Search

Purpose: To describe clinical features, risk factors, and outcomes of patients with perineal and perianal rhabdomyosarcoma., Methods: The records of 51 patients (38 perineal and 13 perianal) enrolled on Children's Oncology Group clinical trials between 1997 and 2012 were reviewed., Results: At presentation, 53% were female, 65% were older than 10 years of age, 76% were alveolar histology, 76% were more than 5 cm, 84% were invasive, 65% were regional node positive by imaging, 49% were metastatic, only 16% were grossly resected upfront, and 25% of patients had a delayed excision. At a median follow-up of 6.13 years, estimated 5-year event-free survival (EFS) was 38% [22.17%-53.38%], and overall survival (OS) was 42% [26.66%-58.21%]. The rates of local, regional, and distant failure were 15.6%, 13.7%, 43.1%, respectively; all failures ultimately died. By univariate analysis, only age more than 10 years negatively impacted 5-year EFS (p = .023) and OS (p = .09), and IRS Group also impacted OS (p = .043). In Cox proportional hazards model, neither of these variables were significant after adjusting for other factors., Conclusion: Patients with perineal and perianal rhabdomyosarcoma have a poor overall prognosis, probably related to poor patient and disease characteristics at presentation., (© 2024 Wiley Periodicals LLC.)

Background: Treatment strategies for paratesticular rhabdomyosarcoma (PT RMS) are based on stage, which requires accurate lymph node (LN) evaluation. Previous methodology for determining quantity of LN for negative nodal status is based on LN positivity rates, without accounting for the relationship between LNs or amongst patients. This study aims to quantify the chance of missing involved LNs based on LN yield (LNY) using a previously established methodology in comparison to current recommendations., Methods: Using the National Cancer Database, patients with a diagnosis of PT RMS were queried from 2004 to 2018. Patients >10 years and those ≤10 years with cN1 disease were included, based on COG guidelines for who should undergo retroperitoneal LN sampling (RPLNS). The beta-binomial model was used to calculate the rate of false negative RPLNS and identified the LNY threshold to reduce the risk of a missing an involved LN node to <10 %., Results: Sixty-two patients were included for analysis over the study period. Median LNY was 17 (IQR 9-28.75), and the median number of involved LNs was 2.5 (IQR 2-5). The median LN density was 0.27 (IQR 0.10-0.34). Application of the beta-binomial model identified that a LNY of 26 LNs corresponds to a <10 % chance of missing occult disease (Fig. 3)., Conclusion: Previous models estimate that sampling of 7-12 LN is adequate for accurate staging. However, the beta binomial model quantifies sampling at least 26 LNs to reduce the chance of missing occult metastatic disease to <10 % in the majority of patients. Surgeons should consider this false negative rate during RPLNS for patients with PT RMS., Level of Evidence: III., Competing Interests: Declaration of competing interest None of the authors of this manuscript have any financial or personal relationships to disclose that could inappropriately influence or bias our work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: The authors report no conflicts of interest.

Although survival for many pediatric cancers has improved with advances in conventional chemotherapeutic regimens and surgical techniques in the last several decades, it remains a leading cause of disease-related death in children. Outcomes in patients with recurrent, refractory, or metastatic disease are especially poor. Recently, the advent of alternative classes of therapies, including immunotherapies, have revolutionized systemic treatment for pediatric malignancies. Several classes of immunotherapies, including chimeric antigen receptor (CAR) T cell therapy, transgenic T-cell receptor (TCR)-T cell therapy, bispecific T-cell engagers, and monoclonal antibody checkpoint inhibitors have been FDA-approved or entered early-phase clinical trials in children and young adults. The pediatric surgeon is likely to encounter these therapies during the care of children with malignancies and should be familiar with the classes of therapy, indications, adverse events, and potential need for surgical intervention in these cases. This review from the APSA Cancer Committee offers a brief discussion of the three most encountered classes of immunotherapy in children and young adults and discusses surgical relevance. LEVEL OF EVIDENCE: IV., Competing Interests: Conflict of interest The authors have no competing interests in this work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, requires multimodal therapy which is determined by risk group stratification. Local control may be achieved by surgical resection, radiation, or both. Resection may occur upfront or following induction chemotherapy as a delayed primary excision. An R1 resection may allow a reduction in radiation exposure; however, debulking is not indicated nor is excision of residual masses at the end of therapy. Regional lymph node assessment is an important component of surgical care, as positive nodal basins require radiation. Depending on the tumor site and biology, sentinel lymph node biopsy vs biopsy of clinically or radiographically concerning nodes is indicated. Therapeutic lymph node dissection is never indicated. Familiarity with site-specific oncologic principles for RMS and participation in a multidisciplinary team including Pediatric Oncology and Radiation Oncology are necessary components of surgical care to ensure optimal outcomes., (Copyright © 2023. Published by Elsevier Inc.)

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric and adolescent population, with 350 new cases diagnosed each year. While they can develop anywhere in the body, the genitourinary tract is the second most common primary location for an RMS to develop. Overall survival has improved through the increased use of protocols and multidisciplinary approaches. However, the guidelines for management continue to change as systemic and radiation therapeutics advance. Given the relative rarity of this disease compared to other non-solid childhood malignancies, healthcare providers not directly managing RMS may not be familiar with their presentation and updated management. This review aims to provide foundational knowledge of the management of RMSs with an emphasis on specific management paradigms for those arising from the genitourinary tract. The genitourinary tract is the second most common location for an RMS to develop but varies greatly in symptomology and survival depending on the organ of origin. As the clinical understanding of these tumors advances, treatment paradigms have evolved. Herein, we describe the breadth of presentations for genitourinary RMSs with diagnostic and treatment management considerations, incorporating the most recently available guidelines and societal consensus recommendations.

The International Soft-Tissue Sarcoma Consortium (INSTRuCT) was founded as an international collaboration between different pediatric soft-tissue sarcoma cooperative groups (Children's Oncology Group, European Pediatric Soft-Tissue Sarcoma Group, and Cooperative Weichteilsarkom Studiengruppe). Besides other tasks, a major goal of INSTRuCT is to develop consensus expert opinions for best clinical treatment. This consensus paper for patients with rhabdomyosarcoma of the female genital tract (FGU-RMS) provides treatment recommendations for local treatment, long-term follow-up, and fertility preservation. Therefore, a review of the current literature was combined with recommendations of the treatment protocols of the appropriate clinical trials. Additionally, opinions of international FGU-RMS experts were incorporated into recommendations. Results were that the prognosis of FGU-RMS is favorable with an excellent response to chemotherapy. Initial complete surgical resection is not indicated, but diagnosis should be established properly. In patients with tumors localized at the vagina or cervix demonstrating incomplete response after induction chemotherapy, local radiotherapy (brachytherapy) should be carried out. In patients with persistent tumors at the corpus uteri, hysterectomy should be performed. Fertility preservation should be considered in all patients. In conclusion, for the first time, an international consensus for the treatment of FGU-RMS patients could be achieved, which will help to harmonize the treatment of these patients in different study groups., (© 2020 Wiley Periodicals LLC.)

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., (© 2020 Wiley Periodicals LLC.)

In this article, we will discuss the genesis, evolution, and progress of the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT), which aims to foster international research and collaboration focused on pediatric soft tissue sarcoma. We will begin by highlighting the current state of clinical research for pediatric soft tissue sarcomas, including rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma. We will then explore challenges and research priorities, describe the development of INSTRuCT, and discuss how the consortium aims to address key research priorities., (© 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Pediatric cancer patients have improved outcomes over the past several decades leading to a greater number of survivors living well into adulthood. Owing to their increased longevity, adult care providers are encountering childhood cancer survivors with greater frequency in their clinics and hospitals. Childhood cancer treatments are associated with varied and significant systemic complications that either persist or develop well into adulthood, including secondary malignancies, cardiomyopathies, and adhesive disease that can complicate even the simplest operation. This article reviews four of the most common solid abdominal tumors in the pediatric population and the long-term sequelae of their respective treatment regimens., Competing Interests: Disclosure J.T. Castle is funded by the NIH Training Grant T32CA160003., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The Children's Oncology Group (COG) uses Clinical Group (CG) and modified Tumor Node Metastasis (TNM) stage to classify rhabdomyosarcoma (RMS). CG is based on surgicopathologic findings and is determined after the completion of initial surgical procedure(s) but prior to chemotherapy and/or radiation therapy. The modified TNM stage is based on clinical and radiographic findings and is assigned prior to any treatment. These systems have evolved over several decades. We review the history, evolution, and rationale behind the current CG and modified TNM classification systems used by COG for RMS. Data from the seven most recently completed and reported frontline COG trials (D9602, D9802, D9803, ARST0331, ARST0431, ARST0531, ARST08P1) were analyzed, and confirm that CG and modified TNM stage remain relevant and useful for predicting prognosis in RMS. We propose updates based on recent data and discuss factors warranting future study to further optimize these classification systems., (© 2022 Wiley Periodicals LLC.)

Background: Testicular germ cell tumors are uncommon tumors that are encountered by pediatric surgeons and urologists and require a knowledge of appropriate contemporary evaluation and surgical and medical management., Method: A review of the recommended diagnostic evaluation and current surgical and medical management of children and adolescents with testicular germ cell tumors based upon recently completed clinical trials was performed and summarized in this article., Results: In this summary of childhood and adolescent testicular germ cell tumors, we review the initial clinical evaluation, surgical and medical management, risk stratification, results from recent prospective cooperative group studies, and clinical outcomes. A summary of recently completed clinical trials by pediatric oncology cooperative groups is provided, and best surgical practices are discussed., Conclusions: Testicular germ cell tumors in children are rare tumors. International collaborations, data-sharing, and enrollment of patients at all stages and risk classifications into active clinical trials will enhance our knowledge of these rare tumors and most importantly improve outcomes of patients with testicular germ cell tumors., Level of Evidence: This is a review article of previously published and referenced level 1 and 2 studies, but also includes expert opinion level 5, represented by the American Pediatric Surgical Association Cancer Committee., (Copyright © 2021. Published by Elsevier Inc.)

Children and adolescents with rhabdomyosarcoma (RMS) comprise a heterogeneous population with variable overall survival rates ranging between approximately 6% and 100% depending on defined risk factors. Although the risk stratification of patients has been refined across five decades of collaborative group studies, molecular prognostic biomarkers beyond FOXO1 fusion status have yet to be incorporated prospectively in upfront risk-based therapy assignments. This review describes the evolution of risk-based therapy and the current risk stratification, defines a new risk stratification incorporating novel biomarkers, and provides the rationale for the current and upcoming Children's Oncology Group RMS studies., (© 2022 Wiley Periodicals LLC.)

Background/purpose: Cancer predisposition syndromes (CPS) are a heterogeneous group of inherited disorders that greatly increase the risk of developing malignancies. CPS are particularly relevant to pediatric surgeons since nearly 10% of cancer diagnoses are due to inherited genetic traits, and CPS often contribute to cancer development during childhood., Materials/methods: The English language literature was searched for manuscripts, practice guidelines, and society statements on "cancer predisposition syndromes in children". Following review of these manuscripts and cross-referencing of their bibliographies, tables were created to summarize findings of the most common CPS associated with surgically treated pediatric solid malignancies., Results: Pediatric surgeons should be aware of CPS as the identification of one of these syndromes can completely change the management of certain tumors, such as WT. The most common CPS associated with pediatric solid malignancies are outlined, with an emphasis on those most often encountered by pediatric surgeons: neuroblastoma, Wilms' tumor, hepatoblastoma, and medullary thyroid cancer. Frequently associated non-tumor manifestations of these CPS are also included as a guide to increase surgeon awareness. Screening and management guidelines are outlined, and published genetic testing and counseling guidelines are included where available., Conclusion: Pediatric surgeons play an important role as surgical oncologists and are often the first point of contact for children with solid tumors. In their role of delivering a diagnosis and developing a follow-up and treatment plan as part of a multidisciplinary team, familiarity with common CPS will ensure evidence-based practices are followed, including important principles such as organ preservation and intensified surveillance plans. This review defines and summarizes the CPS associated with common childhood solid tumors encountered by the pediatric surgeon, as well as common non-cancerous disease stigmata that may help guide diagnosis., Type of Study: Summary paper., Level of Evidence: 5., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: The ARST0332 trial for pediatric and young adults with nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) used risk-based treatment including primary resection with lower-than-standard radiation doses to optimize local control (LC) while minimizing long-term toxicity in those requiring radiation therapy (RT). RT for high-grade NRSTS was based on extent of resection (R0: negative margins, R1: microscopic margins, R2/U: gross disease/unresectable); those with >5 cm tumors received chemotherapy (CT; ifosfamide/doxorubicin). This analysis evaluates LC for patients assigned to RT and prognostic factors associated with local recurrence (LR)., Methods and Materials: Patients aged <30 years with high-grade NRSTS received RT (55.8 Gy) for R1 ≤5 cm tumor (arm B); RT (55.8 Gy)/CT for R0/R1 >5 cm tumor (arm C); or neoadjuvant RT (45 Gy)/CT plus delayed surgery, CT, and postoperative boost to 10.8 Gy R0 <5 mm margins/R1 or 19.8 Gy for R2/unresected tumors (arm D)., Results: One hundred ninety-three eligible patients had 24 LRs (arm B 1/15 [6.7%], arm C 7/65 [10.8%], arm D 16/113 [14.2%]) at median time to LR of 1.1 years (range, 0.11-5.27). Of 95 eligible for delayed surgery after neoadjuvant therapy, 89 (93.7%) achieved R0/R1 margins. Overall LC after RT were as follows: R0, 106 of 109 (97%); R1, 51 of 60 (85%); and R2/unresectable, 2 of 6 (33%). LR predictors include extent of delayed resection (P <.001), imaging response before delayed surgery (P < .001), histologic subtype (P <.001), and no RT (P = .046). The 5-year event-free survival was significantly lower (P = .0003) for patients unable to undergo R0/R1 resection., Conclusions: Risk-based treatment for young patients with high-grade NRSTS treated on ARST0332 produced very high LC, particularly after R0 resection (97%), despite lower-than-standard RT doses. Neoadjuvant CT/RT enabled delayed R0/R1 resection in most patients and is preferred over adjuvant therapy due to the lower RT dose delivered., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., (© 2021 Wiley Periodicals LLC.)

Pediatric nonrhabdomyosarcoma soft tissue sarcomas (NRSTSs) encompass a heterogeneous group of mesenchymal tumors with more than 50 histologic variants. The incidence of NRSTS is greater than rhabdomyosarcoma; however, each histologic type is rare. The treatment schema for all NRSTSs is largely surgical. The treatment is a risk-adapted approach based on tumor size, localization, tumor grade, and presence of metastases. Low-grade tumors are mainly managed by surgery alone, whereas for high-grade tumors a multimodal treatment concept is necessary. The multimodal treatment consists of tumor biopsy, chemotherapy, local treatment (surgery ± radiotherapy), and immunotherapy in selected conditions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Treatment of children and adolescents with alveolar rhabdomyosarcoma (ARMS) and regional nodal involvement (N1) have been approached differently by North American and European cooperative groups. In order to define a better therapeutic strategy, we analyzed two studies conducted between 2005 and 2016 by the European paediatric Soft tissue sarcoma Study Group (EpSSG) and Children's Oncology Group (COG)., Methods: We retrospectively identified patients with ARMS N1 enrolled in either EpSSG RMS2005 or in COG ARST0531. Chemotherapy in RMS2005 comprised ifosfamide + vincristine + dactinomycin + doxorubicin (IVADo), IVA and maintenance (vinorelbine, cyclophosphamide); in ARST0531, it consisted of either vincristine + dactinomycin + cyclophosphamide (VAC) or VAC alternating with vincristine + irinotecan (VI). Local treatment was similar in both protocols., Results: The analysis of the clinical characteristics of 239 patients showed some differences between study groups: in RMS2005, advanced Intergroup Rhabdomyosarcoma Study Group (IRS) and large tumors predominated. There were no differences in outcomes between the two groups: 5-year event-free survival (EFS), 49% (95% confidence interval [CI]: 39-59) and 44% (95% CI: 30-58), and overall survival (OS), 51% (95% CI: 41-61) and 53.6% (95% CI: 40-68) in RMS2005 and ARST0531, respectively. In RMS2005, EFS of patients with FOXO1-positive tumors was significantly inferior to those with FOXO1-negative (49.3% vs 73%, P = .034). In contrast, in ARST0531, EFS of patients with FOXO1-positive tumors was 45% compared with 43.8% for those with FOXO1-negative., Conclusions: The outcome of patients with ARMS N1 was similar in both protocols. However, patients with FOXO1 fusion-negative tumors enrolled in RMS2005 showed a significantly better outcome, suggesting that different strategies of chemotherapy may have an impact in the outcome of this subgroup of patients., (© 2020 Wiley Periodicals LLC.)

Background: Strategies to optimize management in rhabdomyosarcoma (RMS) include risk stratification to assign therapy aiming to minimize treatment morbidity yet improve outcomes. This analysis evaluated the relationship between complete metabolic response (CMR) as assessed by 18 F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET) imaging and event-free survival (EFS) in intermediate-risk (IR) and high-risk (HR) RMS patients., Methods: FDG-PET imaging characteristics, including assessment of CMR and maximum standard uptake values (SUVmax) of the primary tumor, were evaluated by central review. Institutional reports of SUVmax were used when SUVmax values could not be determined by central review. One hundred and thirty IR and 105 HR patients had FDG-PET scans submitted for central review or had SUVmax data available from institutional report at any time point. A Cox proportional hazards regression model was used to evaluate the relationship between these parameters and EFS., Results: SUVmax at study entry did not correlate with EFS for IR (p = 0.32) or HR (p = 0.86) patients. Compared to patients who did not achieve a CMR, EFS was not superior for IR patients who achieved a CMR at weeks 4 (p = 0.66) or 15 (p = 0.46), nor for HR patients who achieved CMR at week 6 (p = 0.75) or 19 (p = 0.28). Change in SUVmax at week 4 (p = 0.21) or 15 (p = 0.91) for IR patients or at week 6 (p = 0.75) or 19 (p = 0.61) for HR patients did not correlate with EFS., Conclusion: Based on these data, FDG-PET does not appear to predict EFS in IR or HR-RMS. It remains to be determined whether FDG-PET has a role in predicting survival outcomes in other RMS subpopulations., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background/purpose: Lymphadenopathy is a common complaint in children. Pediatric surgeons are often called upon to evaluate, treat, and/or biopsy enlarged lymph nodes. With many nonsurgical causes in the differential diagnosis, the surgeon plays the important role of providing reassurance and timely diagnosis while minimizing the pain and morbidity associated with surgical interventions in children. The purpose of this summary paper is to provide a management guide for surgeons working up children with lymphadenopathy., Materials/methods: The English language literature was searched for "lymphadenopathy in children". All manuscript types were considered for review, regardless of medical specialty, with emphasis placed on published guidelines, algorithms, and reviews. After thorough review of these manuscripts and cross-referencing of their bibliographies, the attached algorithm was developed, with emphasis on the role and timing of surgical intervention., Results: The APSA Cancer Committee developed the attached algorithm to fill a gap in the surgical literature. It outlines lymphadenopathy workup and treatment with emphasis on the role and timing of surgical intervention., Conclusion: This review defines and summarizes the common etiologies and presentations of lymphadenopathy in children, and offers a straightforward algorithm for evaluation of and treatment with an emphasis on malignancy risk and surgical management., Type of Study: Summary paper., Level of Evidence: Level V., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Most children with intermediate-risk rhabdomyosarcoma (RMS) have gross disease (group III) at the initiation of chemotherapy. Delayed primary excision (DPE) after induction chemotherapy allows for a reduction in adjuvant radiation dose, but with the risk of potential surgical morbidity. The objectives of this study were to compare outcomes in children with group III RMS who did and did not undergo DPE and to assess surgical morbidity., Methods: The study included 369 patients who had clinical group III RMS at sites amenable to DPE from intermediate-risk Children's Oncology Group studies D9803 (encouraged DPE) and ARST0531 (discouraged DPE)., Results: The primary tumor site was bladder/prostate (136 patients; 37%), extremity (97 patients; 26%), trunk (24 patients; 7%), retroperitoneum (91 patients; 25%), or intrathoracic/perineum/perianal (21 patients; 6%). In total, 112 patients (53.9%) underwent DPE in D9803, and 26 patients (16.2%) underwent DPE in ARST0531 (P < .001), with loss of vital organ or function in 30 of 138 patients (22%). DPE allowed for a reduced radiation dose in 110 of 135 patients (81%; 51% were reduced to 36 Gy, and 30% were reduced to 42 Gy). Patients who underwent DPE had improved unadjusted overall survival (P = .013). In adjusted regression analysis, the risk of death (hazard ratio, 0.71; 95% CI 0.43-1.16) was similar for patients who did and did not undergo DPE and was improved for the subset of patients who had tumors of the trunk and retroperitoneum (hazard ratio, 0.44; 95% CI, 0.20-0.97)., Conclusions: Children with group III RMS have equivalent or improved outcomes with DPE and can receive a decreased radiation dose for definitive local control. The choice of local control modality should weigh the potential morbidity of surgery versus that of higher dose irradiation., (© 2020 American Cancer Society.)

Paratesticular rhabdomyosarcoma (PT-RMS) carries a favorable prognosis, but questions persist regarding optimal management. Our goal was to determine the importance of primary tumor resection and surgical assessment of retroperitoneal lymph nodes during staging in patients with PT-RMS. We analyzed patients with localized PT-RMS enrolled onto one of four Children's Oncology Group studies (D9602, ARST0331, D9803 or ARST0531). Surgical resection of the primary tumor prior to chemotherapy and radiotherapy was encouraged when possible with retroperitoneal lymph node dissection (RPLND) recommended for patients ≥10 years of age. Among 279 patients (median 8.1 years old), most tumors were resected with negative margins (78.5%) and most patients did not have radiographic enlargement of regional lymph nodes (90.3%). In patients older than 10 years, imaging alone will miss over 51.5% of nodal disease. Five-year event-free survival (EFS) was 92.0% (95% CI 88.4%-95.6%). Sampling ≥7 to 12 retroperitoneal lymph nodes appeared optimal for detecting positive nodes; while there was a trend toward improved EFS among those undergoing template RPLND, this was not statistically significant (P = .068). Age (P = .28), N-stage (P = .39), T-stage (P = .11) and pathologic node involvement (P = .53) were not associated with overall survival. However, older age and larger tumor size had an additive impact on EFS (P = .027) though not overall survival (P = .13). In conclusion, outcomes for patients with PT-RMS are excellent. Reliance on imaging to detect nodal involvement will miss pathologic node involvement and may result in undertreatment. Surgical nodal staging requires at least 7 to 12 nodes to accurately identify patients with regional nodal disease., (© 2020 UICC.)

Background: Minimally invasive surgery has broad applicability to pediatric diseases, including pediatric cancer resection. Neuroblastic tumors of childhood are highly variable in presentation, and so careful selection of appropriate candidates for minimally invasive resection is paramount to achieving safe and durable surgical and oncological outcomes., Methods: The American Pediatric Surgical Association Cancer Committee developed questions seeking to better define the role of minimally invasive surgery for neuroblastic tumors. A search using PubMed, Medline, Embase, Web of Science, ProQuest Dissertations, and Clinical Trials was performed for articles published from 1998 to 2018 in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines., Results: The evidence identified is all retrospective in nature. Minimally invasive surgical resection of neuroblastic tumors is safe for carefully selected smaller (4-6 cm) image defined risk factor (IDRF)-negative abdominal tumors when oncologic principles are followed. Size is a less-well defined criterion for thoracic neuroblastic tumors. Open approaches for both abdominal and thoracic tumors may be preferable in the presence of IDRF's., Conclusion: Small tumors without IDRF's are reasonable candidates for minimally invasive resection. Surgical oncologic guidelines should be closely followed. The quality of data supporting this systematic review is poor and highlights the need for refinement in the study of such surgical techniques to improve knowledge and outcomes for patients with neuroblastic tumors., Type of Study: Systematic Review., Level of Evidence: Level III and Level IV., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background/purpose: Rhabdomyosarcoma is the most common soft tissue sarcoma in children and young adults and requires multimodality treatment. The purpose of this review is to present an update on risk stratification as well as surgical and medical management strategies in pediatric rhabdomyosarcoma., Methods: A comprehensive review of the current literature on pediatric rhabdomyosarcoma, including the most recent Children's Oncology Group studies and several international collaboratives, was performed by the authors and key findings were summarized in the manuscript., Results: FOXO1 fusion status is a stronger prognostic factor than histology and is now used for risk stratification in treatment protocols. For assessment of regional nodal involvement, FDG-PET-CT shows poor sensitivity and specificity to detect histologically confirmed nodal metastasis. Thus, surgical assessment of regional lymph nodes is required for rhabdomyosarcoma of the extremities or trunk as well as paratesticular rhabdomyosarcoma in patients ≥10 years of age, although adherence to surgical guidelines remains poor. Hemiscrotectomy performed for scrotal violation in paratesticular rhabdomyosarcoma has not shown an improvement in event free survival and is not recommended., Conclusions: Surgical and medical treatment strategies for rhabdomyosarcoma in children continue to evolve. This review provides current evidence-based treatment standards with an emphasis on surgical care., Type of Study: Review., Level of Evidence: Level IV., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Although most children with cancer can be cured of their disease, a subset of patients with adverse tumor types or biological features, and those with relapsed or refractory disease have significantly worse prognosis. Furthermore, current cytotoxic therapy is associated with significant late effects. Precision oncology, using molecular therapeutics targeted against unique genetic features of the patient's tumor, offers the potential to transform the multimodal therapy for these patients. Potentiated by advances in sequencing technology and molecular therapeutic development, and accelerated by large-scale multi-institutional basket trials, the field of pediatric precision oncology has entered the mainstream. These novel therapeutics have important implications for surgical decision making, as well as pre- and postoperative care. This review summarizes the current state of precision medicine in pediatric oncology including the active North American and European precision oncology clinical trials. LEVEL OF EVIDENCE: Treatment study Level V., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A subset of patients with initially unresected (Clinical Group III) rhabdomyosarcoma achieve less than a complete response (CR) despite multimodal therapy. We assessed outcome based upon tumor response at the completion of all planned therapy. We studied 601 Clinical Group III participants who completed all protocol therapy without developing progressive disease on two Children's Oncology Group studies ARST0531 (n = 285) and D9803 (n = 316). Response was defined by imaging and categorized by response; complete resolution (CR), partial response (PR) or no response (NR). Failure-free survival (FFS) and overall survival (OS) between response groups were compared using the log-rank test. We found that radiographic response was CR in 393 (65.4%) and PR/NR in 208 (34.6%) patients. Achieving CR status was associated with study D9803, nonparameningeal (PM) primary sites, tumors ≤5 cm, noninvasive tumors and alveolar histology/FOXO fusion-positive tumors. The overall 5-year FFS was 75% for those achieving CR and 66.5% in those with PR/NR (adj. p = 0.094). Patients with PM primary site who achieved CR had significantly improved FFS (adj. p = 0.037) while those with non-PM primary sites had similar outcomes (adj. p = 0.47). Radiographic response was not associated with OS (adj. p = 0.21). Resection of the end-of-therapy mass did not improve FFS (p = 0.12) or OS (p = 0.37). In conclusion, CR status at the end of protocol therapy in patients with PM Clinical Group III RMS was associated with improved FFS but not OS. Efforts to understand the biology and treatment response in patients with PM primary site are under investigation., (© 2020 UICC.)

Purpose: The primary aim of this clinical trial was to prioritize bevacizumab or temsirolimus for additional investigation in rhabdomyosarcoma (RMS) when administered in combination with cytotoxic chemotherapy to patients with RMS in first relapse with unfavorable prognosis., Patients and Methods: Patients were randomly assigned to receive bevacizumab on day 1 or temsirolimus on days 1, 8, and 15 of each 21-day treatment cycle, together with vinorelbine on days 1 and 8, and cyclophosphamide on day 1 for a maximum of 12 cycles. Local tumor control with surgery and/or radiation therapy was permitted after 6 weeks of treatment. The primary end point was event-free survival (EFS). Radiographic response was assessed at 6 weeks. The study had a phase II selection that was design to detect a 15% difference between the two regimens (α = .2; 1-β = 0.8; two sided test)., Results: Eighty-seven of 100 planned patients were enrolled when the trial was closed after the second interim analysis after 46 events occurred in 68 patients with sufficient follow-up. The O'Brien Fleming boundary at this analysis corresponded to a two-sided P value of .058 with an observed two-sided P value of .003 favoring temsirolimus. The 6-month EFS for the bevacizumab arm was 54.6% (95% CI, 39.8% to 69.3%) and 69.1% (95% CI, 55.1% to 83%) for the temsirolimus arm. Objective response rates were 28% (95% CI, 13.7% to 41.3%) and 47% (95% CI, 31.5% to 63.2%) for the bevacizumab and temsirolimus arms, respectively ( P = .12) and, 28% of patients on bevacizumab and 11% on temsirolimus had progressive disease at 6 weeks., Conclusion: Patients who received temsirolimus had a superior EFS compared with bevacizumab. Temsirolimus has been selected for additional investigation in newly diagnosed patients with intermediate-risk RMS.

Background: Previous studies of the prognostic importance of FOXO1 fusion status in patients with rhabdomyosarcoma (RMS) have had conflicting results. We re-examined risk stratification by adding FOXO1 status to traditional clinical prognostic factors in children with localized or metastatic RMS., Methods: Data from six COG clinical trials (D9602, D9802, D9803, ARST0331, ARTS0431, ARST0531; two studies each for low-, intermediate- and high-risk patients) accruing previously untreated patients with RMS from 1997 to 2013 yielded 1727 evaluable patients. Survival tree regression for event-free survival (EFS) was conducted to recursively select prognostic factors for branching and split. Factors included were age, FOXO1, clinical group, histology, nodal status, number of metastatic sites, primary site, sex, tumor size, and presence of metastases in bone/bone marrow, soft tissue, effusions, lung, distant lymph nodes, and other sites. Definition and outcome of the proposed risk groups were compared to existing systems and cross-validated results., Results: The 5-year EFS and overall survival (OS) for evaluable patients were 69% and 79%, respectively. Extent of disease (localized versus metastatic) was the first split (EFS 73% vs 30%; OS 84% vs. 42%). FOXO1 status (positive vs negative) was significant in the second split both for localized (EFS 52% vs 78%; OS 65% vs 88%) and metastatic disease (EFS 6% vs 46%; OS 19% vs 58%)., Conclusions: After metastatic status, FOXO1 status is the most important prognostic factor in patients with RMS and improves risk stratification of patients with localized RMS. Our findings support incorporation of FOXO1 status in risk stratified clinical trials., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The objective of this study was to evaluate local control for patients with intermediate-risk rhabdomyosarcoma (RMS) treated on Children's Oncology Group (COG) protocol ARST0531., Methods: This study analyzed 424 patients with intermediate-risk RMS. Patients were randomized to chemotherapy with either vincristine, dactinomycin, and cyclophosphamide (VAC) or VAC alternating with vincristine and irinotecan. With the goal of improving local control, radiation therapy (RT) was delivered early at week 4 and was concurrent with irinotecan in the experimental arm. Individualized local control plans for children 24 months old or younger were allowed. Local failure on ARST0531 was compared with local failure on the preceding COG intermediate-risk study, D9803., Results: For patients with group I/II alveolar RMS (n = 55), the 5-year cumulative incidence of local failure was 13.4%; for group III alveolar RMS (n = 141), it was 20.2%; and for group III embryonal RMS (n = 228), it was 27.9% (P = .03). Among patients with group III disease, local failure did not differ by histology, site, nodal status, RT modality, or treatment arm. Local failure was worse for a tumor size >5 cm (32.3% vs 16.7%; P = .001). Among patients with group III embryonal RMS, local failure was higher on ARST0531 than D9803 (27.9% vs 19.4%; P = .03). After the exclusion of patients 24 months old or younger or patients who did not receive radiation, local failure remained significantly increased on ARST0531 (P = .02). After adjustments for clinical prognostic factors, event-free survival and overall survival were worse on ARST0531 (P = .004 and P = .05, respectively)., Conclusions: Despite interventions designed to enhance local control, local control was inferior on ARST0531 in comparison with D9803. The reason for this is unclear, but it could be the reduced cyclophosphamide dose on ARST0531., (© 2019 American Cancer Society.)

Background: The purpose of this study was to evaluate risk and response-based multi-agent therapy for patients with rhabdomyosarcoma (RMS) at first relapse., Methods: Patients with RMS and measurable disease at first relapse with unfavorable-risk (UR) features were randomized to a 6-week phase 2 window with 1 of 2 treatment schedules of irinotecan with vincristine (VI) (previously reported). Those with at least a partial response to VI continued to receive 44 weeks of multi-agent chemotherapy including the assigned VI regimen. UR patients who did not have measurable disease at study entry, did not have a radiographic response after the VI window, or declined VI window therapy received 31 weeks of multi-agent chemotherapy including tirapazamine (TPZ) at weeks 1, 4, 10, 19, and 28. Favorable-risk (FR) patients received 31 weeks of the same multi-agent chemotherapy without VI and TPZ., Results: One hundred thirty-six eligible patients were enrolled. For 61 patients not responding to VI, the 3-year failure-free survival (FFS) and overall survival (OS) rates were 17% (95% confidence interval [CI], 8%-29%) and 24% (13%-37%), respectively. For 30 UR patients not treated with VI, the 3-year FFS and OS rates were 21% (8%-37%) and 39% (20%-57%), respectively. FR patients had 3-year FFS and OS rates of 79% (47%-93%) and 84% (50%-96%), respectively. There were no unexpected toxicities., Conclusions: Patients with UR RMS at first relapse or disease progression have a poor prognosis when they are treated with this multi-agent therapy, whereas FR patients have a higher chance of being cured with second-line therapy., (© 2019 American Cancer Society.)

Background: The outcome for patients with metastatic rhabdomyosarcoma (RMS) remains poor. A previous Children's Oncology Group (COG) study (ARST0431) for patients with metastatic RMS produced no improvement in outcome using multiple cytotoxic agents in a dose-intensive manner. The authors report results from the subsequent COG study (ARST08P1), which evaluated the feasibility and efficacy of adding cixutumumab (insulin-like growth factor-1 monoclonal antibody) or temozolomide to the ARST0431 intensive chemotherapy backbone., Methods: Two nonrandomized pilot studies were conducted in patients with metastatic RMS, initially to determine feasibility, and both pilots were expanded to assess efficacy. All patients received 54 weeks of chemotherapy, including vincristine/irinotecan, interval-compressed vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide. In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. In pilot 2, patients received oral temozolomide (100 mg/m 2 ) daily for 5 days with irinotecan. All patients received radiation to the primary tumor and to metastatic sites., Results: One hundred sixty-eight eligible patients were enrolled (97 on pilot 1 and 71 on pilot 2). Most patients were aged ≥10 years (73%), with alveolar histology (70%), and had bone and/or bone marrow metastases (59%). Toxicities observed in each pilot were similar to those reported on ARST0431. With a median follow-up of 2.9 years, the 3-year event-free survival rate was 16% (95% confidence interval, 7%-25%) with cixutumumab and 18% (95% confidence interval, 2%-35%) with temozolomide., Conclusions: The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy for metastatic RMS was safe and feasible. Neither agent improved outcome compared with the same chemotherapy that was used on ARST0431., (© 2018 American Cancer Society.)

Purpose: For infants with localized rhabdomyosarcoma who were enrolled on Children's Oncology Group ARST0331 and ARST0531, local therapy guidelines were provided, but adherence was not mandated because of toxicity concerns. We examined adherence to protocol for local therapy guidelines, treatment variations, and outcomes for these patients., Methods: Children aged ≤24 months who were enrolled on ARST0331 and ARST0531 were evaluated. Data were verified through radiologic, surgical, pathologic, and clinical records. Local therapy was assessed for adherence to protocol guidelines, with variations termed "individualized local therapy." The subdistribution hazards model assessed local failure, the Kaplan-Meier product limit method assessed event-free survival (EFS) and overall survival, and the log-rank test was used to evaluate prognostic impact., Results: The median age of the patients was 14 months, and 124 patients were eligible. Common primary sites were genitourinary (40%), parameningeal (14%), and the extremities (11%). Most patients had unresected disease (group 3, 64%) and embryonal histology (73%). Fifty-eight percent of patients received radiation therapy at a median of week 12 (weeks 1-45). The median radiation dose was 48.6 Gy (30.6-54 Gy). Forty-three percent of patients received individualized local therapy (outside protocol guidelines), typically omission or delay of radiation therapy. Delayed primary excision was performed in 28% at a median of week 14 (weeks 7-34). With a median follow-up of 5.6 years, the 5-year local failure, EFS, and overall survival rates were 24%, 68%, and 82%, respectively. Local failure was significantly higher (35%) in patients receiving individualized local therapy than in patients who received protocol-specified local therapy (16%; P = .02). The site of failure was local in 64% of patients, local and distant in 5%, and distant only in 23%. EFS was significantly higher among patients who were aged 12 to 24 months, had tumors ≤5 cm, had group 1/2 disease, and underwent protocol-specified therapy., Conclusions: Local recurrence was the predominant pattern of failure and was more common in those receiving individualized local therapy. De-escalation of effective therapies because of concerns about treatment toxicity should be considered cautiously., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Team training programs adapt crew resource management principles from aviation to foster communication and prevent medical errors. Although multiple studies have demonstrated that team training programs such as TeamSTEPPS improve patient outcomes and safety across medical disciplines, limited data exist about their application to pediatric surgical teams. The purpose of this study was to investigate usage and perceptions of team training programs by pediatric surgeons and anesthesiologists. We hypothesized that team training programs are not widely available to pediatric surgical teams., Materials and Methods: We performed an online survey of Pediatric Surgery (General, Plastic, Urologic, Orthopedic, Otolaryngologic, and Ophthalmologic) and Anesthesiology members of the American Academy of Pediatrics. The survey inquired about completion and perceptions regarding efficacy of team training programs. Simple descriptive statistics and a Student t-test were used to evaluate the data., Results: One hundred fifty-two pediatric surgeons and 12 anesthesiologists completed the survey with a 10% response rate. Over half of the respondents were general pediatric surgeons. Home institutions offered TeamSTEPPS or another crew resource management style team training program for 39% of respondents. Of those with a program, 77% of respondents had completed training. Although most (76%) who participated in team training programs did so by requirement, 90% found it helpful. Of the 61% of surgeons who said their institution did not offer team training programs, 60% said they would participate if one were offered and an additional 32% said they might participate. The biggest barriers to participation were not enough free time or that the team training program was not offered to their department., Conclusions: Team training programs are considered beneficial among pediatric surgeons and anesthesiologists who have completed them. Unfortunately, despite substantial evidence showing training for team work improves team functioning and patient outcomes, many pediatric surgical teams do not have team training programs at their institutions. Further expansion of team training programs may be valuable to improving a culture of safety in children's hospitals., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Treatment recommendations for localized paratesticular rhabdomyosarcoma (PT RMS) differ in North America and Europe. We conducted a pooled analysis to identify demographic features and treatment choices that affect outcome., Patients and Methods: We retrospectively analyzed the effect of nine demographic variables and four treatment choices on event-free survival (EFS) and overall survival (OS) from 12 studies conducted by five cooperative groups., Results: Eight hundred forty-two patients with localized PT RMS who enrolled from 1988 to 2013 were included. Patients age ≥ 10 years were more likely than younger patients to have tumors that were > 5 cm, enlarged nodes (N1), or pathologically involved nodes ( P ≤ .05 each). With a median follow-up of 7.5 years, Kaplan-Meier estimates for 5-year EFS and OS were 87.7% and 94.8%, respectively. Of demographic variables, cooperative group, era of enrollment, age category, tumor size, Intergroup Rhabdomyosarcoma Study group, and T stage affected EFS ( P ≤ .05 each). Surgical assessment of regional nodes, which was performed in 23.5% of patients-usually in those age ≥ 10 years or with suspicious or N1 nodes-was the only treatment variable associated with EFS by univariable and multivariable analyses ( P ≤ .05 each) in patients age ≥ 1 year. A variable selection procedure on a proportional hazards regression model selected era of enrollment, age, tumor size, and surgical assessment of regional nodes as significant ( P ≤ .05 each) in the EFS model, and era of enrollment, age, tumor size, and histology ( P ≤ .05 each) in the OS model., Conclusion: Localized PT RMS has a favorable prognosis. Age ≥ 10 years at diagnosis and tumor size larger than 5 cm are unfavorable prognostic features. Surgical assessment of regional nodes is important in patients age ≥ 10 years and in those with N1 nodes as it affects EFS.

Purpose Intermediate-risk rhabdomyosarcoma (RMS) includes patients with either nonmetastatic, unresected embryonal RMS (ERMS) with an unfavorable primary site or nonmetastatic alveolar RMS (ARMS). The primary aim of this study was to improve the outcome of patients with intermediate-risk RMS by substituting vincristine and irinotecan (VI) for half of vincristine, dactinomycin, and cyclophosphamide (VAC) courses. All patients received a lower dose of cyclophosphamide and earlier radiation therapy than in previous trials. Patients and Methods Patients were randomly assigned at study entry to either VAC (cumulative cyclophosphamide dose, 16.8 g/m 2 ) or VAC/VI (cumulative cyclophosphamide dose, 8.4 g/m 2 ) for 42 weeks of therapy. Radiation therapy started at week 4, with individualized local control plans permitted for patients younger than 24 months. The primary study end point was event-free survival (EFS). The study design had an 80% power (5% one-sided α-level) to detect an improved long-term EFS from 65% (with VAC) to 76% (with VAC/VI). Results A total of 448 eligible patients were enrolled in the study. At a median follow-up of 4.8 years, the 4-year EFS was 63% with VAC and 59% with VAC/VI ( P = .51), and 4-year overall survival was 73% for VAC and 72% for VAC/VI ( P = .80). Within the ARMS and ERMS subgroups, no difference in outcome by treatment arm was found. Severe hematologic toxicity was less common with VAC/VI therapy. Conclusion The addition of VI to VAC did not improve EFS or OS for patients with intermediate-risk RMS. VAC/VI had less hematologic toxicity and a lower cumulative cyclophosphamide dose, making VAC/VI an alternative standard therapy for intermediate-risk RMS.

Background: Vaginal/uterine rhabdomyosarcoma (VU RMS) is one of the most favorable RMS sites. To determine the optimal therapy, the experience of four cooperative groups (Children's Oncology Group [COG], International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor Group [MMT], Italian Cooperative Soft Tissue Sarcoma Group [ICG], and European pediatric Soft tissue sarcoma Study Group [EpSSG]) was analyzed., Procedure: From 1981 to 2009, 237 patients were identified. Median age (years) at diagnosis differed by tumor location; it was 1.9 for vagina (n = 160), 2.7 for uterus corpus (n = 26), and 13.5 for uterus cervix (n = 51). Twenty-eight percent of patients received radiation therapy (RT) as part of primary therapy (23% COG, 27% MMT, 46% ICG, and 42% EpSSG), with significant differences in the use of brachytherapy between the cooperative groups (23% COG, 76% MMT, 64% ICG, and 88% EpSSG)., Results: Ten-year event-free (EFS) and overall survival (OS) were 74% (95% CI, 67-79%) and 92% (95% CI, 88-96%), respectively. In univariate analysis, OS was inferior for patients with uterine RMS and for those with regional lymph node involvement. Although EFS was slightly lower in patients without initial RT (71% without RT vs. 81% with RT; P = 0.08), there was no difference in OS (94% without RT vs. 89% with RT; P = 0.18). Local control using brachytherapy was excellent (93%). Fifty-one (51.5%) of the 99 survivors with known primary therapy and treatment for relapse were cured with chemotherapy with or without conservative surgery., Conclusions: About half of all patients with VU RMS can be cured without systematic RT or radical surgery. When RT is indicated, modalities that limit sequelae should be considered, such as brachytherapy., (© 2018 Wiley Periodicals, Inc.)

Purpose: Patients with metastatic rhabdomyosarcoma (RMS), except those younger than 10 years with embryonal RMS, have an estimated long-term event-free survival (EFS) of less than 20%. The main goal of this study was to improve outcome of patients with metastatic RMS by dose intensification with interval compression, use of the most active agents determined in phase II window studies, and use of irinotecan as a radiation sensitizer., Patients and Methods: Patients with metastatic RMS received 54 weeks of therapy: blocks of therapy with vincristine/irinotecan (weeks 1 to 6, 20 to 25, and 47 to 52), interval compression with vincristine/doxorubicin/cyclophosphamide alternating with etoposide/ifosfamide (weeks 7 to 19 and 26 to 34), and vincristine/dactinomycin/cyclophosphamide (weeks 38 to 46). Radiation therapy occurred at weeks 20 to 25 (primary) but was also permitted at weeks 1 to 6 (for intracranial or paraspinal extension) and weeks 47 to 52 (for extensive metastatic sites)., Results: One hundred nine eligible patients were enrolled, with a median follow-up of surviving patients of 3.8 years (3-year EFS for all patients, 38% [95% CI, 29% to 48%]; survival, 56% [95% CI, 46% to 66%]). Patients with one or no Oberlin risk factor (age > 10 years or < 1 year, unfavorable primary site of disease, ≥ three metastatic sites, and bone or bone marrow involvement) had a 3-year EFS of 69% (95% CI, 52% to 82%); high-risk patients with two or more risk factors had a 3-year EFS of 20% (95% CI, 11% to 30%). Toxicity was similar to that on prior RMS studies., Conclusion: Patients with metastatic RMS with one or no Oberlin risk factor had an improved 3-year EFS of 69% on ARST0431 compared with an historical cohort from pooled European and US studies; those with two or more risk factors have a dismal prognosis, and new approaches are needed for this very-high-risk group., Competing Interests: Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2015 by American Society of Clinical Oncology.)

Purpose: To determine local control according to clinical variables for patients with intermediate-risk rhabdomyosarcoma (RMS) treated on Children's Oncology Group protocol D9803., Patients and Methods: Of 702 patients enrolled, we analyzed 423 patients with central pathology-confirmed group III embryonal (n=280) or alveolar (group III, n=102; group I-II, n=41) RMS. Median age was 5 years. Patients received 42 weeks of VAC (vincristine, dactinomycin, cyclophosphamide) or VAC alternating with VTC (T = topotecan). Local therapy with 50.4 Gy radiation therapy with or without delayed primary excision began at week 12 for group III patients. Patients with group I/II alveolar RMS received 36-41.4 Gy. Local failure (LF) was defined as local progression as a first event with or without concurrent regional or distant failure., Results: At a median follow-up of 6.6 years, patients with clinical group I/II alveolar RMS had a 5-year event-free survival rate of 69% and LF of 10%. Among patients with group III RMS, 5-year event-free survival and LF rates were 70% and 19%, respectively. Local failure rates did not differ by histology, nodal status, or primary site, though there was a trend for increased LF for retroperitoneal (RP) tumors (P=.12). Tumors ≥5 cm were more likely to fail locally than tumors <5 cm (25% vs 10%, P=.0004). Almost all (98%) RP tumors were ≥5 cm, with no difference in LF by site when the analysis was restricted to tumors ≥5 cm (P=.86)., Conclusion: Local control was excellent for clinical group I/II alveolar RMS. Local failure constituted 63% of initial events in clinical group III patients and did not vary by histology or nodal status. The trend for higher LF in RP tumors was related to tumor size. There has been no clear change in local control over RMS studies, including IRS-III and IRS-IV. Novel approaches are warranted for larger tumors (≥5 cm)., Competing Interests: none., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The majority of intermediate-risk rhabdomyosarcoma (RMS) patients have gross residual disease (Group III) after their first operative procedure. It is currently not known if local control rates can be maintained when, following induction chemotherapy, the radiation therapy (RT) dose is decreased after a delayed primary excision (DPE). To answer this question we evaluated patients enrolled on COG D9803 (1999-2005) who had Group III tumors of the bladder dome, extremity or trunk (thorax, abdomen and pelvis) were candidates for DPE at Week 12 if the primary tumor appeared resectable. RT dose was then adjusted by the completeness of DPE: no evidence of disease 36 Gy, microscopic residual 41.4 Gy and gross residual disease (GRD) 50.4 Gy. A total of 161 Group III patients were evaluated (24 bladder dome, 63 extremity and 74 trunk). Seventy-three patients (45%) underwent DPE which achieved removal of all gross disease in 61 (84%) who were then eligible for reduced RT dose (43/73 received 36 Gy, 19/73 received 41.4 Gy). The local 5-year failure rate (0% for bladder dome, 7% for extremity and 20% for trunk) was similar to IRS-IV, which did not encourage DPE and did not allow for DPE adapted RT dose reduction. In conclusion, DPE was performed in 45% of Group III RMS patients with tumors at select anatomic sites (bladder dome, extremity and trunk) and 84% of those who had DPE were eligible for RT dose reduction. Local control outcomes were similar to historic results with RT alone., (© 2014 UICC.)

Background: The prognostic significance of response to induction therapy for rhabdomyosarcoma (RMS) by anatomic imaging [computerised tomographic (CT) or magnetic resonance imaging (MRI) scan] is controversial. We previously reported no relationship between early response and failure-free survival (FFS) on Intergroup Rhabdomyosarcoma Study (IRS)-IV. We repeated the same analysis using a more recent clinical trial as an independent cohort of patients with non-metastatic, initially unresected RMS., Methods: A total of 338 patients enrolled in Children's Oncology Group (COG) study D9803 met the inclusion criteria for this analysis: (1) non-metastatic, initially unresected (Group III); (2) embryonal (ERMS) or alveolar (ARMS) histology; (3) documented protocol week 12 response to induction chemotherapy (excluding progressive disease) based on anatomic imaging (CT/MRI) and (4) documented protocol therapy beyond week 12. Response at week 12 was determined by the treating institution as complete response (CR), partial response (PR) or no response (NR). FFS was estimated using the Kaplan-Meier method and comparisons between patient subsets were made using the log-rank test., Results: Overall objective response rate (CR+PR) at week 12 of therapy was 85% and was similar between ERMS and ARMS. FFS was similar among all patients with CR, PR or NR (p=0.49). Restricting the analysis to either ERMS or ARMS, there was no difference in FFS by response within either histology subset (p=0.89 and p=0.08, respectively)., Conclusions: These findings provide additional evidence that anatomic imaging to assess early response to therapy among patients with RMS does not predict outcome and has questionable use in tailoring subsequent therapy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: To simplify the recommended staging evaluation by correlating tumor and clinical features with patterns of distant metastasis in newly diagnosed patients with embryonal rhabdomyosarcoma (ERMS) or alveolar rhabdomyosarcoma (ARMS)., Patients and Methods: Patient data from the Intergroup Rhabdomyosarcoma Study Group and the Children's Oncology Group over two periods were analyzed: 1991 to 1997 and 1999 to 2004. We used recursive partitioning analyses to identify factors (including histology, age, regional nodal and distant metastatic status, tumor size, local invasiveness, and primary site) that divided patients into subsets with the most different rates of metastatic disease., Results: Of the 1,687 patients analyzed, 5.7% had lung metastases, 4.8% had bone involvement, and 6% had bone marrow (BM) involvement. Rhabdomyosarcoma (RMS) without local invasion (T1) had a low rate of metastasis for all distant sites, especially ERMS (0% bone, 0% BM). ARMS with local invasion (T2) had a higher rate of metastasis for all distant sites (13% lung, 18% bone, 23% BM). ERMS, T2 also had a higher rate of metastatic lung involvement (9%). The likelihood of bone or BM involvement increased in the presence of lung metastases (41% with, 6% without). Regional nodal metastases (N1) predicted a high rate of metastasis in all distant sites (14% lung, 14% bone, 18% BM). A staging algorithm was developed., Conclusion: Staging studies in childhood RMS can be tailored to patients' presenting characteristics. Bone marrow aspirate and biopsy and bone scan are unnecessary in at least one third of patients with RMS.

Purpose: To analyze the effect of reduced-dose radiotherapy on local control in children with low-risk rhabdomyosarcoma (RMS) treated in the Children's Oncology Group D9602 study., Methods and Materials: Patients with low-risk RMS were nonrandomly assigned to receive radiotherapy doses dependent on the completeness of surgical resection of the primary tumor (clinical group) and the presence of involved regional lymph nodes. After resection, most patients with microscopic residual and uninvolved nodes received 36 Gy, those with involved nodes received 41.4 to 50.4 Gy, and those with orbital primary tumors received 45 Gy. All patients received vincristine and dactinomycin, with cyclophosphamide added for patient subsets with a higher risk of relapse in Intergroup Rhabdomyosarcoma Study Group III and IV studies., Results: Three hundred forty-two patients were eligible for analysis; 172 received radiotherapy as part of their treatment. The cumulative incidence of local/regional failure was 15% in patients with microscopic involved margins when cyclophosphamide was not part of the treatment regimen and 0% when cyclophosphamide was included. The cumulative incidence of local/regional failure was 14% in patients with orbital tumors. Protocol-specified omission of radiotherapy in girls with Group IIA vaginal tumors (n = 5) resulted in three failures for this group., Conclusions: In comparison with Intergroup Rhabdomyosarcoma Study Group III and IV results, reduced-dose radiotherapy does not compromise local control for patients with microscopic tumor after surgical resection or with orbital primary tumors when cyclophosphamide is added to the treatment program. Girls with unresected nonbladder genitourinary tumors require radiotherapy for postsurgical residual tumor for optimal local control to be achieved., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Rhabdomyosarcoma (RMS) is a malignant childhood tumor of mesenchymal origin that currently has a greater than 70% overall 5-year survival. Multimodality treatment is determined by risk stratification according to pretreatment stage, postoperative group, histology, and site of the primary tumor. Pretreatment staging is dependent on primary tumor site, size, regional lymph node status, and presence of metastases. Unique to RMS is the concept of postoperative clinical grouping that assesses the completeness of disease resection and takes into account lymph node evaluation. At all tumor sites, the clinical grouping, and therefore completeness of resection, is an independent predictor of outcome. Overall, the prognosis for RMS is dependent on primary tumor site, patient age, completeness of resection, extent of disease, including the presence and number of metastatic sites and histology and biology of the tumor cells. Therefore, the surgeon plays a vital role in RMS by contributing to risk stratification for treatment, local control of the primary tumor, and outcome. The current state-of-the-art treatment is determined by treatment protocols developed by the Soft Tissue Sarcoma Committee of the children's Oncology Group., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children, occurs less commonly in infants. Historically, poorer outcomes have been reported for infants diagnosed with RMS than for older children., Methods: The authors analyzed the characteristics, treatment administered, outcomes, and patterns of failure for infants aged < 1 year with nonmetastatic RMS who received multimodal therapy on Intergroup Rhabdomyosarcoma Study (IRS) protocols IRS-IV, D9602, and D9803., Results: Seventy-six infants with nonmetastatic RMS were treated on the 3 protocols from 1991 to 2005. Their median age was 7.4 months (range, 0.1-12 months). Tumor histology included embryonal (57%), alveolar (21%), and undifferentiated sarcoma/other (22%). A parameningeal primary tumor site was less common in this infant cohort (3%) than in all patients who were treated on IRS-IV (25%). The estimated 5-year failure-free survival and overall survival rates (95% confidence interval [CI]) were 57% (95% CI, 44%-67%) and 76% (95% CI, 65%-85%), respectively, for infants compared with 81% (95% CI, 79%-83%) and 87% (95% CI, 85%-89%), respectively, for children ages 1 to 9 years. Twenty-three of 32 infants with treatment failure had local recurrence/progression with distant failure (n = 3) or without distant failure (n = 20). The overall local failure rate was 30%. The median time to treatment failure was 13 months. The failure-free survival rate was worse for infants who had IRS Group III tumors and for those who received less than protocol-recommended radiation therapy., Conclusions: Infants with RMS appeared to have worse outcomes than older patients, in part because of high rates of local failure. The authors concluded that concerns regarding morbidity in infants and reluctance to use aggressive local control measures may lead to higher rates of local failure., (Copyright © 2011 American Cancer Society.)

Purpose: To evaluate the incidence and prognostic factors for regional failure, with attention to the in-transit pathways of spread, in children with nonmetastatic rhabdomyosarcoma of the extremity., Methods and Materials: The Intergroup rhabdomyosarcoma studies III, IV-Pilot, and IV enrolled 226 children with rhabdomyosarcoma of the extremity. Failure at the in-transit (epitrochlear/brachial and popliteal) and proximal (axillary/infraclavicular and inguinal/femoral) lymph nodes was evaluated. The median follow-up for the surviving patients was 10.4 years., Results: Of the 226 children, 55 (24%) had clinical or pathologic evidence of either in-transit and/or proximal lymph node involvement at diagnosis. The actuarial 5-year risk of regional failure was 12%. The prognostic factors for poor regional control were female gender and lymph node involvement at diagnosis. In the 116 patients with a distal extremity primary tumor, 5% had in-transit lymph node involvement at diagnosis. The estimated 5-year incidences of in-transit and proximal nodal failure was 12% and 8%, respectively. The in-transit failure rate was 0% for patients who underwent radiotherapy and/or underwent lymph node sampling of the in-transit nodal site but was 15% for those who did not (p = .07). However, the 5-year event-free survival rate did not differ between these two groups (64% vs. 55%, respectively, p = .47)., Conclusion: The high incidence of regional involvement necessitates aggressive identification and treatment of regional lymph nodes in patients with rhabdomyosarcoma of the extremity. In patients with distal extremity tumors, in-transit failures were as common as failures in more proximal regional sites. Patients who underwent complete lymph node staging with appropriate radiotherapy to the in-transit nodal site, if indicated, were at a slightly lower risk of in-transit failure., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The objectives of this study were to compare tumor volume and patient weight versus traditional factors of tumor size (greatest dimension) and patient age and to determine which parameters best discriminated outcome among pediatric patients with intermediate-risk rhabdomyosarcoma (RMS)., Methods: Complete information was available for 370 patients with nonmetastatic RMS who were enrolled in the Children's Oncology Group (COG) intermediate-risk study D9803 (1999-2005). The Kaplan-Meier method was used to estimate survival distributions. A recursive partitioning model was used to identify prognostic factors that were associated with event-free survival (EFS). Cox proportional hazards regression models were used to estimate the association between patient characteristics and the risk of failure or death., Results: For all patients with intermediate-risk RMS, a recursive partitioning algorithm for EFS suggested that prognostic groups should be defined optimally by tumor volume (with a transition point at 20 cm(3) ), patient weight (with a transition point at 50 kg), and embryonal histology. Tumor volume and patient weight added significant outcome information to the standard prognostic factors, including greatest tumor dimension and patient age (P = .02). The ability to resect the tumor completely was not associated significantly with the size of the patient, and patient weight did not significantly modify the association between tumor volume and EFS after adjustment for standard risk factors (P = .2)., Conclusions: The factors that had the strongest association with EFS were tumor volume, patient weight, and histology. On the basis of regression modeling, tumor volume and patient weight were superior predictors of outcome compared with greatest tumor dimension and patient age in children with intermediate-risk RMS. The current results indicated that the prognostic performance of tumor volume and patient weight should be assessed in an independent prospective study., (Copyright © 2010 American Cancer Society.)

Purpose: Regional lymph node disease (RLND) is a component of the risk-based treatment stratification in rhabdomyosarcoma (RMS). The purpose of this study was to determine the contribution of RLND to prognosis for patients with RMS., Patients and Methods: Patient characteristics and survival outcomes for patients enrolled onto Intergroup Rhabdomyosarcoma Study IV (N = 898, 1991 to 1997) were evaluated among the following three patient groups: nonmetastatic patients with clinical or pathologic negative nodes (N0, 696 patients); patients with clinical or pathologic positive nodes (N1, 125 patients); and patients with a single site of metastatic disease (77 patients)., Results: Outcomes for patients with nonmetastatic alveolar N0 RMS were significantly better than for patients with N1 RMS (5-year failure-free survival [FFS], 73% v 43%, respectively; 5-year overall survival [OS], 80% v 46%, respectively; P < .001). Patients with a single site of alveolar metastasis had even worse FFS and OS (23% FFS and OS, P = .01) when compared with patients with N1 RMS; however, the differences was not as large as the differences between patients with N0 RMS and N1 RMS. For embryonal RMS, there was no statistically significant difference in FFS or OS (P = .41 and P = .77, respectively) for patients with N1 versus N0 RMS. Gene array analysis of primary tumor specimens identified that genes associated with the immune system and antigen presentation were significantly increased in N1 versus N0 alveolar RMS., Conclusion: RLND alters prognosis for alveolar but not embryonal RMS. For patients with N1 disease and alveolar histology, outcomes were more similar to distant metastatic disease rather than local disease. Current data suggest that more aggressive therapy for patients with alveolar N1 RMS may be warranted.

The purpose of this study was to determine patient characteristics and outcomes for bladder/prostate (BP) rhabdomyosarcoma (RMS) using an international cohort of prospectively treated patients comparing different treatment algorithms. Data were collected from 379 patients (1979-1998) treated on protocol; Intergroup Rhabdomyosarcoma Study, IRS-IV (n = 239 patients), International Society of Pediatric Oncology Malignant Mesenchymal Tumors (MMT) Committee MMT-84 and -89 (n = 74), Italian Cooperative Group, RMS-79 and RMS-88 Studies (n = 37) or German Cooperative Soft Tissue Sarcoma Study CWS-91 protocols (n = 29). A total of 322 (85%) patients had localized embryonal RMS (ERMS) and 27 had metastatic disease. Thirty patients (21 local disease; 9 metastatic) had nonembryonal BP RMS. Patients with localized ERMS had large tumors (64% >5 cm) that were invasive (54%) with uninvolved regional lymph nodes (N0, 93%). The 5-year failure-free survival (FFS) was 75% and the overall survival (OS) was 84%, with 89% of deaths attributed to disease. Treatment failures were usually local disease recurrence (60%). Predictors of FFS included T-stage (invasiveness), size, and histology. FFS was decreased for patients not receiving initial radiotherapy but this did not translate into a decreased OS. The 21 patients with localized nonembryonal BP RMS had a FFS and OS of 47%. The 36 patients with metastatic disease were more likely to be older and had large tumors that were invasive with alveolar histology and regional lymph node involvement. The 5-year FFS and OS were 41 and 44%, respectively. In conclusion, the majority of BP RMS patients had localized ERMS with a resultant good prognosis using current treatment algorithms. There were differences in FFS between treatment protocols but this did not result in an altered OS., (Copyright © 2010 UICC.)

Purpose: To assess local control, event-free survival (EFS), and overall survival (OS) rates in 71 patients with localized, completely resected (Group I) alveolar rhabdomyosarcoma (ALV RMS) and their relation to radiation therapy (RT) on IRSG Protocols III and IV, 1984-1997., Methods: Chart review and standard statistical procedures. PATIENTS AND TUMORS: Patients were 1-18 years at diagnosis (median, 6 years). Primary tumor sites were extremity/trunk (N = 54), head/neck (N = 9), genitourinary tract (N = 7), and perineum (N = 1). Thirty patients received VA +/- C with RT; 41 received VA +/- C alone. RT was assigned, not randomized., Results: Fifty-four patients had Stage 1 (favorable site, any size) or Stage 2 (unfavorable site, < or = 5 cm) tumors. Eight-year EFS was 90%, with 100% local control for 17 patients given RT. Eight-year EFS was 88%, with 92% local control for 37 patients without RT; P = 0.52 for EFS comparisons, 0.3 for local control comparisons. In 17 Stage 3 patients (unfavorable site, tumors >5 cm, N0), 8-year EFS was 84% with 100% local control in 13 patients given RT; 8-year EFS was only 25% and local control 50% in 4 patients without RT. Local recurrence was the most common site of first failure in non-irradiated patients., Conclusion: Patients with Stage 1-2 ALV RMS had slightly but statistically insignificantly improved local control, EFS, and OS rates when local RT was given. The need for local RT in Stage 1-2 patients deserves evaluation in a randomized study. Local control, EFS, and OS rates were significantly improved in Stage 3 patients receiving local RT., (Copyright 2010 Wiley-Liss, Inc.)

Purpose: The purpose of this study was to compare the outcome of patients with intermediate-risk rhabdomyosarcoma (RMS) treated with standard VAC (vincristine, dactinomycin, and cyclophosphamide) chemotherapy to that of patients treated with VAC alternating with vincristine, topotecan, and cyclophosphamide (VAC/VTC)., Patients and Methods: Patients were randomly assigned to 39 weeks of VAC versus VAC/VTC; local therapy began after week 12. Patients with parameningeal RMS with intracranial extension (PME) were treated with VAC and immediate x-ray therapy. The primary study end point was failure-free survival (FFS). The study was designed with 80% power (5% two-sided alpha level) to detect an increase in 5-year FFS from 64% to 75% with VAC/VTC., Results: A total of 617 eligible patients were entered onto the study: 264 were randomly assigned to VAC and 252 to VAC/VTC; 101 PME patients were nonrandomly treated with VAC. Treatment strata were embryonal RMS, stage 2/3, group III (33%); embryonal RMS, group IV, less than age 10 years (7%); alveolar RMS or undifferentiated sarcoma (UDS), stage 1 or group I (17%); alveolar RMS/UDS (27%); and PME (16%). At a median follow-up of 4.3 years, 4-year FFS was 73% with VAC and 68% with VAC/VTC (P = .3). There was no difference in effect of VAC versus VAC/VTC across risk groups. The frequency of second malignancies was similar between the two treatment groups., Conclusion: For intermediate-risk RMS, VAC/VTC does not significantly improve FFS compared with VAC.