Desmoplastic Small Round Cell Tumor Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Results of a Phase 2 Trial.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma that primarily affects adolescents and young adults. Patients can present with many peritoneal implants. We conducted a phase 2 clinical trial utilizing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) with cisplatin for DSRCT and pediatric-type abdominal sarcomas. PATIENTS AND METHODS: A prospective cohort study was performed on 20 patients, who underwent CRS-HIPEC procedures, with cisplatin from 2012 to 2013. All patients were enrolled in the phase 2 clinical trial. Patients with extraabdominal disease and in whom complete cytoreduction (CCR0-1) could not be achieved were excluded. All outcomes were recorded. RESULTS: Fourteen patients had DSRCT, while five patients had other sarcomas. One patient had repeat HIPEC. Patients with DSRCT had significantly longer median overall survival after surgery than patients with other tumors (44.3 vs. 12.5 months, p = 0.0013). The 3-year overall survival from time of diagnosis for DSRCT patients was 79 %. Estimated median recurrence-free survival (RFS) was 14.0 months. However, RFS for patients with DSRCT was significantly longer than for non-DSRCT patients (14.9 vs. 4.5 months, p = 0.0012). Among DSRCT patients, those without hepatic or portal metastases had longer median RFS than those with tumors at these sites (37.9 vs. 14.3 months, p = 0.02). In 100 % of patients without hepatic or portal metastasis, there was no peritoneal disease recurrence after CRS-HIPEC. CONCLUSIONS: Complete CRS-HIPEC with cisplatin is effective in select DSRCT patients. DSRCT patients with hepatic or portal metastasis have poorer outcomes.

Retroperitoneal lymph node staging in paratesticular rhabdomyosarcoma-are we meeting expectations?

BACKGROUND: Staging retroperitoneal lymph node dissection (RPLND) for paratesticular rhabdomyosarcoma (RMS) is recommended for all patients aged ≥10 y. The purpose of this study was to evaluate adherence with surgical resection guidelines for RPLND in patients with paratesticular RMS as a measure for surgical quality. MATERIALS AND METHODS: All patients with paratesticular RMS were identified in the Surveillance, Epidemiology, and End Results database from 1973 to 2012. Patients were divided into two eras to reflect before (1973-2002) and after (2003-2012) the release and dissemination of the 2001 surgical guidelines for staging ipsilateral RPLND in all patients aged ≥10 y with paratesticular RMS. Survival outcomes associated with lymph node dissection were calculated using the Kaplan-Meier method and Cox proportional hazards analysis. RESULTS: Two hundred thirty-five patients with paratesticular RMS were identified and included in the study, among whom 111 were adolescents aged 10-20. RPLND did not significantly increase after 2003 among adolescents (45%-61%, P = 0.09). The benefit of RPLND on improved 5-y overall survival was evident among adolescents (92% versus 64%, P = 0.003). Adjusting for histology, age, stage at diagnosis, and race/ethnicity, RPLND was associated with improved overall survival among patients aged ≥10 y (hazard ratio 0.37, 95% confidence interval 0.17-0.83). CONCLUSIONS: Despite surgical guidelines recommending RPLND in pediatric patients aged ≥10 y, nearly one-third of adolescent patients did not undergo RPLND. These findings are disturbing considering the survival benefit associated with RPLND among adolescent patients and indicate an opportunity for improvement in surgical quality.

45 Gy is not sufficient radiotherapy dose for Group III orbital embryonal rhabdomyosarcoma after less than complete response to 12 weeks of ARST0331 chemotherapy: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

BACKGROUND: Recent Children's Oncology Group (COG) trials tested the efficacy of reduced therapy in an effort to lessen late effects compared to the Intergroup Rhabdomyosarcoma Study (IRS) IV regimen with associated hematologic and hepatic toxicity, and infertility. Here, we analyze the efficacy of 45 Gray (Gy) local radiotherapy (RT) in patients with Group III orbital embryonal rhabdomyosarcoma (ERMS) enrolled on the COG low-risk study ARST0331. PROCEDURE: Sixty-two patients with Group III orbital ERMS were treated on ARST0331 with four cycles of vincristine (VCR), dactinomycin (DACT), and cyclophosphamide (CPM; VAC, total cumulative CPM dose 4.8 g/m2 ) followed by four cycles of VCR and DACT over 22 weeks. Forty-five Gray of radiation was administered in 25 fractions beginning at week 13 of therapy. RESULTS: Fifty-three patients were evaluable for this response analysis; seven had missing week 12 response evaluation data and two had progressive disease prior to starting RT. Median follow-up was 7.8 years. None of the 15 patients with radiographic complete response (CR) compared to 6 of the 38 patients with

Analysis of a Modified Two-Stage Approach to Ileal Pouch-Anal Anastomosis Without Fecal Diversion in Pediatric Patients.

BACKGROUND: Fecal diversion after ileal pouch anal anastomosis (IPAA) in children with ulcerative colitis (UC) remains controversial. We hypothesize that a modified two-stage IPAA omitting diverting ileostomy (DI) after IPAA, found to be safe in adults, would produce similar results in children. METHODS: Retrospective, single-institution study of children (≤18 years) undergoing staged total proctocolectomy with IPAA from 2014 to 2020. Traditional two-stage and three-stage approaches including DI after IPAA were compared to two-stage approach without DI. RESULTS: 32 patients were included; of these, 7 (22%), 14 (44%), and 11 (34%) patients underwent traditional two-stage, modified two-stage, or three-stage IPAA, respectively. Following IPAA, modified two-stage patients had shorter operative time, decreased opioid utilization, quicker return to regular diet, and shorter stoma duration. After IPAA, there was similar postoperative length of stay, complication rates, readmissions, visits to the emergency department, or unplanned return to the operating room (OR) within 30 days. Anastomotic leak occurred in 2 patients; both were managed nonoperatively without evidence of pouch dysfunction. CONCLUSION: Modified two-stage IPAA with omission of DI after the IPAA stage is safe to perform in pediatric UC patients. Prospective studies with larger sample sizes are needed to identify risk factors associated with operative complications.

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.

Colon Cancer in Patients Under 25 Years Old: A Different Disease?

BACKGROUND: The aim of this study was to compare the stage-for-stage overall (OS) and recurrence-free (RFS) survival between adult and pediatric/adolescent colon cancer patients. STUDY DESIGN: A retrospective review of pediatric/adolescent patients less than 25 years old, treated between 1991 and 2017 at University of Texas MD Anderson Cancer Center, was compared with a prospectively maintained database of adult patients. Outcomes variables were compared, and OS and RFS were estimated using the Kaplan-Meier method and compared between groups using the log rank test and multivariable Cox models. RESULTS: The cohort contained 94 pediatric patients and 765 adult patients. Overall, the 3-year OS rates for adult and pediatric patients, respectively, were 90% and 41.92% (95% CI 87% to 92%) (p < 0.0001), and the 3-year RFS rates were 78% and 32% (p < 0.0001). The stage-for-stage 5-year OS rates for adult vs pediatric patients were: Stage 1: 96% vs 100% (p = 0.793); stage 2: 90% vs 64% (p < 0.0001); stage 3: 85% vs 58% (p < 0.0001); stage 4; 55% vs 16% (p < 0.0001). The stage-for-stage 5-year RFS rates for adults vs children were: stage 1: 95% vs 100%; stage 2: 85% vs 55% (p = 0.0002); stage 3: 73% vs 31% (p < 0.0001); stage 4: 27% vs 5% (p < 0.0001). Pediatric/adolescent patients had a higher risk of recurrence or death than adult patients on multivariate analysis (hazard ratio [HR] 2.312, 95% CI: 1.615 to 3.313 (p < 0.0001). Peritoneal metastasis was significantly higher in pediatric patients. (p = 0.00001) CONCLUSIONS: Stage-for-stage, pediatric/adolescent patients had shorter 3- and 5-year OS and RFS rates than adult patients. Peritoneal disease and carcinomatosis were significantly higher in pediatric, adolescent, and young adult patients less than 25 years old. Predisposing conditions, such as polyposis or congenital colon disease, did not contribute to this difference.

Aerosol Gemcitabine after Amputation Inhibits Osteosarcoma Lung Metastases but Not Wound Healing.

BACKGROUND: In newly diagnosed osteosarcoma (OS) patients, the time between surgery and resumption of chemotherapy is 2-7 weeks. Delays > 16 days are associated with increased risk of relapse and decreased overall survival. Identifying an effective therapy that can be used postoperatively may prevent relapse. We investigated whether aerosol gemcitabine (GCB) initiated after tumor resection inhibited the growth of OS lung metastases without affecting the wound-healing process. METHODS: Mice were injected intratibially with OS cells. Amputation was performed when the tumor reached 1.5 cm. Full-thickness excisional wounds were also made on the dorsal skin and tail. Aerosol GCB or PBS was initiated 48 hours after amputation (3 times/week for 3 weeks). Wound sections were evaluated by immunohistochemistry for Ki-67 (proliferation), CD31 (vessels), VEGF, IL-10, bFGF, mast cells, macrophages, and M1/M2 macrophage ratios. The lungs were analyzed for macro- and micrometastases. RESULTS: Aerosol GCB inhibited the growth of the lung metastases but had no effect on the 3 phases of wound healing in the dorsal skin, tail, or bone. Production of cytokines at the wound sites was the same. CONCLUSION: These data indicate that initiating aerosol GCB postoperatively may kill residual lung metastases thereby preventing relapse and improve survival.

Efficacy of ONC201 in Desmoplastic Small Round Cell Tumor.

Desmoplastic Small Round Cell Tumor (DSRCT) is a rare sarcoma tumor of adolescence and young adulthood, which harbors a recurrent chromosomal translocation between the Ewing's sarcoma gene (EWSR1) and the Wilms' tumor suppressor gene (WT1). Patients usually develop multiple abdominal tumors with liver and lymph node metastasis developing later. Survival is poor using a multimodal therapy that includes chemotherapy, radiation and surgical resection, new therapies are needed for better management of DSRCT. Triggering cell apoptosis is the scientific rationale of many cancer therapies. Here, we characterized for the first time the expression of pro-apoptotic receptors, tumor necrosis-related apoptosis-inducing ligand receptors (TRAILR1-4) within an established human DSRCT cell line and clinical samples. The molecular induction of TRAIL-mediated apoptosis using agonistic small molecule, ONC201 in vitro cell-based proliferation assay and in vivo novel orthotopic xenograft animal models of DSRCT, was able to inhibit cell proliferation that was associated with caspase activation, and tumor growth, indicating that a cell-based delivery of an apoptosis-inducing factor could be relevant therapeutic agent to control DSRCT.

Effect of concurrent metastatic disease on survival in children and adolescents undergoing lung resection for metastatic osteosarcoma.

PURPOSE: To evaluate the impact of treated extra-pulmonary metastatic disease on overall (OS) and event-free survival (EFS) for pediatric osteosarcoma patients undergoing pulmonary metastatectomy. METHODS: We retrospectively reviewed pediatric patients who were treated for osteosarcoma at our institution from 2001 to 2011 and received pulmonary metastatectomy (n=76). We compared OS and EFS between patients with metastases limited to the lungs (Group A, n=58) to those with treated extra-pulmonary metastases (Group B, n=18) at the time of first pulmonary metastatectomy. RESULTS: The estimated median OS and EFS from first pulmonary metastatectomy were 2.0years (95% CI 1.5-2.8years) and 5.5months (95% CI 3.0-8.1months), respectively. Median OS was significantly greater for Group A (2.6years, 95% CI 1.9-3.8) compared to Group B (0.9years, 95% CI 0.6-1.5) (log rank p=0.0001). Median EFS was significantly greater for Group A (7.9months, 95% CI 5.0-10.7) compared to Group B (1.6months, 95% CI 0.8-2.7) (log rank p<0.0001). Independent predictors of OS included extra-pulmonary metastatic disease at the time of first thoracotomy, bilateral pulmonary metastases, and >4 nodules resected at first thoracotomy (all p<0.001). CONCLUSIONS: Osteosarcoma patients with treated extra-pulmonary metastatic disease at the time of pulmonary metastatectomy have significantly worse survival compared to those with disease limited to the lungs.

Shorter-duration therapy using vincristine, dactinomycin, and lower-dose cyclophosphamide with or without radiotherapy for patients with newly diagnosed low-risk rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

PURPOSE: Intergroup Rhabdomyosarcoma Study Group (IRSG) studies III and IV showed improved failure-free survival (FFS) rates with vincristine, dactinomycin, and cyclophosphamide (VAC; total cumulative cyclophosphamide dose, 26.4 g/m(2)) compared with vincristine and dactinomycin (VA) for patients with subset-one low-risk embryonal rhabdomyosarcoma (ERMS; stage 1/2 group I/II ERMS or stage 1 group III orbit ERMS). The objective of Children's Oncology Group ARST0331 was to reduce the length of therapy without compromising FFS for this subset of low-risk patients by using VA in combination with lower-dose cyclophosphamide (total cumulative dose, 4.8 g/m(2)) plus radiotherapy (RT). PATIENTS AND METHODS: This noninferiority prospective clinical trial enrolled newly diagnosed patients with subset-one clinical features. Therapy included four cycles of VAC followed by four cycles of VA over 22 weeks. Patients with microscopic or gross residual disease at study entry received RT. RESULTS: With a median follow-up of 4.3 years, we observed 35 failures among 271 eligible patients versus 48.4 expected failures, calculated using a fixed outcome based on the FFS expected for similar patients treated on the IRSG D9602 protocol. The estimated 3-year FFS rate was 89% (95% CI, 85% to 92%), and the overall survival rate was 98% (95% CI, 95% to 99%). Patients with paratesticular tumors had the most favorable outcome. Three-year cumulative incidence rates for any local, regional, or distant failures were 7.6%, 1.5%, and 3.4%, respectively. CONCLUSION: Shorter-duration therapy that included lower-dose cyclophosphamide and RT did not compromise FFS for patients with subset-one low-risk ERMS.