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

Wang, Bi-Cheng; Xiao, Bo-Ya; Lin, Guo-He

doi:10.1186/s12885-022-09469-5

Cited by 8 publications

(7 citation statements)

References 24 publications

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“…The pharmacological activation of irinotecan (or CPT-11) involves the participation of carboxylesterases (CE) to generate the active metabolite SN-38, a promising prodrug for the treatment of STS [ 17 ]. Earlier, both irinotecan and temozolomide proved to be effective in Ewing sarcoma clinical trials [ 18 , 19 , 20 , 21 ], and this encouraged the evaluation of these compounds in RMS. A phase II study from the STSC (2002–2004) revealed an interesting response rate of refractory and recurrent STS patients, including RMS, to irinotecan [ 22 ].…”

Section: The Evolution Of the Treatment For Rms And Recent Clinical T...mentioning

confidence: 99%

The Capacity of Drug-Metabolising Enzymes in Modulating the Therapeutic Efficacy of Drugs to Treat Rhabdomyosarcoma

Picher,

Wahajuddin,

Barth

et al. 2024

Cancers

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Rhabdomyosarcoma (RMS) is a rare soft tissue sarcoma (STS) that predominantly affects children and teenagers. It is the most common STS in children (40%) and accounts for 5–8% of total childhood malignancies. Apart from surgery and radiotherapy in eligible patients, standard chemotherapy is the only therapeutic option clinically available for RMS patients. While survival rates for this childhood cancer have considerably improved over the last few decades for low-risk and intermediate-risk cases, the mortality rate remains exceptionally high in high-risk RMS patients with recurrent and/or metastatic disease. The intensification of chemotherapeutic protocols in advanced-stage RMS has historically induced aggravated toxicity with only very modest therapeutic gain. In this review, we critically analyse what has been achieved so far in RMS therapy and provide insight into how a diverse group of drug-metabolising enzymes (DMEs) possess the capacity to modify the clinical efficacy of chemotherapy. We provide suggestions for new therapeutic strategies that exploit the presence of DMEs for prodrug activation, targeted chemotherapy that does not rely on DMEs, and RMS-molecular-subtype-targeted therapies that have the potential to enter clinical evaluation.

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Section: The Evolution Of the Treatment For Rms And Recent Clinical T...mentioning

confidence: 99%

The Capacity of Drug-Metabolising Enzymes in Modulating the Therapeutic Efficacy of Drugs to Treat Rhabdomyosarcoma

Picher,

Wahajuddin,

Barth

et al. 2024

Cancers

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“…Irinotecan has been evaluated in many clinical trials in different tumor types [26,[53][54][55]. We provide an overview of sarcoma trials in Table 1.…”

Section: Irinotecan (Camptothecin-11)mentioning

confidence: 99%

Current Role of Topoisomerase I Inhibitors for the Treatment of Mesenchymal Malignancies and Their Potential Future Use as Payload of Sarcoma-Specific Antibody-Drug Conjugates

Schöffski,

Wang,

Schöffski

et al. 2023

Oncol Res Treat

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Background: Topoisomerase I is an enzyme that plays a crucial part in DNA replication and transcription by the relaxation of supercoiled double-stranded DNA. Topoisomerase I inhibitors bind to the topoisomerase I cleavage complex, thereby stabilizing it and preventing the religation of the DNA strands, leading to DNA damage, cell cycle arrest, and apoptosis. Various topoisomerase I inhibitors have been evaluated in solid tumors, and irinotecan and topotecan have been approved for the treatment of epithelial malignancies. None of them have been approved for sarcoma, a diverse group of rare solid tumors with an unmet need for effective treatments. Summary: Topoisomerase I inhibitors have been evaluated in preclinical studies as single agents or in combination in solid tumors, some of which have included sarcomas where activity was observed. Clinical trials evaluating topoisomerase I inhibitors for the treatment of sarcoma have shown limited efficacy as monotherapy. In combination with other cytotoxic agents, topoisomerase I inhibitors have become part of clinical routine in selected sarcoma subtypes. Regimens such as irinotecan/vincristine/temozolomide are used in relapsed rhabdomyosarcoma, irinotecan/temozolomide and vincristine/topotecan/cyclophosphamide are commonly given in refractory Ewing sarcoma, and topotecan/carboplatin showed some activity in advanced soft tissue sarcoma. This review provides an overview of key studies with topoisomerase I inhibitors for the treatment of sarcoma. Topoisomerase I inhibitors are currently also being assessed as “payloads” for antibody-drug conjugates (ADCs), allowing for the targeting of specific antigen-expressing tumor cells and the delivery of the inhibitor directly to the tumor cells with the potential of enhancing therapeutic efficacy while minimizing systemic toxicity. Here, we also provide a brief overview on topoisomerase I-ADCs. Key Message: Topoisomerase I inhibitors are an important component of some systemic therapies for selected sarcomas and have potent cytotoxic properties and pharmacological characteristics that make them relevant candidates as payloads for the development of sarcoma-specific ADCs. ADCs are antibody-based targeted agents allowing for efficient and specific delivery of a given drug to the tumor cell. Topoisomerase I-ADCs are a novel targeted delivery approach which may have the potential to improve the therapeutic index of topoisomerase I inhibitors in the treatment of sarcoma and warrants investigation in a broad variety of mesenchymal malignancies.

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“…1,2 Depending on location and timing of relapse, traditional approaches to second line therapy have been dominated by cytotoxic chemotherapies. 3,4 However, outcomes with cytotoxic chemotherapy remain poor and the recently published studies reporting the activity of tyrosine kinase inhibitors (TKIs) in patients with relapsed bone tumours were met with great hope. [5][6][7][8] Tyrosine kinases are key signalling proteins involved in cell growth and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Real‐world experience of tyrosine kinase inhibitors in children, adolescents and adults with relapsed or refractory bone tumours: A Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) study

Peretz Soroka,

Vora,

Noujaim

et al. 2023

Cancer Medicine

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ObjectivesWe conducted a retrospective multi‐centre study to assess the real‐world outcome of regorafenib (REGO) and cabozantinib (CABO) in recurrent/refractory bone tumours (BTs) including osteosarcoma (OST), Ewing sarcoma (EWS) and chondrosarcoma (CS)/extra‐skeletal mesenchymal CS (ESMC).MethodsAfter regulatory approval, data from patients with recurrent BT (11 institutions) were extracted from CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) database. Patient characteristics, treatment and outcomes were collected. Progression‐free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method.ResultsFrom July 2018 to May 2022, 66 patients received REGO or CABO; 39 OST, 18 EWS, 4 CS and 5 ESMC. Median age was 27.8 years (range 12–76); median starting dose was 60 mg for CABO (n = 37, range 40–60) and 120 mg for REGO (n = 29, range 40–160). Twenty‐eight (42.4%) patients required dose reduction: hand‐foot syndrome 7 (10.6%), nausea/vomiting 1 (1.5%), diarrhoea 1 (1.5%), 2 elevated LFTs (3%), elevated bilirubin 1 (1.5%) and mucositis 1 (1.5%). The median OS for patients with OST, EWS, CS and ESMC was 8.5 months (n = 39, 95% CI 7–13.1); 13.4 months (n = 18, 95% CI 3.4–27.2), 8.1 (n = 4, 95% CI 4.1–9.3) and 18.2 (n = 5, 95% CI (10.4–na), respectively. Median PFS for OST, EWS, CS and ECMS was 3.5 (n = 39, 95% CI 2.8–5), 3.9 (n = 18, 95% CI 2.1–5.9), 5.53 (n = 4. 95% CI 2.13–NA) and 11.4 (n = 5, 95% CI 1.83–14.7), respectively. Age, line of therapy, REGO versus CABO, or time from diagnosis to initiation of TKI were not associated with PFS on univariable analysis.ConclusionOur real‐world data show that TKIs have meaningful activity in recurrent BT with acceptable toxicities when started at modified dosing. Inclusion of TKIs in earlier lines of treatment and/or maintenance therapy could be questions for future research.

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

Cited by 8 publications

References 24 publications

The Capacity of Drug-Metabolising Enzymes in Modulating the Therapeutic Efficacy of Drugs to Treat Rhabdomyosarcoma

The Capacity of Drug-Metabolising Enzymes in Modulating the Therapeutic Efficacy of Drugs to Treat Rhabdomyosarcoma

Current Role of Topoisomerase I Inhibitors for the Treatment of Mesenchymal Malignancies and Their Potential Future Use as Payload of Sarcoma-Specific Antibody-Drug Conjugates

Real‐world experience of tyrosine kinase inhibitors in children, adolescents and adults with relapsed or refractory bone tumours: A Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) study

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