Irinotecan and temozolomide chemotherapy in paediatric and adult populations with relapsed Ewing Sarcoma

Salah, Samer; To, Yat Hang; Khozouz, Omar; Ismail, T.; Yaser, Sameer; Alnsour, Anoud; Shahin, Omar; Sultan, Iyad; Abu-Hijlih, Ramiz; Halalsheh, Hadeel; Abuhijla, Fawzi; Lewin, Jeremy

doi:10.1007/s12094-020-02466-9

Cited by 10 publications

(13 citation statements)

References 25 publications

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“…408, Figure 4 B). Since irinotecan and temozolomide were considered to be effective in relapsed ES [ 35 , 36 , 37 , 38 ] on the one hand and to be safe and effective in combination with dinutuximab in children with relapsed and refractory neuroblastoma on the other hand [ 7 ], an individualized treatment protocol was designed including irinotecan, temozolomide, and dinutuximab beta. The aim of the treatment was to reach stable disease at least and concomitantly provide the best possible quality of life, minimizing hospitalization and acute side effects.…”

Section: Resultsmentioning

confidence: 99%

“…Historical data from small cohort analyses indicated a median time to progression of patients with relapsed or refractory ES who had received IT for treatment, ranging between 4.6 and 8.3 months [ 35 , 36 , 38 , 50 ]. A retrospective analysis of 51 relapsed ES patients calculated a PFS of 7.7 months for the pediatric subgroup [ 37 ]. However, interim analyses from an international randomized controlled trial of chemotherapy for the treatment of recurrent and primary refractory Ewing’s sarcoma (rEECur) revealed a median PFS of 4.7 months (95% CI: 3.4 to 5.7) for patients who had been treated in the IT arm [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

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Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma

Wingerter

Malki

Sandhoff

et al. 2021

Cancers

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The ganglioside GD2 is an important target in childhood cancer. Nevertheless, the only therapy targeting GD2 that is approved to date is the monoclonal antibody dinutuximab, which is used in the therapy of neuroblastoma. The relevance of GD2 as a target in other tumor entities remains to be elucidated. Here, we analyzed the expression of GD2 in different pediatric tumor entities by flow cytometry and tested two approaches for targeting GD2. H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) samples showed the highest expression of GD2 with all cells strongly positive for the antigen. Ewing’s sarcoma (ES) samples also showed high expression, but displayed intra- and intertumor heterogeneity. Osteosarcoma had low to intermediate expression with a high percentage of GD2-negative cells. Dinutuximab beta in combination with irinotecan and temozolomide was used to treat a five-year-old girl with refractory ES. Disease control lasted over 12 months until a single partially GD2-negative intracranial metastasis was detected. In order to target GD2 in H3K27M-mutant DMG, we blocked ganglioside synthesis via eliglustat, since dinutuximab cannot cross the blood–brain barrier. Eliglustat is an inhibitor of glucosylceramide synthase, and it is used for treating children with Gaucher’s disease. Eliglustat completely inhibited the proliferation of primary H3K27M-mutant DMG cells in vitro. In summary, our data provide evidence that dinutuximab might be effective in tumors with high GD2 expression. Moreover, disrupting the ganglioside metabolism in H3K27M-mutant DMG could open up a new therapeutic option for this highly fatal cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma

Wingerter

Malki

Sandhoff

et al. 2021

Cancers

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“…Cytotoxic chemotherapy regimens for Ewing sarcoma were actively investigated until recently. Temozolomide-based salvage chemotherapy was evaluated prospectively for approximately 20 years and showed promising objective responses [ 70 , 71 , 72 , 73 , 74 ], and a temozolomide-based regimen was under investigation as a first-line therapy [ 75 ]. Topotecan-based therapies also provided objective clinical responses [ 24 , 76 , 77 ], but the use of topotecan-based combination chemotherapy as a first-line treatment failed to show survival benefit in a phase III trial [ 78 ].…”

Section: Ewing Sarcoma Of Bonementioning

confidence: 99%

Challenges of Systemic Therapy Investigations for Bone Sarcomas

Nakano

2022

IJMS

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Bone sarcoma is a rare component of malignant solid tumors that accounts for only ~0.2% of malignancies. Bone sarcomas present various histological types, and genomic mutations differ markedly by the histological types. Although there are vast mutations in various bone sarcomas, most of them are non-actionable, and even potential targetable mutations that are actionable targets in other malignancies have not shown the appropriate responses in clinical trials for bone sarcomas. Investigations of new systemic therapy, including molecular targeted therapies for bone sarcomas, have thus not progressed like those for other solid tumors. Another problem is that high rates of pediatric/adolescent and young adult patients have bone sarcomas such as osteosarcoma, and patient recruitment for clinical trials (especially randomized trials) is challenging. For pediatric patients, evaluations of tolerability and appropriate dose modifications of new drugs are needed, as their findings could provide the threshold for investigating new drugs for bone sarcomas. To solve these problems, improvements in registry systems, real world data, and pediatric extrapolation have been attempted. We review the issues regarding targeted drug investigations for bone sarcomas, focusing on the current clinical evidence and efforts to resolve these issues.

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“…In patient level, two studies with 104 patients were enrolled [ 12 , 13 ]. The pooled incidences of neutropenia and thrombocytopenia were 18% (95% CI 7–32%) and 6% (95% CI 2–11%).…”

Section: Toxicitiesmentioning

confidence: 99%

Irinotecan plus temozolomide in relapsed Ewing sarcoma: an integrated analysis of retrospective studies

2022

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Background The prognosis of patients with relapsed Ewing sarcoma is poor. In this study, we aimed to pooled-analyze the efficacy and safety of the combination of irinotecan and temozolomide in treating patients with relapsed Ewing sarcoma. Methods PubMed, Cochrane CENTRAL, Web of Science, and EMBASE were systematically searched on September 27, 2021. The primary outcomes were rates of objective response and disease control, and the secondary outcomes were toxicities. Results Six retrospective studies with 184 patients were enrolled in the analysis. The median age ranged from 14 to 21. The integrated rates were 44% (95% confidence interval [CI] 31–58) for objective response and 66% (55–77) for disease control. Grade 3–4 neutropenia, thrombocytopenia, and diarrhea occurred in 8% (3–16), 7% (3–11), and 8% (5–10) of chemotherapeutic cycles, respectively. 18% (7–32) and 6% (2–11) of patients suffered grade 3–4 neutropenia and thrombocytopenia after irinotecan plus temozolomide treatment. Conclusion Irinotecan plus temozolomide combination chemotherapy showed antitumor activity and an acceptable safety profile in patients with relapsed Ewing sarcoma. More future prospective studies are needed to confirm the retrospective results.

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Irinotecan and temozolomide chemotherapy in paediatric and adult populations with relapsed Ewing Sarcoma

Cited by 10 publications

References 25 publications

Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma

Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma

Challenges of Systemic Therapy Investigations for Bone Sarcomas

Irinotecan plus temozolomide in relapsed Ewing sarcoma: an integrated analysis of retrospective studies

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