Management of recurrent or refractory Ewing sarcoma: A systematic review of phase�II clinical trials in the last 15�years

Xu, Jie; Xie, Lu; Sun, Xin; Dong, Song; Tang, Xiaodong; Guo, Wei

doi:10.3892/ol.2019.10328

Cited by 6 publications

(6 citation statements)

References 72 publications

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“…Currently, several novel avenues of immunotherapeutic treatment are being explored for ESFT patients in the relapsed or metastatic stage; however, most have shown limited success or are in early clinical trials. 58 Anti-insulin like growth factor receptor-1 (IGFR1) therapy may provide therapeutic benefit for a selected group of patients. 59 Here, characterization of the immune TME in clinical trials using CIBERSORT may be of interest to identify predictive biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Prognostic profiling of the immune cell microenvironment in Ewing´s Sarcoma Family of Tumors

et al. 2019

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Ewing´s Sarcoma Family of Tumors (ESFT) are clinically aggressive bone and soft tissue tumors in children and young adults. Analysis of the immune tumor microenvironment (TME) provides insight into tumor evolution and novel treatment options. So far, the scarcity of immune cells in ESFT has hindered a comprehensive analysis of rare subtypes. We determined the relative fraction of 22 immune cell types using 197 microarray gene expression datasets of primary ESFT tumor samples by using CIBERSORT, a deconvolution algorithm enumerating infiltrating leucocytes in bulk tumor tissue. The most abundant cells were macrophages (mean 43% of total tumor-infiltrating leukocytes, TILs), predominantly immunosuppressive M2 type macrophages, followed by T cells (mean 23% of TILs). Increased neutrophils, albeit at low number, were associated with a poor overall survival (OS) (p = .038) and increased M2 macrophages predicted a shorter event-free survival (EFS) (p = .033). High frequency of T cells and activated NK cells correlated with prolonged OS (p = .044 and p = .007, respectively). A small patient population (9/32) with combined low infiltrating M2 macrophages, low neutrophils, and high total T cells was identified with favorable outcome. This finding was confirmed in a validation cohort of patients with follow up (11/38). When comparing the immune TME with expression of known stemness genes, hypoxia-inducible factor 1 α (HIF1α) correlated with high abundance of macrophages and neutrophils and decreased T cell levels. The immune TME in ESFTs shows a distinct composition including rare immune cell subsets that in part may be due to expression of HIF1α.

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Section: Discussionmentioning

confidence: 99%

Prognostic profiling of the immune cell microenvironment in Ewing´s Sarcoma Family of Tumors

et al. 2019

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“…Specifically, a fixed anlotinib level of 12 mg was given to cohort A and 8 or 12 mg to cohort B (12 mg if body surface area [BSA] is ≥1.0 m 2 or 8 mg if BSA is <1.0 m 2 ). Different dose levels of irinotecan were predesigned according to previous literature and experience [ 4 ]. Recommended phase II dose (RP2D) was defined as the highest dose at which no more than 30% patients experienced a DLT during the first two courses.…”

Section: Subjects Materials and Methodsmentioning

confidence: 99%

“…The prognosis of patients with EWS refractory to first‐line treatment or recurring after radical therapy is relatively poor [ 1 ]. Although numerous potential drugs, including targeted therapy and immunotherapy, have been tested over the past 15 years [ 2 , 3 ], the best therapeutic response was achieved by traditional irinotecan‐based regimens [ 4 ]. Compared to single‐bolus dose, a protracted administration of irinotecan for more than 5 days could lead to better outcomes in pediatric patients with sarcoma [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Anlotinib, Vincristine, and Irinotecan for Advanced Ewing Sarcoma After Failure of Standard Multimodal Therapy: A Two-Cohort, Phase Ib/II Trial

Xie

Sun

et al. 2021

The Oncologist

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Background Both protracted irinotecan and antiangiogenesis therapy have shown promising efficacy against Ewing sarcoma (EWS). Methods Patients diagnosed with recurrent or refractory EWS were enrolled and further categorized into cohort A (≥16 years) or cohort B (<16 years). In the dose‐defining phase Ib portion, anlotinib was given daily at a fixed dose, while a 3+3 design with dose de‐escalation was used to determine the dose of irinotecan. The next dose‐expanding phase II portion employed a conventional two‐stage study design model. The primary endpoint was objective response rate at 12 weeks (ORR12w). Results A total of 41 patients finally received the treatment regimen, including 29 in cohort A and 12 in cohort B. For cohort A, the first five patients were treated at the initial level of 20 mg/m2/d d × 5 × 2, and two of them subsequently a dose‐limiting toxicity (DLT). An additional six patients were then treated at 15 mg/m2 without any DLT, and the RP2D was determined. Notably, 23 out of 24 patients in cohort A were available for response evaluation at 12 weeks. ORR12w was determined to be 62.5%. For cohort B, no DLT was observed in the first six patients at the initial dose level. At last, 12 patients were included in cohort B. The ORR12w was 83.3%. The most frequently observed grade 3/4 adverse events were leukopenia (28.5%), neutropenia (24.4%), anemia (8.7%), and diarrhea (3.7%). Conclusion The combination of vincristine, irinotecan, and anlotinib demonstrated an acceptable toxicity profile and promising clinical efficacy in patients with advanced EWS. Implications for Practice This is the first trial to evaluate an irinotecan‐based regimen in combination with antiangiogenesis tyrosine kinase inhibitors in Ewing sarcoma (EWS). A 3+3 design with dose de‐escalation was used to determine the most appropriate dose of irinotecan in each cohort. The next dose‐expanding phase II portion employed a conventional two‐stage study design model. The objective response rate was 62.5% for adults and 83.3% for children. Median overall survival was not matured. This study shows that the combination of vincristine, irinotecan, and anlotinib demonstrates an acceptable toxicity profile and promising clinical efficacy in patients with advanced EWS.

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“…There have been numerous clinical trials aiming at the prognosis of R2pulm group or recurrent/relapsed (RR) ES patients [1,5,8,9]. However, for those who had extensive L/Pmeta and then completely responded to chemotherapy, there is insufficient high quality data to answer the following questions: 1.…”

Section: Introductionmentioning

confidence: 99%

Long-term outcome and relapse patterns in Ewing sarcoma patients with extensive lung/pleural metastases after a complete response to systemic therapy

Zhi

Xie

et al. 2022

BMC Cancer

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Background Ewing sarcoma (ES) is sensitive to systemic therapy, including chemotherapy and anti-angiogenesis Tyrosine Kinase Inhibitors(aaTKIs). However, the prognosis of patients with metastatic disease remains poor. Recurrence or distant metastasis after a complete response (CR) or near-CR due to systemic therapy is not rare. Methods We reviewed data from 187 ES patients between 2014–2019 treated at a single institute in China. Patients with extensive lung/pleural metastases (L/Pmeta) who had a CR or near-CR after first- or second-line chemotherapy with or without aaTKIs were retrospectively enrolled. Event-free survival (EFS) and overall survival (OS) were determined using the Kaplan–Meier method. For patients who had L/P recurrence, images were reviewed to define the exact location of each recurrent lesion, compared with the primary L/P lesion before chemotherapy and summarized as the relapse pattern. Results Seventeen patients and 21 cases of CR/nCR (5 by VDC/IE, 3 by VIT, and 13 by AVI) were finally analyzed. Median follow-up for surviving patients was 39.6 (range, 14.5–60.9) months. Median EFS and OS were 9.3 (95% confidence interval [CI], 2.0–16.6) months and 37.5 (95% CI, 21.8–53.1) months, respectively. The 2-year EFS was 19% and the 2-year OS was 70.6%, respectively. Most patients (82.4%) received whole lung irradiation (WLI). Lung/pleural relapse occurred in 71.4% (15/21) of CR/nCR cases. Most notably, all recurrent lesions exactly coincided with the original metastatic lesions before chemotherapy (exactly in situ) in 9 of the 15 recurrent cases, which was thus the major relapse pattern, whereas 42.9% had distant metastases other than L/Pmeta. Conclusions Survival of ES patients with extensive L/Pmeta remains poor, even if they have a CR after systemic therapy. Recurrence exactly in situ is the major relapse pattern. WLI is not sufficient to prevent local recurrence in lung or pleura. More aggressive local treatment for metastatic lesions is warranted.

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Management of recurrent or refractory Ewing sarcoma: A systematic review of phase�II clinical trials in the last 15�years

Cited by 6 publications

References 72 publications

Prognostic profiling of the immune cell microenvironment in Ewing´s Sarcoma Family of Tumors

Prognostic profiling of the immune cell microenvironment in Ewing´s Sarcoma Family of Tumors

Anlotinib, Vincristine, and Irinotecan for Advanced Ewing Sarcoma After Failure of Standard Multimodal Therapy: A Two-Cohort, Phase Ib/II Trial

Long-term outcome and relapse patterns in Ewing sarcoma patients with extensive lung/pleural metastases after a complete response to systemic therapy

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