Efficacy of dose intensification in induction therapy for localized Ewing sarcoma: Italian Sarcoma Group (ISG) and Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP) ISG/AIEOP EW-1 study.
Authors: Roberto Luksch, Giuseppe Maria Milano, Francesco Barretta, Alessandra Longhi, Emanuela Palmerini, Nadia Puma, Sebastian Dorin Asaftei, Marta Giorgia Podda, Giovanni Grignani, Gianni Bisogno, Rossella Bertulli, Luca Coccoli, Angela Tamburini, Carla Manzitti, Virginia Ferraresi, Maurizio Mascarin, Marco Rabusin, Stefano Ferrari, Piero Picci, Franca Fagioli
Journal: Journal of Clinical Oncology (2021)

11501 Background: The role of dose intensification of chemotherapy in Ewing sarcoma (ES) is under evaluation in prospective trials. This is a controlled, randomized phase III study evaluating the impact on event-free survival (EFS) of two arms at different intensity of induction therapy in localized ES at onset. Methods: Newly diagnosed localized ES patients aged 2-40 were eligible. They were randomized to receive 4-courses induction therapy - 1 every 21 days - either with a standard arm (arm A) as per ISG/SSGIII protocol (Ferrari S, et at, Ann Oncol. 2011;22(5):1221) or with an intense arm B, consisting of vincristine 1,5mg/sqm+ doxorubicin 80mg/sqm+ifosfamide 9g/sqm for each course. After induction, patients underwent surgery and/or radiotherapy,followed by an adaptive treatment. Good responders received standard courses chemotherapy: arm A pts received 9 courses, while arm B pts received 5 courses. Poor responders in both arms received 4 courses followed by high-dose busulfan/melphalan+autologous stem cell rescue. The primary outcome measure was EFS for the 2 arms in the intention-to-treat population. Kaplan-Meier curves compared with log-rank test and Cox model were performed to assess differences between study arms. A secondary outcome was toxicity differences, assessed by means of the Fisher’s exact test. Initial sample size was 230 pts, type I error rate 5%, power 80%. Results: Between 2009 and 2019, 234 patients were randomized (arm A-115; arm B-119). M:F ratio was 1.8; median age 14 years (range 2-40); tumour site extremity in 55%, axial/pelvis in 45%; tumour volume &lt; 200ml in 31% and ≥200ml in 69%. A good response was obtained in 56% in arm A and 60% in arm B. Median follow-up was 68 months. EFS was not significantly different between arms; HR: 0.85; 95% CI: 0,51-1,41, 5-year EFS (95% CI) was 73% (64-82%) in arm A and 75% (67-83%) in arm B ( p = 0.526). Good responders in arm A and in arm B and poor responders in arm B had comparable results: 5-year EFS (95% CI) was 80% (71-91%), 77% (67-88%), and 72% (59-86%), respectively, while poor responders in arm A showed a worse, not statistically significant (p = 0.164) performance (63%; 50-78%). Subgroup analyses showed similar outcome for age, tumour site and volume in both arms. Hematological, gastrointestinal, and cardiovascular grade ≥3 toxicities were more pronounced in arm B (p &lt; 0.05). Conclusions: Intense induction therapy with arm B did not improve 5-year EFS when compared with the standard arm A. The higher toxicity observed in arm B than in arm A was counterbalanced, in good responders, by a similar outcome with a shorter treatment plan. For poor responders, with almost 30 patients per arm event-free and with &lt; 48-month FUP, better 5-year EFS in arm B than in arm A was observed but needs further observation. Clinical trial information: NCT02063022.