Outcome of patients with relapsed or refractory nonrhabdomyosarcoma soft tissue sarcomas enrolled in phase 2 cooperative group clinical trials: A report from the Children's Oncology Group.

BACKGROUND: The aim of this study was to estimate the event-free survival (EFS) of children and young adults with relapsed or refractory nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) treated in nonrandomized phase 2 studies conducted by the Children's Oncology Group (COG) and predecessor groups to establish a benchmark EFS for future phase 2 NRSTS trials evaluating the activity of novel agents. METHODS: A retrospective analysis of patients with recurrent or refractory NRSTS prospectively enrolled in nonrandomized phase 2 COG and predecessor group trials between 1994 and 2015 was conducted. EFS was defined as disease progression/relapse or death and calculated via the Kaplan-Meier method. The log-rank test and relative risk regression were used to compare EFS distribution by age at enrollment, sex, race, NRSTS histology, prior lines of therapy, calendar year of trial, and type of radiographic response. RESULTS: In total, 137 patients were enrolled in 13 phase 2 trials. All trials used radiographic response rate as a primary outcome, and none of the agents used were considered active on the basis of trial-specified thresholds. The estimated median EFS and 6-month EFS of the entire study cohort was 1.5 months (95% confidence interval [CI], 1.3-1.8 months) and 19.4% (95% CI, 12.7%-26%), respectively. No difference in EFS was observed by age at enrollment, sex, race, NRSTS histology subtype, prior lines of therapies, and trial initiation year. EFS significantly differed by radiographic response. CONCLUSIONS: The EFS for children and young adults with relapsed or refractory NRSTS remains suboptimal. Established EFS can be referenced as a benchmark for future single-agent phase 2 trials incorporating potentially active novel agents in this population.

Patients' values and preferences regarding endoscopic therapy for Barrett's esophagus: A cross-sectional survey study.

Introduction: Endoscopic eradication therapy (EET) has evolved as a minimally invasive and efficacious option to treat patients with dysplastic Barret's esophagus. We aimed to conduct a cross-sectional study to assess patient values and preferences on EET. Methods: All consecutive patients at our clinic and endoscopy center were enrolled between November 2020 and April 2022. The primary outcome was their willingness to undergo EET measured using a validated survey tool. Predictors of this outcome included patient demographics, disease characteristics, procedure types, and physician characteristics. We used a multivariable logistic regression model to assess the association between the primary outcome and its predictors. Results: A total of 101 consecutive Barret's esophagus patients were surveyed. The median age was 67 years, and 71.3% were males. About 48% (n = 48) of the patients had dysplasia, 19% had no dysplasia and others were unsure about the presence or absence of dysplasia. About one-third (30%, n = 30) of patients placed equal values on preventing cancer and avoiding adverse events, and 68% said they were somewhat or definitely willing to undergo EET (ablation and resection). On multivariable logistic regression analysis, the patient value of high emphasis on cancer prevention (odds ratio [OR] 2.9 [1.1-7.6], p = 0.0344) and positive relationship with a gastroenterologist (OR 4.7 [1.3-17], p = 0.02) were strongly associated with increased willingness to undergo EET. Conclusions: In this single-center prospective study of Barret's esophagus patients, the willingness to undergo EET was strongly associated with two predictors: high emphasis on cancer prevention and a positive relationship with the gastroenterologist.

Adolescents and young adults with rhabdomyosarcoma: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

INTRODUCTION: The impact of established prognostic factors on survival outcomes for childhood rhabdomyosarcoma (RMS) have not been well described in the adolescent and young adult (AYA) RMS patient population. METHODS: This is a retrospective analysis of patients with newly diagnosed RMS enrolled between 1997 and 2016 on seven previously reported Children's Oncology Group (COG) clinical trials. Demographics, clinical features, treatment details, and outcome data were collected. Five-year event-free survival (EFS) and overall survival (OS) were estimated for patients diagnosed at age 15-39 years and those diagnosed under age 15 years using the Kaplan-Meier method. Log-rank test was used to compare prognostic factors for EFS and OS. Factors significant in the univariable analysis were included in a Cox proportional hazards regression model. Nonsignificant covariates were removed from the multiple regression model. RESULTS: Total 2151 patients including 402 AYAs were analyzed. AYAs were more likely to present with primary tumors ≥5 cm in size, metastatic disease, alveolar histology, and have FOXO1 fusions compared to children. Five-year EFS for the AYA cohort was 44.2% versus 67% for children (p < .001), and 5-year OS was 52% for the AYA cohort versus 78% for children (p < .001). Multivariable analysis revealed tumor site, size and invasiveness, clinical group, and histology were prognostic in AYAs. CONCLUSION: AYAs with RMS have a poorer prognosis compared to younger children due to multiple factors. Further research focused on AYAs to better understand RMS biology and improve treatments is critical to improve survival.

Prognosis of children and young adults with newly diagnosed rhabdomyosarcoma metastatic to bone marrow treated on Children's Oncology Group studies.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Metastatic disease occurs in 16% of all RMS cases and has a poor prognosis. There are limited studies examining the outcomes specific to patients with RMS metastatic to bone marrow despite an incidence of 6% at diagnosis. Our study aims to document the outcomes, prognostic factors, and clinical courses of children presenting with RMS metastatic to bone marrow treated on Children's Oncology Group (COG) cooperative trials. METHODS: We performed a retrospective analysis of the patients diagnosed with RMS metastatic to bone marrow between 1997 and 2013 enrolled on one of four COG RMS clinical trials of D9802, D9803, ARST0431, and ARST08P1. RESULTS: We identified 179 cases with RMS metastatic to bone marrow. Patients had a median age of 14.8 years, 58% were male, predominantly alveolar histology (76%), extremity was the most common primary site (32%), and 87% had metastatic disease to additional sites; 83% (n = 149) received radiation as a treatment modality. The 3- and 5-year event-free survival was 9.4% and 8.2%, respectively. The 3- and 5-year overall survival was 26.1% and 12.6%, respectively. Age ≥10 years, alveolar histology, FOXO1 fusion presence, unfavorable primary location, higher Oberlin score, and lack of radiation were identified as poor prognostic/predictive characteristics. CONCLUSIONS: This study represents the largest analysis of RMS metastatic to bone marrow, defining the poor prognostic outcome for these patients. These patients may be eligible for therapy deintensification or early pursuit of novel treatments/approaches that are desperately needed.

Management and outcomes of chest wall rhabdomyosarcoma: A report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

INTRODUCTION: Rhabdomyosarcoma (RMS) of the chest wall presents unique management challenges and local control considerations. The benefit of complete excision is uncertain and must be weighed against potential surgical morbidity. Our aim was to assess factors, including local control modality, associated with clinical outcomes in children with chest wall RMS. METHODS: Forty-four children with RMS of the chest wall from low-, intermediate-, and high-risk Children's Oncology Group studies were reviewed. Predictors of local failure-free survival (FFS), event-free survival (EFS), and overall survival (OS) were assessed, including clinical characteristics and staging, primary tumor anatomic locations, and local control modalities. Survival was assessed by Kaplan-Meier analysis and the log-rank test. RESULTS: Tumors were localized in 25 (57%) and metastatic in 19 (43%), and they involved the intercostal region (52%) or superficial muscle alone (36%). Clinical group was I (18%), II (14%), III (25%), and IV (43%), and ultimately 19 (43%) patients had surgical resection (upfront or delayed), including 10 R0 resections. Five-year local FFS, EFS, and OS were 72.1%, 49.3%, and 58.5%, respectively. Univariate factors associated with local FFS included age, International Rhabdomyosarcoma Study (IRS) group, extent of surgical excision, tumor size, superficial tumor location, and presence of regional or metastatic disease. Other than tumor size, the same factors were associated with EFS and OS. CONCLUSIONS: Chest wall RMS has variable presentation and outcome. Local control is a significant contributor to EFS and OS. Complete surgical excision, whether upfront or after induction chemotherapy, is usually only possible for smaller tumors confined to the superficial musculature but is associated with improved outcomes. While overall outcomes remain poor for patients with initially metastatic tumors, regardless of local control modality, complete excision may be beneficial for patients with localized tumors if it can be achieved without excess morbidity.

Barrett's Esophagus in Obese Patient Post-Roux-en-Y Gastric Bypass: a Systematic Review.

PURPOSE: Barrett's esophagus (BE) is a relative contraindication for sleeve gastrectomy, but not for Roux-en-Y gastric bypass (RNY). However, studies assessing the effect of RNY on BE are limited. We aimed to conduct a systematic review and meta-analysis of studies of obese patients who also had BE and underwent RNY. MATERIALS AND METHODS: We conducted a systematic review of literature using multiple search engines from inception to January 2021. The primary outcome of interest was the rate of BE resolution post-RNY. This was reported as a proportion with 95% confidence intervals (CI). Publication bias was assessed by funnels plots and the classic fail test. Forest plots were used to report pooled effect estimates. Heterogeneity was assessed using I2 and p-value. RESULTS: The final search included 4389 citations, 16 were reviewed in full text, and 9 were included in the final analysis, including 7 manuscripts and 2 recent meeting abstracts. In the 9 studies, 104 patients had BE and underwent RNY. On random effect modeling, the rate of complete remission of intestinal metaplasia (CRIM) was 50% [95%CI: 40-61%], p = 0.937, I2 = 4.6%, Q = 8.4, p = 0.396. The pooled rate of BE improvement was 52% [95%CI: 37-66%], p = 0.8, I2 = 16.5%, Q = 4.8, p = 0.31. Complete remission of dysplasia (CRD) was also reported in 4 of 6 patients. CONCLUSION: Despite the limited data, a majority of patient with BE who underwent RNY for weight loss had remission or improvement in BE on follow-up endoscopy. However, a significant minority had no change to BE on follow-up.

Surveillance of Barrett's esophagus using wide-area transepithelial sampling: systematic review and meta-analysis.

Background and study aims Wide-area transepithelial sampling (WATS) is an emerging technique that may increase dysplasia detection in Barrett's esophagus (BE). We conducted a systematic review and meta-analysis of patients who underwent surveillance for BE assessing the additional yield of WATS to forceps biopsy (FB). Methods We searched Pubmed, Embase, Web of science, and the Cochrane library, ending in January 2021. The primary outcomes of interest were the relative and absolute increase in dysplasia detection when adding WATS to FB. Heterogeneity was assessed using I 2 and Q statistic. Publication bias was assessed using funnel plots and classic fail-safe test. Results A total of seven studies were included totaling 2,816 patients. FB identified 158 dysplasia cases, whereas WATS resulted in an additional 114 cases. The pooled risk ratio (RR) of all dysplasia detection was 1.7 (1.43-2.03), P  < 0.001, I 2  = 0. For high-grade dysplasia (HGD), the pooled RR was 1.88 (1.28-2.77), P  = 0.001, I 2  = 33 %. The yield of WATS was dependent on the prevalence of dysplasia in the study population. Among studies with high rates of dysplasia, the absolute increase in dysplasia detection (risk difference, RD) was 13 % (8 %-18 %, P  < 0.0001, number needed to treat [NNT] = 8). The pooled RD in HGD was 9 % (2 %-16 %), P  < 0.001, NNT = 11. For studies with a low prevalence of dysplasia, RD for all dysplasia was 2 % (1 %-3 %), P  = 0.001, NNT = 50. For HGD, the RD was 0.6 % (0.2 %-1.3 %), P  = 0.019, NNT = 166. Conclusions In populations with a high prevalence of dysplasia, adding WATS to FB results in a significant increase in dysplasia detection.

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.

Barriers to Clinical Practice Guideline Implementation Among Physicians: A Physician Survey.

INTRODUCTION: Clinical practice guidelines can help physicians provide evidence-based, standardized clinical decisions. We aimed to assess physician attitudes toward and barriers to guideline adherence. METHODS: We conducted a single center, cross-sectional, survey-based study. Physicians from many specialties participated in the study. All outcomes were measured using a validated survey tool. The primary outcome of interest was barriers to guideline adherence. Secondary outcomes included general attitudes toward guidelines and factors that could improve adherence to guidelines. Outcomes were measured by the survey tool. All outcomes were reported on a 5-point Likert scale. RESULTS: The email survey was received by 1819 physicians with 400 responders (22% response rate). About 50% (n=200) were in practice for >5 years, while 27% (n=107) were still in training. Trainees were less likely to understand the process of guideline development (RR= 0.76 [0.65-0.88], p=0.0017), to have input in guideline development (RR= 0.52 [0.41-0.65], p<0.0001), and to report up-to-date knowledge in practice guidelines (RR=0.53 [0.30-0.73], p=0.0002). Three factors were identified as major barriers to guideline adherence: complexity of guideline documents (61%, n=240), high number of weak or conditional recommendations (62%, n=245), and time constraints due to clinical responsibilities (65%, n=255). Factors that would improve guideline adherence included access to relevant guidelines at the point of care (87%), improved focus on guidelines during training (82%), and transparency on physician commercial affiliation (62%). CONCLUSION: Improved focus on guidelines during training and access to relevant guidelines at the point of care may be important to improve adherence to guidelines.

High rate of over-staging of Barrett's neoplasia with endoscopic ultrasound: Systemic review and meta-analysis.

BACKGROUND: The use of endoscopic ultrasound (EUS) to stage patients with Barrett's esophagus (BE) with suspected neoplasia is controversial due to high rates of over-staging. However, this rate of over-staging has not been adequately investigated or quantified. AIM: To determine the rate of over-staging related EUS in this population. METHODS: Search included Medline, Embase, Web of Science, and Cochrane Central ending on 9/30/2016. The primary effect-estimate of interest was the false positive rate of advanced disease on EUS at the tumor level (T1a vs. T1b). Secondary outcomes included false detection rate, false negative rate, accuracy, sensitivity, and specificity. Study heterogeneity was assessed using the I2 and Cochrane's Q. RESULTS: Of 1872 studies, 11 met our inclusion criteria totaling 895 patients. Based on random effects models, the pooled FPR for advanced disease was 9.1% ([6.5-12.5%], p<0.001). Tests of heterogeneity showed no significant heterogeneity for this outcome. The pooled false negative rate was 9.2% [95%CI: 4.7-17.3%], p<0.01. Overall, the pooled accuracy of EUS results in BE neoplasia patients was low at 74.6% [58.7-85.8%], p=0.004. CONCLUSIONS: The use of EUS in BE patients with dysplasia and early neoplasia results in a large proportion of patients falsely over-staged and under-staged.

Adverse Events After Radiofrequency Ablation in Patients With Barrett's Esophagus: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Radiofrequency ablation (RFA) with or without endoscopic mucosal resection (EMR) is routinely used for treatment of Barrett's esophagus with dysplasia. Despite the relative safety of this method, there have been imprecise estimates of the rate of adverse events. We performed a systematic review and meta-analysis to assess the rate of adverse events associated with RFA with and without EMR. METHODS: We searched MEDLINE, Embase, Web of Science, and Cochrane Central through October 22, 2014. The primary outcome of interest was the overall rate of adverse events after RFA with or without EMR. We used forest plots to contrast effect sizes among studies. RESULTS: Of 1521 articles assessed, 37 met our inclusion criteria (comprising 9200 patients). The pooled rate of all adverse events from RFA with or without EMR was 8.8% (95% confidence interval [CI], 6.5%-11.9%); 5.6% of patients developed strictures (95% CI, 4.2%-7.4%), 1% had bleeding (95% CI, 0.8%-1.3%), and 0.6% developed a perforation (95% CI, 0.4%-0.9%). In studies that compared RFA with vs without EMR, the relative risk for adverse events was significantly higher for RFA with EMR (4.4) (P = .015). There was a trend toward higher proportions of adverse events in prospective studies compared with retrospective studies (11.3% vs 7.8%, P = .20). Other factors associated with adverse events included Barrett's esophagus and length and baseline histology. CONCLUSIONS: In a systematic review and meta-analysis, we found the relative risk for adverse events from RFA to be about 4-fold higher with EMR than without; we identified factors associated with these events. Endoscopists should discuss these risks with patients before endoscopic eradication therapy.