe and North America. A common RMS risk stratification system would facilitate the comparison of clinical trial results across cooperative groups. Before generating a RMS risk stratification system, INSTRuCT agreed upon a standard RMS data dictionary, leveraging the University of Chicago’s Pediatric Cancer Data Commons expertise in data standardization.3 The compilation of COG, CWS, and EpSSG data (and data from their legacy groups) from finished studies into a single INSTRuCT dataset is nearly complete, and will include more than 7000 patients enrolled on previous RMS clinical trials. Once the RMS risk stratification project is finished, INSTRuCT will mine its dataset for answers to questions that can only be addressed with large, well-annotated clinical data. Future work will also include expanding the RMS data dictionary and adding a non-RMS soft tissue sarcoma dataset, also drawn from COG, CWS, and EpSSG clinical trials.As the multi-disciplinary members of INSTRuCT were defining their RMS data dictionary, they realized they had the opportunity to develop international consensus statements on the diagnosis, evaluation, and management of pediatric soft tissue sarcomas. Clinical trial protocols include guidelines for pathologic diagnosis, imaging staging evaluation, and local control approaches with surgery and radiation therapy varied by primary anatomic site. INSTRuCT provided the forum for international discussion and consensus building, with the goal of publishing these expert opinions for broad dissemination and use by pediatric oncologists, surgeons, radiation oncologists, radiologists, and pathologists worldwide. In this issue of Pediatric Blood & Cancer, Morris et al. publish the one of first in a series of consensus statements from INSTRuCT, focusing on the surgical management in the diagnosis and local control of RMS arising in the extremity.4 Morris et al. outline recommended biopsy approaches, the rational for routine use of regional lymph node evaluation including the role of fluorodeoxyglucose positron emission tomography, and the decision-making behind up-front versus delayed primary excision. The recommendations are guided by the principles of maximizing oncologic outcome while maintaining extremity function. Given the rarity of extremity RMS and the absence of randomized trials comparing different management strategies, Morris et al. draw upon a combination of clinical data and expert opinion in their consensus guidelines, carefully documenting the level of evidence that supports each of their recommendations. Nonetheless, these guidelines represent the current state of the art for surgical management of extremity RMS and the basis for future clinical trial recommendations. A similar consensus statement on RMS of the female genital tract has also been published in Pediatric Blood & Cancer, by Lautz et al.5 With these two consensus statements, the INSTRuCTPediatric Blood & Cancer special series is off to an excellent start, with manuscripts on the surgical management for other primary sites and the pathologic evaluation of RMS to follow soon. As INSTRuCT co-chairs, we are pleased to introduce INSTRuCT to the global pediatric oncology community and look forward to many more contributions to come.

Malignant peripheral nerve sheath tumors in children, adolescents, and young adults: Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that present as large, invasive tumors. Our aim was to assess outcomes, identify prognostic factors, and analyze treatment strategies in a prospectively collected pediatric cohort. Patients less than 21 years with MPNST treated in the consecutive prospective European Cooperative Weichteilsarkom Studiengruppe (CWS)-trials (1981-2009) and the CWS-SoTiSaR registry (2009-2015) were analyzed. A total of 159 patients were analyzed. Neurofibromatosis type I (NF1) was reported in thirty-eight patients (24%). Most were adolescents (67%) with large (>10 cm, 65%) tumors located at extremities (42%). Nodal involvement was documented in 15 (9%) and distant metastases in 15 (9%) upon diagnosis. Overall, event-free survival (EFS) was 40.5% at 5 and 36.3% at 10 years, and overall survival (OS) was 54.6% at 5 and 47.1% at 10 years. Age, NF1 status, tumor site, tumor size, Intergroup Rhabdomyosarcoma Study (IRS) group, metastatic disease, and achieving first complete remission (CR1) were identified as prognostic factors for EFS and/or OS in the univariate analysis. Prognostic factors were identified and research questions for future clinical trials were addressed.

Surgical management of extremity rhabdomyosarcoma: A consensus opinion from the Children's Oncology Group, the European Pediatric Soft-Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe.

The treatment of extremity rhabdomyosarcoma remains a challenge due to several adverse prognostic factors frequently associated with this tumor site. The International Soft-Tissue Sarcoma Database Consortium (INSTRuCT) is a collaboration of the Children's Oncology Group Soft-Tissue Sarcoma Committee, the European Pediatric Soft-Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe. The INSTRuCT surgical committee developed an internationally applicable consensus opinion document for the surgical treatment of extremity rhabdomyosarcoma. This document addresses surgical management, including biopsy, nodal staging, timing of therapy, resection and reexcision, reconstruction, and surgical approach at relapse.