Roadmap for the next generation of Children's Oncology Group rhabdomyosarcoma trials.

Clinical trials conducted by the Intergroup Rhabdomyosarcoma (RMS) Study Group and the Children's Oncology Group have been pivotal to establishing current standards for diagnosis and therapy for RMS. Recent advancements in understanding the biology and clinical behavior of RMS have led to more nuanced approaches to diagnosis, risk stratification, and treatment. The complexities introduced by these advancements, coupled with the rarity of RMS, pose challenges to conducting large-scale phase 3 clinical trials to evaluate new treatment strategies for RMS. Given these challenges, systematic planning of future clinical trials in RMS is paramount to address pertinent questions regarding the therapeutic efficacy of drugs, biomarkers of response, treatment-related toxicity, and patient quality of life. Herein, the authors outline the proposed strategic approach of the Children's Oncology Group Soft Tissue Sarcoma Committee to the next generation of RMS clinical trials, focusing on five themes: improved novel agent identification and preclinical to clinical translation, more efficient trial development and implementation, expanded opportunities for knowledge generation during trials, therapeutic toxicity reduction and quality of life, and patient engagement.

Event-free survival in relapsed and refractory rhabdomyosarcoma treated on cooperative group phase II trials: A report from the Children's Oncology Group.

BACKGROUND: Novel therapies are needed for relapsed and refractory rhabdomyosarcoma (RRMS). Phase II clinical trials in RRMS have typically utilized radiologic response as the primary activity endpoint, an approach that poses several limitations in RRMS. In this analysis, we aimed to estimate an event-free survival (EFS) endpoint for RRMS that could be used as a benchmark for future studies. PROCEDURE: We performed a retrospective study of patients with RRMS enrolling on 13 single-agent phase II Children's Oncology Group and legacy group trials from 1997 to 2016. All included trials used radiographic response as their primary activity endpoint. Six-month EFS was estimated from time of trial enrollment with 95% confidence intervals. Clinical characteristics, including trial of enrollment, sex, age, race, histology, number of prior chemotherapies, and radiographic response were evaluated for their impact on 6-month EFS. RESULTS: We identified 175 patients across 13 trials. The 6-month EFS was 16.8% (11.6%-22.8%). No differences were seen in 6-month EFS based on age, sex, race, or histology. There were nonsignificant trends toward improved 6-month EFS for patients with less than or equal to two prior lines of therapy versus higher than two, for patients enrolled on trials that achieved their primary radiographic response endpoint versus trials that did not, and for patients who achieved complete or partial response compared to those achieving stable disease. CONCLUSIONS: The prognosis of RRMS enrolled on single-agent phase II trials is poor. This pooled 6-month EFS of RRMS on single-agent trials may be used as a RRMS-specific benchmark for future single-agent phase II trials.

Survival of patients with orbital and eyelid rhabdomyosarcoma treated on Children's Oncology Group studies from 1997 to 2013: A report from the Children's Oncology Group.

BACKGROUND: Orbital rhabdomyosarcoma (ORMS) commonly presents as low-risk disease (stage 1, group I-III, embryonal RMS) with excellent outcome. Long-term follow-up of patients with low-risk ORMS and outcomes of less common subgroups of ORMS treated on recent Children's Oncology Group (COG) trials have not been reported. METHODS: Patients with ORMS enrolled on COG trials from 1997 to 2013 were identified. Demographic information and disease characteristics were collected. Outcomes were determined for the following subgroups: 1) low-risk ORMS, 2) resected (group I/II) low-risk ORMS, 3) non-low-risk ORMS, and 4) recurrent ORMS. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan-Meier method. ResultsThe authors identified 218 patients with ORMS. Most tumors were embryonal/botryoid (n = 169; 77.5%), <5 cm (n = 213; 97.7%), group III (n = 170; 78.0%), and without lymph node involvement (N0; n = 215; 98.6%). For 192 patients with low-risk ORMS, the 10-year EFS and OS rates were 85.5% (95% confidence interval [CI], 77.0%-94.0%) and 95.6% (95% CI, 90.8%-100.0%), respectively. Those with group I/II low-risk ORMS (n = 5 in group I; n = 39 in group IIA) had 10-year EFS and OS rates of 88.0% (95% CI, 72.6%-100.0%) and 97.6% (95% CI, 90.0%-100.0%), respectively. Twenty-six patients with non-low-risk ORMS had 5-year EFS and OS rates of 88.5% (95% CI, 75.6%-100.0%) and 95.8% (95% CI, 87.7%-100.0%), respectively. For patients with recurrent ORMS, the 10-year OS rate from the time of recurrence was 69.4% (95% CI, 50.0%-88.8%). CONCLUSIONS: Patients with ORMS had favorable long-term survival outcomes on COG studies from 1997 to 2013, including those who had both low-risk and non-low-risk disease. A significant proportion of patients with recurrent ORMS may achieve long-term survival.

Strategies for the Treatment of Infantile Soft Tissue Sarcomas With BCOR Alterations.

BCOR alterations are described in ultra-rare infantile soft tissue sarcomas including primitive myxoid mesenchymal tumor of infancy and undifferentiated round cell sarcoma (URCS). Previous reports often describe dismal outcomes. Thus, we undertook a retrospective, multi-institutional study of infants with BCOR -rearranged soft tissue sarcomas. Nine patients aged 6 weeks to 15 months were identified. One tumor carried a BCOR :: CCNB3 fusion, whereas 7 tumors harbored internal tandem duplication of BCOR , including 4 cases classified as primitive myxoid mesenchymal tumor of infancy, 1 case as URCS, and 2 cases characterized by a "hybrid morphology" in our evaluation. Four patients underwent upfront surgery with residual disease that progressed locally after a median of 2.5 months. Locoregional recurrences were observed in hybrid patients, and the URCS case recurred with brain metastases. Complete radiographic responses after chemotherapy were achieved in patients treated with vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide (regimen I), and ifosfamide/carboplatin/etoposide. Seven patients received radiotherapy. With a median of 23.5 months off therapy, 8 patients are with no evidence of disease. In our study, observation was inadequate for the management of untreated postsurgical residual disease. Tumors demonstrated chemosensitivity with anthracycline-based regimens and ifosfamide/carboplatin/etoposide. Radiotherapy was required to achieve durable response in most patients.

The Incidence of Thromboembolic Events During Hospitalizations Following Surgical Resection of Lower Extremity Sarcomas in Children: Utilizing the Pediatric Health Information System Database.

BACKGROUND: Venous thromboembolism (VTE) is a frequent occurrence during treatment for adults with sarcoma. The incidence and underlying risk factors of postsurgical VTE in children and adolescents undergoing resection of sarcoma are unknown. METHODS: Using International Classification of Disease revision-9 diagnostic and procedure codes, the Pediatric Health Information System database was queried for patients aged 18 years and younger, discharged from 2004 to 2015 with a diagnosis of lower extremity malignant neoplasm who had a tumor resection or amputation performed during the encounter. Malignant neoplasms of the pelvic bones and soft tissues were categorized as "pelvis tumors", whereas malignant neoplasms of bone and soft tissues of the lower limbs were categorized as "lower limb tumors". Hospitalizations were evaluated for the occurrence of VTE. Demographic characteristics (age at admission, sex, race, and race/ethnicity) and incidence of VTE were reported. RESULTS: There were 2400 patients identified. Of these, 19 experienced VTE (0.79%) during their surgical hospitalization encounter. By anatomic group, the rate of VTE was 1.4% (CI: 0.5%-3.2%) for tumors in the pelvis and 0.6% (CI: 0.3%-1.0%) in lower limb tumors. Categorizing by age, the incidence of VTE was 1.2% in patients aged zero to 5, 0.3% in patients 6 to 13, and 1.2% in patients 14 to 18 years old. (Table 1). The extremely low rate of VTE occurrence precluded further analysis of risk factors. CONCLUSIONS: In this analysis, postsurgical VTE during hospitalization after pelvic and lower extremity sarcoma resection was an uncommon event in children and adolescents. There seemed to be an increased incidence of postsurgical VTE in pelvic tumors when compared with lower limb tumors, however, the rarity of all events precluded formal statistical analysis. A more robust data set would be required to determine if there are subsets of children and adolescents with sarcoma at higher risk of VTE that could benefit from thromboprophylaxis in the postoperative setting. LEVEL OF EVIDENCE: Level II.

A phase I study of irinotecan and temozolomide with bevacizumab in children with recurrent/refractory central nervous system tumors.

PURPOSE: Children with relapsed/refractory central nervous system (CNS) tumors require novel combinations of therapies. Irinotecan and temozolomide (IT) is a frequently used therapy with an established toxicity profile. Bevacizumab is an anti-VEGF monoclonal antibody with demonstrated activity in CNS tumors. Therefore, the combination of these agents has therapeutic potential in CNS tumors. The objective of this study was to determine the maximum tolerated dose (MTD) of escalating dose IT combined with a fixed dose of bevacizumab (BIT) in children with relapsed/refractory CNS tumors. METHODS: A phase I trial was performed in a 3 + 3 design. Therapy toxicities and radiologic responses to treatment were described. RESULTS: One hundred eighty cycles of therapy were administered to 26 patients. The MTD of BIT was dose level 1, (bevacizumab 10 mg/kg on days 1 and 15, irinotecan 125 mg/m2 on days 1 and 15, and temozolomide 125 mg/m2 on days 1-5 of 28-day cycles). The regimen was well tolerated with primarily hematologic toxicity, which was not dose limiting. Among 22 response-evaluable patients, there was 1 complete response (CR), 6 partial responses (PR), and 10 stable diseases (SD) with an overall response rate (ORR: CR + PR) of 31.8%. CONCLUSION: At the MTD, BIT therapy was well tolerated, and prolonged treatment courses of up to 24 cycles were feasible, with radiographic responses observed. Further evaluation is needed for efficacy in a phase II trial (NCT00876993, registered April 7, 2009, www. CLINICALTRIALS: gov ).

Gemcitabine/nab-paclitaxel for pediatric relapsed/refractory sarcomas.

BACKGROUND: Pediatric patients with relapsed/refractory sarcomas have poor outcomes and need novel therapies that provide disease control while maintaining an acceptable quality of life. The activity and toxicity of gemcitabine and nab-paclitaxel in combination has not been reported in pediatrics. PROCEDURE: We reviewed the records of fifteen relapsed/refractory patients and one treatment-naïve patient who received gemcitabine/nab-paclitaxel at our institution. RESULTS: Sixteen patients (median age 13.5 years, range 3-19 years) received 53 cycles of gemcitabine/nab-paclitaxel. Twenty-nine cycles (55%) resulted in ≥Grade 3 toxicity, with nonhematologic Grade ≥3 toxicities occurring in only eight of 53 cycles (15%). Patients received red blood cell and platelet transfusions in 23% and 4% of cycles, respectively. Grade ≥3 infectious toxicities occurred in 4% of cycles. Of 14 patients with measurable disease, there were no complete responses (CR), one partial response (PR; 7%), and six patients (43%) with stable disease (SD; median SD: 4.5 months, range: 2-19 months). In total, 31% of the patients derived clinical benefit (CR + PR + SD ≥ 4 months). Median time to progression was 72 days with a 4-month progression-free survival of 31% ± 12% and 1-year overall survival of 19% ± 10%. With a median follow-up for all 16 patients of 21 months from the first treatment with gemcitabine/nab-paclitaxel, one (6%) remains alive with disease. CONCLUSIONS: Gemcitabine/nab-paclitaxel is a relatively safe regimen with mainly hematologic toxicities. It offers a well-tolerated, palliative option providing clinical benefit in a subset of patients. A phase I trial of this combination is underway.

Concurrent myeloid sarcoma, atypical teratoid/rhabdoid tumor, and hypereosinophilia in an infant with a germline SMARCB1 mutation.

We report a 1-year-old female child presenting with hypereosinophilia who was found to have concurrent myeloid sarcoma and a central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT). She was later found to have a germline mutation in SMARCB1. Concurrent hematologic malignancy and CNS AT/RT have not previously been described in the context of a SMARCB1 loss-of-function germline mutation.

Infantile Hemangioma Mimics Dermatofibrosarcoma Protuberans.

Infantile hemangiomas are commonly encountered at all levels of medical practice. Clinicians should be aware of their typical clinical history and findings in order to expedite early diagnosis and management. It is also necessary to be aware of differential diagnoses that may mimic infantile hemangiomas but have a more concerning prognosis. The objective of this report is to describe the clinical case of one such mimic, dermatofibrosarcoma protuberans. This report highlights key clinical findings of infantile hemangiomas, while also identifying "red flags" that necessitate urgent additional investigations and referral to a multidisciplinary team. Additionally, key features in the management of both infantile hemangiomas and extremity masses are discussed.

Appendiceal mucinous neoplasm in adolescence: Diagnosis, management, and surveillance.

This case report describes a 17-year-old patient with a low-grade appendiceal mucinous neoplasm. The patient presented with non-bloody diarrhea, abdominal pain, and weight loss. A colonoscopy revealed a cecal polypoid mass that required laparoscopic surgery. The residual appendix was dilated with myxoglobulosis and histopathology confirmed the diagnosis of a low-grade appendiceal mucinous neoplasm staged pT3Nx. The potential risk of pseudomyxoma peritonei is a serious complication of these tumors. Surveillance plans include computed tomography abdomen and pelvis, and tumor markers every 6 months for the next 2 years. This case highlights the importance of considering appendiceal malignancy in patients with abdominal pain and weight loss, despite the rarity of the disease. It also emphasizes the need for careful monitoring due to the possible complications associated with these tumors. Treatment and prognosis for appendiceal neoplasms depend on the histopathologic characteristics, tumor-nodes-metastasis stage, tumor grade, and presence of peritoneal disease.

Pediatric Leukemia Roadmaps Are a Guide for Positive Metastatic Bone Sarcoma Trials.

ALL cures require many MRD therapies. This strategy should drive experiments and trials in metastatic bone sarcomas.

Clinical Trials on Cellular Therapy for Children and Adolescents With Cancer: A 15-Year Trend in the United States.

INTRODUCTION: Cellular therapies are frequently studied in clinical trials for pediatric patients with malignant disease. Characteristics of ongoing and completed cellular therapy clinical trials in the U.S. involving children and adolescents have not previously been reported. METHODS: We searched ClinicalTrials.gov for clinical trials involving cellular therapies enrolling patients under 18 years of age in the U.S. Trials were initially stratified into child-only (maximum age of eligibility <18 years), child/adolescent and young adult (AYA) (maximum age of eligibility ≤21 years), and child/adult (maximum age of eligibility >21 years). Descriptive characteristics and trends over time were analyzed. RESULTS: We included 202 trials posted 2007-2022. Of the 202 trials, only three trials were child-only; thus, our subsequent analysis focused on comparing child/AYA (≤21 years) and child/adult trials (>21 years). One hundred sixty-nine (84%) enrolled both child and adult populations. The vast majority of trials were early phase (phase 1, 1/2, and 2, 198/202, 98%). Chimeric antigen receptor T cell therapies were most commonly studied (88/202, 44%), while natural-killer cell therapies were most common in child/AYA trials (42% vs. 16%). Most trials were single institution-only (130/202, 64%) and did not receive industry funding (163/202, 81%). Studies with industry funding were more likely to be multicenter (64% vs. 29%) and international (31% vs. 0.6%). Notably, no central nervous system tumor-specific trials had industry funding. There was no difference in therapy type based on funding source. Yearly new trial activations increased over the time period studied (p=0.01). CONCLUSION: The frequency of cellular therapy trial activations enrolling child/AYA patients with cancer in the U.S. has increased over time. Most studies were phase 1 or 2, single institution-only, and not industry-supported. Future opportunities for cell therapy for pediatric cancer should include multi-institutional approaches.

Trends in Pediatric Cancer Care in Florida From 1981-2020: Changing Patterns in a Growing and Increasingly Diverse Population.

Background The Florida Association of Pediatric Tumor Programs (FAPTP) has used the Statewide Patient Information Reporting System (SPIRS) since 1981 to track all new cases of pediatric cancer. We reviewed the last 40 years of data to see how pediatric cancer care has evolved. Methods We retrospectively analyzed SPIRS data from 1981 through 2020 in five-year increments, looking at numbers of new diagnoses, care delivery sites, and trial enrollment in Children's Oncology Group (COG) studies. Results From 1981-2020 Florida's population increased almost 88% while the pediatric population only grew 61%. New pediatric cancer diagnoses increased 326% to over 1,000 new cases/year. The percentage of patients treated at FAPTP centers grew from 30% to 57% with an annual percentage change (APC) of 10.3% (95% Confidence Interval [CI] of 0.6 to 20.9%). The rate of COG clinical trial enrollment decreased from 32% in 1981-1985 to 20% in 2016-2020, for an APC of 8.91% (95% CI of -13.3 to -4.3%). Conclusions The striking increase in pediatric cancer cases in Florida over the last 40 years was out of proportion to the population growth. More patients received care at FAPTP centers, but a lower percentage were enrolled on COG trials.

A phase I trial of metformin in combination with vincristine, irinotecan, and temozolomide in children with relapsed or refractory solid and central nervous system tumors: A report from the national pediatric cancer foundation.

BACKGROUND: Patients with relapsed and refractory solid and central nervous system (CNS) tumors have poor outcomes and need novel therapeutic options. Vincristine, irinotecan, and temozolomide (VIT) is a common chemotherapy regimen in relapsed pediatric tumors with an established toxicity profile. Metformin shows preclinical anti-cancer activity through multiple pathways. METHODS: The objective of this Phase I trial was to establish the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of metformin in combination with VIT in children with relapsed and refractory solid and CNS tumors. A 3 + 3 design was used to test the addition of metformin at five dose levels (666, 999, 1333, 1666, and 2000 mg/m2 /day). Therapy toxicity, pharmacokinetics, and radiologic response to treatment were evaluated. RESULTS: Twenty-six patients (median age 13 years, range 2-18 years) were enrolled with 22 evaluable for toxicity. The most common diagnoses were Ewing sarcoma (n = 8), rhabdomyosarcoma (n = 3) and atypical teratoid/rhabdoid tumor (n = 3). The MTD was exceeded at Dose Level 5 due to two dose-limiting toxicities; both were Grade 3 diarrhea requiring prolonged hospitalization and intravenous fluids. The MTD was not determined due to study closure with less than six patients enrolled at Dose Level 4. Frequently observed toxicities were gastrointestinal (most notably diarrhea) and hematologic. Amongst 16 patients evaluable for best overall response, there was one complete response (Ewing sarcoma), three partial responses (Ewing sarcoma, glioblastoma multiforme, and alveolar rhabdomyosarcoma), and five patients with stable disease. CONCLUSIONS: The MTD of VIT with metformin was not determined due to premature study closure. We recommend an RP2D of Dose Level 4, 1666 mg/m2 /day. Radiographic responses were seen in multiple tumor types. Further evaluation for efficacy could be investigated in a Phase II trial.

Modeling phenotypic heterogeneity towards evolutionarily inspired osteosarcoma therapy.

Osteosarcoma is the most common bone sarcoma in children and young adults. While universally delivered, chemotherapy only benefits roughly half of patients with localized disease. Increasingly, intratumoral heterogeneity is recognized as a source of therapeutic resistance. In this study, we develop and evaluate an in vitro model of osteosarcoma heterogeneity based on phenotype and genotype. Cancer cell populations vary in their environment-specific growth rates and in their sensitivity to chemotherapy. We present the genotypic and phenotypic characterization of an osteosarcoma cell line panel with a focus on co-cultures of the most phenotypically divergent cell lines, 143B and SAOS2. Modest environmental (pH, glutamine) or chemical perturbations dramatically shift the success and composition of cell lines. We demonstrate that in nutrient rich culture conditions 143B outcompetes SAOS2. But, under nutrient deprivation or conventional chemotherapy, SAOS2 growth can be favored in spheroids. Importantly, when the simplest heterogeneity state is evaluated, a two-cell line coculture, perturbations that affect the faster growing cell line have only a modest effect on final spheroid size. Thus the only evaluated therapies to eliminate the spheroids were by switching therapies from a first strike to a second strike. This extensively characterized, widely available system, can be modeled and scaled to allow for improved strategies to anticipate resistance in osteosarcoma due to heterogeneity.

A Proposed Trial Design for the Treatment of Widely Metastatic Ewing Sarcoma Inspired by Evolutionary Dynamics.

Metastatic Ewing sarcoma has dismal long-term survival despite multiple attempts to intensify standard therapy through the addition of new agents to the existing chemotherapy backbone. Here, based on the application of evolutionary dynamics to pediatric sarcoma, we propose an alternative treatment strategy that varies exposure to agents and dosing intensities, termed sequential second-strike therapy (SSST). We announce an upcoming clinical trial to apply these principles to patients with widely metastatic Ewing sarcoma, those with metastatic disease beyond the lungs.

Gastrointestinal Complications of Intra-Abdominal Desmoid Tumors: A Case Report and Review of the Literature.

A 15-year-old male with a mesenteric desmoid tumor and underlying familial adenomatous polyposis presented 2 weeks after initiating sorafenib with severe abdominal pain and chills and was found to have an acute abdomen. Exploratory laparotomy revealed a necrotic, ruptured tumor with impending small bowel obstruction. The patient was later able to resume sorafenib and experienced sustained a radiographic response. It is possible that sorafenib toxicity contributed to tumor rupture yet later provided clinical benefit. Here we review the gastrointestinal complications that are associated with intra-abdominal desmoid tumors and their therapies.

Adoptive Cellular Therapy for Pediatric Solid Tumors: Beyond Chimeric Antigen Receptor-T Cell Therapy.

ABSTRACT: Children and adolescents with high-risk (metastatic and relapsed) solid tumors have poor outcomes despite intensive multimodal therapy, and there is a pressing need for novel therapeutic strategies. Adoptive cellular therapy (ACT) has demonstrated activity in multiple adult cancer types, and opportunity exists to expand the use of this therapy in children. Employment of immunotherapy in the pediatric population has realized only modest overall clinical trial results, with success thus far restricted mainly to antibody-based therapies and chimeric antigen receptor T-cell therapies for lymphoid malignancy. As we improve our understanding of the orchestrated cellular and molecular mechanisms involved in ACT, this will provide biologic insight and improved ACT strategies for pediatric malignancies. This review focuses on ACT strategies outside of chimeric antigen receptor T-cell therapy, including completed and ongoing clinical trials, and highlights promising preclinical data in tumor-infiltrating lymphocytes that enhance the clinical efficacy of ACT for high-risk pediatric solid tumors.

Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a heterogeneous disease with a high relapse rate. Cytokine receptor targeted therapies are therapeutically attractive but are subject to resistance-conferring mutations. Likewise, targeting downstream signaling pathways has been difficult. Recent success in the development of synergistic combinations has provided new hope for refractory AML patients. While generally not efficacious as monotherapy, BH3 mimetics are very effective in combination with chemotherapy agents. With this in mind, we further explored novel BH3 mimetic drug combinations and showed that pimozide cooperates with mTOR inhibitors and BH3 mimetics in AML cells. The three-drug combination was able to reach cells that were not as responsive to single or double drug combinations. In Flt3-internal tandem duplication (ITD)-positive cells, we previously showed pimozide to be highly effective when combined with imipramine blue (IB). Here, we show that Flt3-ITD+ cells are sensitive to an IB-induced dynamin 1-like (Drp1)-p38-ROS pathway. Pimozide contributes important calcium channel blocker activity converging with IB on mitochondrial oxidative metabolism. Overall, these data support the concept that antioxidants are a double-edged sword. Rationally designed combination therapies have significant promise for further pre-clinical development and may ultimately lead to improved responses.