Clinical group and modified TNM stage for rhabdomyosarcoma: A review from the Children's Oncology Group.

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.

A Case of Cyclic Neutropenia and Associated Amyloidosis.

Cyclic neutropenia has been rarely associated with chronic inflammation and development of reactive AA amyloidosis. We report a family with cyclic neutropenia with associated renal and thyroid amyloid. A 12-year-old female presented with thyromegaly, recurrent aphthous ulcers, severe neutropenia, and renal failure. Renal and thyroid biopsies revealed abundant amyloid deposition. Presence of a heterozygous ELANE c.358 A>T gene mutation p.I120F variant with autosomal dominant inheritance confirmed the diagnosis of cyclic neutropenia. The patient's father also had neutropenia and amyloidosis with renal failure. We started filgrastim to attenuate neutropenia and thereby reduce chronic inflammation and minimize further amyloid deposition.

Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial.

BACKGROUND: Outcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone. METHODS: In this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and <18 years) from 57 hospitals in the USA and Canada with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma, which were larger than 5 cm in diameter and of intermediate or high grade. Eligible patients had Lansky (if aged ≤16 years) or Karnofsky (if aged >16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m2 per dose intravenously on days 1-3 with mesna) and doxorubicin (37·5 mg/m2 per dose intravenously on days 1-2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients <18 years 350 mg/m2 once daily; if patients ≥18 years 600 mg once daily) or not (control group), with pazopanib not given immediately before or after surgery at week 13. The study projected 100 randomly assigned patients were needed to show an improvement in the number of participants with a 90% or higher pathological response at week 13 from 40% to 60%. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867. FINDINGS: Between July 7, 2014, and Oct 1, 2018, 81 eligible patients were enrolled and randomly assigned to the pazopanib group (n=42) or the control group (n=39). At the planned second interim analysis with 42 evaluable patients and a median follow-up of 0·8 years (IQR 0·3-1·6) in the pazopanib group and 1 year (0·3-1·6) in the control group, the number of patients with a 90% pathological response or higher was 14 (58%) of 24 patients in the pazopanib group and four (22%) of 18 patients in the control group, with a between-group difference in the number of 90% or higher pathological response of 36·1% (83·8% CI 16·5-55·8). On the basis of an interim analysis significance level of 0·081 (overall one-sided significance level of 0·20, power of 0·80, and O'Brien-Fleming-type cumulative error spending function), the 83·8% CI for response difference was between 16·5% and 55·8% and thus excluded 0. The improvement in pathological response rate with the addition of pazopanib crossed the predetermined boundary and enrolment was stopped. The most common grade 3-4 adverse events were leukopenia (16 [43%] of 37 patients), neutropenia (15 [41%]), and febrile neutropenia (15 [41%]) in the pazopanib group, and neutropenia (three [9%] of 35 patients) and febrile neutropenia (three [9%]) in the control group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. Paediatric and adult patients had a similar number of grade 3 and 4 toxicity. There were seven deaths (three in the pazopanib group and four in the control group), none of which were treatment related. INTERPRETATION: In this presumed first prospective trial of soft tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathological near complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft tissue sarcoma. The comparison of survival outcomes requires longer follow-up. FUNDING: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation.

Risk-based treatment for patients with first relapse or progression of rhabdomyosarcoma: A report from the Children's Oncology Group.

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.

The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy is feasible but does not improve outcome for patients with metastatic rhabdomyosarcoma: A report from the Children's Oncology Group.

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/m2 ) 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.

Consensus and controversies regarding the treatment of rhabdomyosarcoma.

Optimal treatment of rhabdomyosarcoma (RMS) requires multidisciplinary approach, incorporating chemotherapy with local control. Although current therapies are built on cooperative group trials, a comprehensive standard of care to guide clinical decision making has been lacking, especially for relapsed patients. Therefore, we assembled a panel of pediatric and adolescent and young adult sarcoma experts to develop treatment guidelines for managing RMS and to identify areas in which further research is needed. We created algorithms incorporating evidence-based care for patients with RMS, emphasizing the importance of clinical trials and close integration of all specialties involved in the care of these patients.

Reduction of cyclophosphamide dose for patients with subset 2 low-risk rhabdomyosarcoma is associated with an increased risk of recurrence: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

BACKGROUND: Failure-free survival (FFS) and overall survival (OS) rates were found to improve on Intergroup Rhabdomyosarcoma Study (IRS) IV (IRS-IV) compared with IRS-III for patients with subset 2 (IRS stage 1, group III nonorbit or stage 3, group I/II) low-risk embryonal rhabdomyosarcoma with the addition of cyclophosphamide (total cumulative cyclophosphamide dose of 26.4 g/m2 ) to the combination of vincristine and dactinomycin (VAC). The goal of Children's Oncology Group ARST0331 for subset 2 low-risk patients was to reduce the total cumulative cyclophosphamide dose without compromising FFS. METHODS: Therapy included 4 cycles of VAC (total cumulative cyclophosphamide dose of 4.8 g/m2 ) followed by 12 cycles of vincristine and dactinomycin over 46 weeks. Patients with group II or III tumors received radiotherapy, except for girls with group III vaginal tumors who enrolled before September 2009 and achieved a complete response with chemotherapy with or without delayed surgical resection. RESULTS: Among 66 eligible patients who were followed for a median of 3.5 years, there were 20 failures versus 10.53 expected failures. The estimated 3-year FFS and OS rates were 70% (95% confidence interval [95% CI], 57%-80%) and 92% (95% CI, 83%-97%), respectively. The estimated 3-year FFS rate was 57% (95% CI, 33%-75%) for girls with subset 2 genital tract embryonal rhabdomyosarcoma (21 patients) and 77% (95% CI, 61%-87%) for all other subset 2 patients (45 patients) (P = .02). CONCLUSIONS: The authors observed suboptimal FFS among patients with subset 2 low-risk rhabdomyosarcoma using reduced total cyclophosphamide. Eliminating radiotherapy for girls with group III vaginal tumors in combination with reduced total cyclophosphamide appeared to contribute to the suboptimal outcome. Cancer 2017;123:2368-2375. © 2017 American Cancer Society.

Patterns of chemotherapy-induced toxicities and outcome in children and adolescents with metastatic rhabdomyosarcoma: A report from the Children's Oncology Group.

BACKGROUND: We sought to determine whether adolescents with metastatic alveolar rhabdomyosarcoma (ARMS) or embryonal RMS (ERMS) had a different event-free survival (EFS) compared with younger patients, and to identify treatment-related factors (adverse events, AEs) that may be associated with differences in outcome. METHODS: The prevalence of AEs in adolescents older than 13 years was compared with that in patients less than or equal to 13 years of age (Fisher exact test) in patients enrolled onto ARST0431. EFS by age and histology was compared by log-rank test. RESULTS: Of 109 patients, 60 (55%) were older than 13 years; they were more likely to have nausea (17 vs. 4%, P = 0.06) and pain (20 vs. 6%, P = 0.05) compared with younger patients. Adolescents were less likely to complete therapy (63 vs. 76%) and more likely to have unplanned dose modifications outside of protocol guidelines (23 vs. 2.7%). The 3-year EFS was 26% (95% confidence interval [CI]: 15-38) for adolescents compared with 46% (95% CI: 32-60) for those less than or equal to 13 years (P = 0.011). Forty-two (59%) adolescents with ARMS had a 3-year EFS of 13% (95% CI: 2-23) compared with 30% (95% CI: 10-51) for those less than or equal to 13 years (P = 0.032). EFS was comparable between older and younger patients with ERMS (64 vs. 55%, P = 0.53). CONCLUSIONS: Although there was a significant difference in EFS and protocol compliance by age, the differences in age-related toxicity are unlikely to account for this. Observed differences in pain and nausea by age could be real or be dependent on patient reporting of symptoms. Future studies in RMS should include patient-reported outcomes to better evaluate health-related quality of life.

Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: A report from the Children's Oncology Group.

BACKGROUND: Distinguishing alveolar rhabdomyosarcoma (ARMS) from embryonal rhabdomyosarcoma (ERMS) has historically been of prognostic and therapeutic importance. However, classification has been complicated by shifting histologic criteria required for an ARMS diagnosis. Children's Oncology Group (COG) studies after IRS-IV, which included the height of this diagnostic shift, showed both an increased number of ARMS and an increase in the proportion of fusion-negative ARMS. Following diagnostic standardization and histologic re-review of ARMS cases enrolled during this era, analysis of low-risk (D9602) and intermediate-risk (D9803) rhabdomyosarcoma (RMS) studies showed that fusion status rather than histology best predicts prognosis for patients with RMS. This analysis remains to be completed for patients with high-risk RMS. PROCEDURE: We re-reviewed cases on high-risk COG studies D9802 and ARST0431 with an enrollment diagnosis of ARMS. We compared the event-free survival (EFS) and overall survival by histology, PAX-FOXO1 fusion, and clinical risk factors (Oberlin score) for patients with metastatic RMS using the log-rank test. RESULTS: Histology re-review resulted in reclassification as ERMS for 12% of D9802 cases and 5% of ARST0431 cases. Fusion-negative RMS had a superior EFS to fusion-positive RMS; however, poorer outcome for metastatic RMS was most related to clinical risk factors including age, primary site, and number of metastatic sites. CONCLUSIONS: In contrast to low- or intermediate-risk RMS, in metastatic RMS, clinical risk factors have the most impact on patient outcome. PAX-FOXO1 fusion is more common in patients with a high Oberlin score, but fusion status is not an independent biomarker of prognosis.

Prognostic Factors for Outcome in Localized Extremity Rhabdomyosarcoma. Pooled Analysis from Four International Cooperative Groups.

BACKGROUND: Extremity rhabdomyosarcomas do not always show satisfactory outcomes. We analyzed data from 643 patients treated in 14 studies conducted by European and North American groups between 1983 and 2004 to identify factors predictive of outcome. PROCEDURE: Clinical factors, including age; histology; site of primary (hand and foot vs. other); size; invasiveness (T stage); nodal involvement (N stage); and treatment factors, including post-surgical group; chemotherapy type and duration; radiotherapy; and treatment (before or after 1995); were evaluated for impact on overall survival (OS). RESULTS: 5-year OS were 67% (se 1.8). Multivariate analysis showed that lower OS correlated with age >3 years, T2 and N1 stage, incomplete initial surgery, treatment before 1995, and European cooperative group treatment. Patients with gross residual disease after initial incomplete resection/biopsy had similar outcomes in both continental groups. The better global survival of patients treated in American studies was accounted for by differences in outcome in the subset of those with grossly resected tumors (OS 86% [se 3] for COG patients vs. 68% [se 4] for European patients (P = 0.004)). When excluding chemotherapy duration from the model, analysis in this subset of patients showed that cooperative group (P = 0.001), site (P = 0.001), and T stage (P = 0.05) were all significant. However, after adding duration of chemotherapy (≥27 weeks) to the model, only primary site remained significant (P = 0.006). CONCLUSION: This meta-analysis confirms the role of many established prognostic factors but identifies for the first time that chemotherapy duration may have an impact on outcome in patients with grossly resected tumors.

Relevance of historical therapeutic approaches to the contemporary treatment of pediatric solid tumors.

Children with solid tumors, most of which are malignant, have an excellent prognosis when treated on contemporary regimens. These regimens, which incorporate chemotherapeutic agents and treatment modalities used for many decades, have evolved to improve relapse-free survival and reduce long-term toxicity. This review discusses the evolution of the treatment regimens employed for management of the most common solid tumors, emphasizing the similarities between contemporary and historical regimens. These similarities allow the use of historical patient cohorts to identify the late effects of successful therapy and to evaluate remedial interventions for these adverse effects.

Alveolar rhabdomyosarcoma has superior response rates to vinorelbine compared to embryonal rhabdomyosarcoma in patients with relapsed/refractory disease: A meta-analysis.

BACKGROUND: Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options are needed for these patients. Vinorelbine is a semisynthetic vinca alkaloid that has clinical activity in relapsed rhabdomyosarcoma (RMS) when used alone or in combination with cyclophosphamide. AIMS: The goal of our study was to evaluate whether RMS histology subtype influences response rate to vinorelbine alone or in combination. MATERIALS & METHODS: Five Phase 2 trials that enrolled RMS patients were included in the meta-analysis. Two studies evaluated vinorelbine alone, two studies evaluated vinorelbine in combination with low dose oral cyclophosphamide, and one study evaluated vinorelbine and intravenous cyclophosphamide in combination with temsirolimus or bevacizumab. All RMS patients had relapsed or refractory disease and had received at least one prior therapy. Response was reported according to RECIST1.1 and was defined as a complete or partial response. Response data was obtained from published results or from trial principal investigator. RMS NOS patients were grouped with ERMS patients for this analysis. Summary estimates comparing differences between ARMS and ERMS response rates were generated using a random-effects model to account for heterogeneity among the studies. RESULTS: One hundred fifty-six enrolled patients evaluable for response were included in the meta-analysis, 85 ARMS, 64 ERMS and 7 RMS-NOS. The combined effect generated from the random-effects model demonstrated a 41% increase (p = 0.001, 95% CI; 0.21-0.60) in response to vinorelbine as a single agent or in combination in patients with ARMS compared to patients with ERMS. There was no significant difference in the rate of progressive disease between patients with ARMS compared to ERMS (p = 0.1, 95%CI; -0.26-0.02). DISCUSSION: Vinorelbine is an active agent for the treatment of relapsed or refractory RMS and a meta-analysis of Phase 2 studies shows that radiographic responses in patients with ARMS were significantly higher than ERMS or RMS-NOS. CONCLUSION: These data support further investigation of vinorelbine in newly diagnosed patients with RMS particularly those with alveolar histology.

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).

BACKGROUND: 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. METHODS: 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. RESULTS AND CONCLUSION: 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.

The treatment approach to pediatric non-rhabdomyosarcoma soft tissue sarcomas: a critical review from the INternational Soft Tissue SaRcoma ConsorTium.

The current article focuses on non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), the heterogeneous group of mesenchymal tumours different from rhabdomyosarcoma that may affect children and adolescents, with clinical behaviour varying from relatively benign to highly malignant. This review represents the effort of the international scientific paediatric community within the context of the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT), a project founded by the leadership of three large cooperative groups - Children's Oncology Group, Cooperative Weichteilsarkom Studiengruppe and European paediatric Soft tissue sarcoma Study Group - with the main goal to pool expertise and resources on a broader international level in order to improve knowledge of soft tissue sarcomas of children, adolescents and young adults. This article describes the current standard treatment approach in NRSTS, with a focus on the controversies and challenges in the management of these tumours. Developing research projects and clinical protocols for NRSTS has always been challenging, supporting the need to develop international integrated prospective dedicated programs, including paediatric NRSTS experts together with the adult sarcoma community. INSTRuCT provides a unique mechanism to increase international collaboration by agreeing on a common language, developing consensus standards to guide diagnosis and treatment, comparing clinical trial results across cooperative groups, and through a shared data dictionary providing answers to questions that can only be addressed by a larger data set.

Comparison of outcomes based on treatment algorithms for rhabdomyosarcoma of the bladder/prostate: combined results from the Children's Oncology Group, German Cooperative Soft Tissue Sarcoma Study, Italian Cooperative Group, and International Society of Pediatric Oncology Malignant Mesenchymal Tumors Committee.

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.

Local control and outcome in children with localized vaginal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma committee of the Children's Oncology Group.

BACKGROUND: The local control approach for girls with non-resected vaginal rhabdomyosarcoma (RMS) enrolled onto Intergroup RMS Study Group (IRSG)/Children's Oncology Group (COG) studies has differed from that used at other primary sites by delaying or eliminating radiotherapy (RT) based on response achieved with chemotherapy and delayed primary resection. PROCEDURES: We reviewed locoregional treatment and outcome for patients with localized RMS of the vagina on the two most recent COG low-risk RMS studies. RESULTS: Forty-one patients with localized vaginal RMS were enrolled: 25 onto D9602 and 16 onto Subset 2 of ARST0331. Only four of the 39 with non-resected tumors received RT. The 5-year cumulative incidence of local recurrence was 26% on D9602, and the 2-year cumulative incidence of local recurrence was 43% on ARST0331. Increased local failure rates appeared to correlate with chemotherapy regimens that incorporated lower cumulative doses of cyclophosphamide. Estimated 5-year and 2-year failure free survival rates were 70% (95% CI: 46%, 84%) on D9602 and 42% (95% CI: 11%, 70%) on ARST0331, respectively. CONCLUSIONS: To prevent local recurrence, we recommend a local control approach for patients with non-resected RMS of the vagina that is similar to that used for other primary sites and includes RT. We recognize that potential long-term effects of RT are sometimes unacceptable, especially for children less than 24 months of age. However, when making the decision to eliminate RT, the risk of local recurrence must be considered especially when using a chemotherapy regimen with a total cumulative cyclophosphamide dose of ≤ 4.8 g/m².

Prioritization of Novel Agents for Patients with Rhabdomyosarcoma: A Report from the Children's Oncology Group (COG) New Agents for Rhabdomyosarcoma Task Force.

Rhabdomyosarcoma is the most common soft tissue sarcoma diagnosed in children and adolescents. Patients that are diagnosed with advanced or relapsed disease have exceptionally poor outcomes. The Children's Oncology Group (COG) convened a rhabdomyosarcoma new agent task force in 2020 to systematically evaluate novel agents for inclusion in phase 2 or phase 3 clinical trials for patients diagnosed with rhabdomyosarcoma, following a similar effort for Ewing sarcoma. The task force was comprised of clinicians and basic scientists who collectively identified new agents for evaluation and prioritization in clinical trial testing. Here, we report the work of the task force including the framework upon which the decisions were rendered and review the top classes of agents that were discussed. Representative agents include poly-ADP-ribose polymerase (PARP) inhibitors in combination with cytotoxic agents, mitogen-activated protein kinase (MEK) inhibitors in combination with type 1 insulin-like growth factor receptor (IGFR1) inhibitors, histone deacetylase (HDAC) inhibitors, and novel cytotoxic agents.

Metabolic response as assessed by 18 F-fluorodeoxyglucose positron emission tomography-computed tomography does not predict outcome in patients with intermediate- or high-risk rhabdomyosarcoma: A report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

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.

Molecular classification of rhabdomyosarcoma--genotypic and phenotypic determinants of diagnosis: a report from the Children's Oncology Group.

Rhabdomyosarcoma (RMS) in children occurs as two major histological subtypes, embryonal (ERMS) and alveolar (ARMS). ERMS is associated with an 11p15.5 loss of heterozygosity (LOH) and may be confused with nonmyogenic, non-RMS soft tissue sarcomas. ARMS expresses the product of a genomic translocation that fuses FOXO1 (FKHR) with either PAX3 or PAX7 (P-F); however, at least 25% of cases lack these translocations. Here, we describe a genomic-based classification scheme that is derived from the combined gene expression profiling and LOH analysis of 160 cases of RMS and non-RMS soft tissue sarcomas that is at variance with conventional histopathological schemes. We found that gene expression profiles and patterns of LOH of ARMS cases lacking P-F translocations are indistinguishable from conventional ERMS cases. A subset of tumors that has been histologically classified as RMS lack myogenic gene expression. However, classification based on gene expression is possible using as few as five genes with an estimated error rate of less than 5%. Using immunohistochemistry, we characterized two markers, HMGA2 and TFAP2ss, which facilitate the differential diagnoses of ERMS and P-F RMS, respectively, using clinical material. These objectively derived molecular classes are based solely on genomic analysis at the time of diagnosis and are highly reproducible. Adoption of these molecular criteria may offer a more clinically relevant diagnostic scheme, thus potentially improving patient management and therapeutic RMS outcomes.