Gartrell Jessica, Navid Fariba, Yuan Xiaomeng, Ness Kirsten K, Dubrovin Mikhail, Wang Fang, Pan Haitao, McCarville Mary Beth, Shulkin Barry L, Helmig Sara, Krasin Matthew J, Neel Michael D, Davidoff Andrew M, Mandrell Belinda N, Levine Deena R, Cai Zhongheng, Bishop Michael W, Pappo Alberto S, Federico Sara M
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
Cancers (Basel). 2025 Sep 3;17(17):2894. doi: 10.3390/cancers17172894.
Patients with high-risk Ewing sarcoma (ES) have dismal outcomes despite aggressive multimodal therapy. This phase II, single-institution study evaluated the response rate to two up-front cycles of irinotecan, temozolomide, and temsirolimus (ITT) and assessed the tolerability of maintenance therapy following standard treatment in high-risk ES.
Eligible patients had newly diagnosed high-risk ES (age ≥14 years old, metastatic disease, or primary pelvic tumor). The therapy included two cycles of window therapy (ITT) followed by interval-compressed chemotherapy (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide) and maintenance therapy (cyclophosphamide, sorafenib, and bevacizumab). A two-stage sequential design was employed to assess a >50% WHO response (CR or PR) with 80% power. Patients who required emergent radiation were excluded from receiving window therapy.
Sixteen patients (median age 12.2 years; range 4.8-23.6 years) were enrolled (12 evaluable for overall response, 10 for primary tumor response). Only three achieved a PR to window therapy, leading to study closure. All evaluable patients demonstrated a decline in their primary tumor volume (mean decline: 32.5%, standard deviation: 17.6%, -value: 0.0005) and SUV peak (mean decline: 49.9%, standard deviation: 21.1%, -value: 0.002). Maintenance therapy was well tolerated, with only 2/13 patients discontinuing due to toxicity.
ITT did not achieve the prespecified response rate of 50%, according to WHO criteria; however, all patients exhibited decreased volume and metabolic activity, highlighting the limitations of conventional response assessments. Maintenance therapy was feasible and well tolerated. Although limited by small sample size, heterogeneous disease presentations, and the absence of a control arm, this study supports further evaluation of ITT and a maintenance approach in larger, randomized trials for high-risk ES.
尽管采用了积极的多模式治疗，高危尤因肉瘤（ES）患者的预后仍然很差。这项II期单机构研究评估了伊立替康、替莫唑胺和西罗莫司（ITT）两个前期周期的缓解率，并评估了高危ES标准治疗后维持治疗的耐受性。
符合条件的患者为新诊断的高危ES（年龄≥14岁、转移性疾病或原发性盆腔肿瘤）。治疗包括两个周期的窗口期治疗（ITT），随后是间隔压缩化疗（长春新碱、阿霉素和环磷酰胺与异环磷酰胺和依托泊苷交替使用）和维持治疗（环磷酰胺、索拉非尼和贝伐单抗）。采用两阶段序贯设计，以80%的检验效能评估WHO缓解率>50%（完全缓解或部分缓解）。需要紧急放疗的患者被排除在接受窗口期治疗之外。
共纳入16例患者（中位年龄12.2岁；范围4.8 - 23.6岁）（12例可评估总体缓解情况，10例可评估原发肿瘤缓解情况）。只有3例患者对窗口期治疗达到部分缓解，导致研究终止。所有可评估患者的原发肿瘤体积均下降（平均下降：32.5%，标准差：17.6%，P值：0.0005），SUV峰值也下降（平均下降：49.9%，标准差：21.1%，P值：0.002）。维持治疗耐受性良好，只有2/13例患者因毒性反应而停药。
根据WHO标准，ITT未达到预先设定的50%的缓解率；然而，所有患者的肿瘤体积和代谢活性均降低，凸显了传统缓解评估的局限性。维持治疗是可行的且耐受性良好。尽管受样本量小、疾病表现异质性以及缺乏对照组的限制，但本研究支持在更大规模的高危ES随机试验中进一步评估ITT和维持治疗方法。
