Results of the first interim assessment of rEECur, an international randomized controlled trial of chemotherapy for the treatment of recurrent and primary refractory Ewing sarcoma.

Abstract

11007 Background: 5-year survival of RR-ES is about 15%. Several chemotherapy regimens are used, but without robust evidence. rEECur, the first randomised controlled trial in this setting, is defining a standard of care, balancing efficacy and toxicity. Methods: Patients aged 4 to 50 with RR-ES and fit to receive chemotherapy were randomised 2, 3 or 4 ways between topotecan & cyclophosphamide (TC), irinotecan & temolozomide (IT), gemcitabine & docetaxel (GD) or high-dose ifosfamide (IFOS). Primary outcome measure was objective response (OR) after 4 cycles by RECIST 1.1. Secondary outcomes included PFS, OS and toxicity. A probability-based Bayesian approach was used. The first interim assessment to determine which arm should be closed occurred when 50 evaluable patients had been recruited to 3 arms and evaluated for the primary outcome measure. Results: 242 patients (89% RECIST-evaluable) recruited between 18/12/14 and 21/06/18 were randomised to TC (n=75), IT (71), GD (66) and IFOS (30). Median age was 21 years (range 4 to 49). Patients had: refractory ES (20%), 1st recurrence (63%), >1st recurrence (17%); initial primary disease arose in bone in 60%; disease progression sites were primary site (17%), pleuropulmonary (29%) or other metastatic (54%). Median follow up was 11.3 months. Outcomes in the GD arm were: response rate 11.5% (95% CI: 4.4 to 23%), median PFS 3.0 months (95% CI: 1.6 to 8.0), median OS 13.7 months (95% CI: 10.1 to 23.9). The table shows, for each pairwise comparison of GD with the other arms (randomly labelled A, B, C to maintain blinding of open arms), the probabilities given the observed data that OR, PFS and OS were better for GD than for each other arm (RR: relative risk, HR: hazard ratio). For OR and PFS, all comparisons favoured the other arms. There were fewer grade 3/4 adverse events with GD than with the other arms pooled (58% v. 74%). Conclusions: rEECur has shown that GD is a less effective treatment than TC, IT or IFOS in reducing tumour burden or prolonging PFS in RR-ES. Recruitment continues to the remaining arms. Clinical trial information: ISRCTN36453794. [Table: see text]

Phase II trial of gemcitabine and nab‐paclitaxel in patients with recurrent Ewing sarcoma: A report from the National Pediatric Cancer Foundation

“…Two other patients had partial responses after two cycles but came off study due to disease progression or hematologic toxicity before the response could be confirmed with subsequent imaging. This objective response rate of 9% is similar to that seen in prospective multi‐institutional studies of GEM/DOC in this patient population 8,9 …”

“…This objective response rate of 9% is similar to that seen in prospective multi-institutional studies of GEM/DOC in this patient population. 8,9 It was anticipated that myelosuppression would be dose limiting for this regimen, and in fact a previous retrospective report by Metts et al of the use of gemcitabine and nab-paclitaxel showed that 5…”

“…Five single‐institution studies including a variety of tumor types have shown a collective objective response rate of 29% in the 16 cumulative patients with Ewing sarcoma 3‐7 . However, in prospective multi‐institutional trials for relapsed Ewing sarcoma, the response rate for 80 total patients was only 12% 8,9 . In the one study involving newly diagnosed patients with Ewing sarcoma, two cycles of GEM/DOC were used as an upfront window to treat 17 evaluable higher‐risk patients 10 .…”

Sarcoma European and Latin American Network (SELNET) Recommendations on Prioritization in Sarcoma Care During the COVID-19 Pandemic

“… i The benefit from gemcitabine and docetaxel in Ewing sarcoma [64, 65] shows level 2 of recommendation when applying the ESMO‐MCBS V1·1: Form C. The benefit from Cyclophosphamide‐topotecan cannot be properly assessed with the currently available evidence. The benefit from high‐dose ifosfamide in Ewing sarcoma [66] shows level 3 of recommendation when applying the ESMO‐MCBS V1·1‐ Form C. …”

Recent advances in understanding osteosarcoma and emerging therapies

“…However, these randomized trials require more patients and thus are longer than single-arm trials. Bayesian trial designs might be of value in rapidly evaluating multiple treatments for rare tumors as done in Ewing sarcoma (rEECur trial) 65 and to integrate previous historical data (sarcoma 13 trial) 45 , 66 , tying to minimize the number of patients required.…”