Kao, Simon C.

ABSTRACTAccurate staging of nodal involvement in pediatric sarcoma patients is important to determine correct systemic and local therapy, with the goal to reduce subsequent recurrences. However, differences in lymph node staging strategies, definitions, and treatment protocols between the Children's Oncology Group (COG), European paediatric Soft tissue sarcoma Study Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS) complicate comparisons. In this article, we aim to establish internationally recognized recommendations for lymph node assessment and treatment of children and adolescents diagnosed with rhabdomyosarcoma (RMS) and non‐rhabdomyosarcoma soft tissue sarcoma (NRSTS) according to the Consensus Conference Standard Operating Procedure methodology.

Accurate staging of nodal involvement in pediatric sarcoma patients is important to determine correct systemic and local therapy, with the goal to reduce subsequent recurrences. However, differences in lymph node staging strategies, definitions, and treatment protocols between the Children’s Oncology Group (COG), European Pediatric Soft Tissue Sarcoma Study Group (EpSSG), and the Cooperative Weichteil Sarkom Studiengruppe (CWS), complicate comparisons. In this article we try to establish internationally recognized recommendations for lymph node assessment and treatment of children and adolescents diagnosed with RMS and NRSTS according to the Consensus Conference Standard Operating Procedure methodology.

AbstractBackgroundEmbryonal sarcoma of the liver (ESL) is a rare mesenchymal tumor most common in childhood; the optimal treatment approach is uncertain. The clinical features and outcomes of patients with ESL enrolled in a Children’s Oncology Group (COG) clinical trial that evaluated a risk‐based strategy for treating soft tissue sarcomas in patients aged <30 years were evaluated.MethodsThis subset analysis included patients with ESL enrolled in COG study ARST0332. Central review of records, pathology, and imaging confirmed the diagnosis, presenting features, and surgery extent and complications. All patients received dose‐intensive ifosfamide/doxorubicin chemotherapy, with cycle timing dependent on surgery and radiotherapy. Tumor resection occurred before study entry or after four cycles of chemotherapy; radiotherapy for residual tumor was optional.ResultsThirty‐nine eligible/evaluable patients with ESL were analyzed. All tumors were >10 cm in diameter; four were metastatic. Tumor resection was performed upfront in 23 and delayed in 16. Positive surgical margins (n = 6) and intraoperative tumor rupture (n = 6) occurred only in upfront resections. Eight patients received radiotherapy. Estimated 5‐year event‐free and overall survival were 79% (95% confidence interval [CI], 65%–93%) and 95% (95% CI, 87%–100%), respectively. Positive margins increased the local recurrence risk. One of 13 patients with documented hemorrhagic ascites and/or tumor rupture developed extrahepatic intra‐abdominal tumor recurrence.ConclusionsThe treatment strategy used in ARST0332 achieved favorable outcomes for patients with ESL despite a substantial proportion having high‐risk disease features. Deferring tumor resection until after neoadjuvant chemotherapy may decrease the risk of intraoperative tumor rupture and improve the likelihood of adequate surgical margins.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. ARST1321 was a phase II study designed to compare the near complete pathologic response rate after preoperative chemoradiation with/without pazopanib in children and adults with intermediate-/high-risk chemotherapy-sensitive body wall/extremity non-Rhabdomyosarcoma Soft Tissue Sarcoma (ClinicalTrials.gov identifier: NCT02180867 ). Enrollment was stopped early following a predetermined interim analysis that found the rate of near complete pathologic response to be significantly greater with the addition of pazopanib. As a planned secondary aim of the study, the outcome data for this cohort were analyzed. Eight-five eligible patients were randomly assigned to receive (regimen A) or not receive (regimen B) pazopanib in combination with ifosfamide and doxorubicin + preoperative radiotherapy followed by primary resection at week 13 and then further chemotherapy at week 25. As of December 31, 2021, at a median survivor follow-up of 3.3 years (range, 0.1-5.8 years), the 3-year event-free survival for all patients in the intent-to-treat analysis was 52.5% (95% CI, 34.8 to 70.2) for regimen A and 50.6% (95% CI, 32 to 69.2) for regimen B ( P = .8677, log-rank test); the 3-year overall survival was 75.7% (95% CI, 59.7 to 91.7) for regimen A and 65.4% (95% CI, 48.1 to 82.7) for regimen B ( P = .1919, log-rank test). Although the rate of near complete pathologic response was significantly greater with the addition of pazopanib, outcomes were not statistically significantly different between the two regimens.

11070 Background: Pazopanib is a tyrosine kinase inhibitor approved globally for advanced soft tissue sarcomas. The dose finding phase of this cooperative group trial assessed the dose limiting toxicities (DLT) and the maximally tolerated dose (MTD) of adding pazopanib to neoadjuvant chemoradiation or radiation therapy in children and adults with unresected intermediate/high-risk trunk and extremity non-rhabdomyosarcoma soft tissue sarcomas (NRSTS). Methods: ARST1321, a jointly designed intergroup study lead by Children's Oncology Group and NRG Oncology opened for enrollment in July 2014. Eligible adult and pediatric patients with newly diagnosed, unresected trunk/extremity NRSTS with plans for primary tumor resection were enrolled into either the Chemotherapy Cohort (those with chemosensitive NRSTS > 5 cm, grade 3, including all synovial sarcoma) or the Non-Chemotherapy Cohort (those with chemotherapy insensitive NRSTS of any size, grade 2/3, or any chemosensitive NRSTS for whom no chemotherapy was planned per discretion of patients and treatment teams). In the Chemotherapy Cohort, pazopanib was given with ifosfamide (7.5 grams/m2) and doxorubicin (75 mg/m2) plus 45 Gy preoperative RT starting after cycle 2. Primary tumor was resected at week 13, followed by chemotherapy and pazopanib to week 25. In the Non-Chemotherapy Cohort, pazopanib was given with 50 Gy preoperative RT, primary tumor was resected at week 10, and pazopanib continued to week 25. Feasibility was assessed through week 6 of therapy to determine pazopanib dose escalation/de-escalation based on DLT, total doses of pazopanib, and overall adverse event profile. Results: In the Chemotherapy Cohort, MTD was reached at Dose Level 1 (350 mg/m2 peds; 600 mg adults) with two DLTs (1 grade 3 ALT rise, 1 intolerability to therapy) in 10 patients. In the Non-Chemotherapy Cohort, 11 patients enrolled at Dose Level 1 (350 mg/m2 peds; 600 mg adults) without any observed DLTs and all received ≥75% of prescribed total pazopanib dose; MTD was reached at Dose Level 2 (450 mg/m2 peds; 800 mg adults) with 2 DLTs in ten patients enrolled (1 grade 3 dermatitis and 1 intolerability to therapy) and 9/10 receiving ≥75% of full dose. Conclusions: Pazopanib in combination with chemoradiation or radiation therapy alone was found to be safe in children and adults with NRSTS. Following this finding, ARST1321 opened in both arms using the newly determined pazopanib MTDs. Clinical trial information: NCT02180867.

10012 Background: The prognostic significance of response to induction therapy for rhabdomyosarcoma (RMS) by anatomic imaging (computerized tomographic [CT] or magnetic resonance imaging [MRI] scan) is controversial. We previously reported no relationship between early response and failure-free survival (FFS) for patients on IRS-IV. We repeated the same analysis using an independent cohort of patients with non-metastatic, initially unresected RMS treated on a more recent clinical trial. Methods: A total of 338 patients enrolled in Children’s Oncology Group study D9803 met the following inclusion criteria for this analysis: 1) non-metastatic, initially unresected (Group III); 2) embryonal (ERMS) or alveolar (ARMS) histology; 3) documented response to induction chemotherapy (excluding progressive disease) based on anatomic imaging; and 4) documented therapy beyond week 12. Response at week 12 was determined by the treating institution as complete response (CR, complete resolution), partial response (PR, decrease of >= 50% of the sum of the products of maximum perpendicular diameters), or no response (NR, between 50% reduction and 25% increase in the sum of the products of maximum perpendicular diameters). FFS was estimated using the Kaplan-Meier method, and comparisons between groups were made using the log-rank test. Results: Overall objective response rate (CR+PR) at week 12 of therapy was 85%, with similar responses for ERMS and ARMS. FFS was similar among all patients with CR, PR, or NR (p=0.49). Restricting the analysis to either ERMS or ARMS, there was no difference in FFS by histology (p=0.20 and p=0.45, respectively). Conclusions: These findings provide additional evidence that anatomic imaging assessment of early response to therapy among RMS patients does not predict outcome and should not be used to tailor subsequent therapy. Clinical trial information: NCT00003958. [Table: see text]