Addition of temsirolimus to chemotherapy in children, adolescents, and young adults with intermediate-risk rhabdomyosarcoma (ARST1431): a randomised, open-label, phase 3 trial from the Children's Oncology Group
The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic FOXO1 fusion-positive disease. Temsirolimus in combination with chemotherapy has shown promising activity in patients with relap...
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| Veröffentlicht in: | The lancet oncology 2024-07, Vol.25 (7), p.912-921 |
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| creator | Gupta, Abha A Xue, Wei Harrison, Douglas J Hawkins, Douglas S Dasgupta, Roshni Wolden, Suzanne Shulkin, Barry Qumseya, Amira Routh, Jonathan C MacDonald, Tamara Feinberg, Shari Crompton, Brian Rudzinski, Erin R Arnold, Michael Venkatramani, Raj |
| description | The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic FOXO1 fusion-positive disease. Temsirolimus in combination with chemotherapy has shown promising activity in patients with relapsed or refractory rhabdomyosarcoma. We aimed to compare event-free survival in patients with intermediate-risk rhabdomyosarcoma treated with vincristine, actinomycin, and cyclophosphamide alternating with vincristine and irinotecan (VAC/VI) combined with temsirolimus followed by maintenance therapy versus VAC/VI alone with maintenance therapy.
ARST1431 was a randomised, open-label, phase 3 trial conducted across 210 institutions in Australia, Canada, New Zealand, and the USA. Eligible patients were those aged 40 years or younger with non-metastatic FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1-negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1-negative disease with distant metastases. Eligible patients had to have a Lansky performance status score of 50 or higher if 16 years or younger and a Karnofsky performance status score of 50 or higher if older than 16 years; all patients were previously untreated. Patients were randomised (1:1) in blocks of four and stratified by histology, stage, and group. Patients received intravenous VAC/VI chemotherapy with a cyclophosphamide dose of 1·2 g/m2 per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m2 or 0·5 mg/kg per dose for those who weighed less than 10 kg. The total duration of therapy was 42 weeks followed by 6 months of maintenance therapy with oral cyclophosphamide plus intravenous vinorelbine for all patients. Temsirolimus was withheld during radiotherapy and for 2 weeks before any major surgical procedure. The primary endpoint was 3-year event-free survival. Data were analysed with a revised intention-to-treat approach. The study is registered with ClinicalTrials.gov (NCT02567435) and is complete.
Between May 23, 2016, and Jan 1, 2022, 325 patients were enrolled. In 297 evaluable patients (148 assigned to VAC/VI alone and 149 assigned to VAC/VI with temsirolimus), the median age was 6·3 years (IQR 3·0–11·3); 33 (11%) patients were aged 18 years |
| doi_str_mv | 10.1016/S1470-2045(24)00255-9 |
| format | Article |
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ARST1431 was a randomised, open-label, phase 3 trial conducted across 210 institutions in Australia, Canada, New Zealand, and the USA. Eligible patients were those aged 40 years or younger with non-metastatic FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1-negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1-negative disease with distant metastases. Eligible patients had to have a Lansky performance status score of 50 or higher if 16 years or younger and a Karnofsky performance status score of 50 or higher if older than 16 years; all patients were previously untreated. Patients were randomised (1:1) in blocks of four and stratified by histology, stage, and group. Patients received intravenous VAC/VI chemotherapy with a cyclophosphamide dose of 1·2 g/m2 per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m2 or 0·5 mg/kg per dose for those who weighed less than 10 kg. The total duration of therapy was 42 weeks followed by 6 months of maintenance therapy with oral cyclophosphamide plus intravenous vinorelbine for all patients. Temsirolimus was withheld during radiotherapy and for 2 weeks before any major surgical procedure. The primary endpoint was 3-year event-free survival. Data were analysed with a revised intention-to-treat approach. The study is registered with ClinicalTrials.gov (NCT02567435) and is complete.
Between May 23, 2016, and Jan 1, 2022, 325 patients were enrolled. In 297 evaluable patients (148 assigned to VAC/VI alone and 149 assigned to VAC/VI with temsirolimus), the median age was 6·3 years (IQR 3·0–11·3); 33 (11%) patients were aged 18 years or older; 179 (60%) of 297 were male. 113 (77%) of 148 patients were FOXO1 negative in the VAC/VI group, and 108 (73%) of 149 were FOXO1 negative in the VAC/VI with temsirolimus group. With a median follow-up of 3·6 years (IQR 2·8–4·5), 3-year event-free survival did not differ significantly between the two groups (64·8% [95% CI 55·5–74·1] in the VAC/VI group vs 66·8% [57·5–76·2] in the VAC/VI plus temsirolimus group (hazard ratio 0·86 [95% CI 0·58–1·26]; log-rank p=0·44). The most common grade 3–4 adverse events were anaemia (62 events in 60 [41%] of 148 patients in the VAC/VI group vs 89 events in 87 [58%] of 149 patients in the VAC/VI with temsirolimus group), lymphopenia (83 events in 65 [44%] vs 99 events in 71 [48%]), neutropenia (160 events in 99 [67%] vs 164 events in 105 [70%]), and leukopenia (121 events in 86 [58%] vs 132 events in 93 [62%]). There was one treatment-related death in the VAC/VI with temsirolimus group, categorised as not otherwise specified.
Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population.
The Children's Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health).</description><identifier>ISSN: 1470-2045</identifier><identifier>ISSN: 1474-5488</identifier><identifier>EISSN: 1474-5488</identifier><identifier>DOI: 10.1016/S1470-2045(24)00255-9</identifier><identifier>PMID: 38936378</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject><![CDATA[Adolescent ; Adult ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Chemotherapy ; Child ; Child, Preschool ; Children ; Children & youth ; Cyclophosphamide ; Cyclophosphamide - administration & dosage ; Dactinomycin - administration & dosage ; Female ; Forkhead Box Protein O1 - genetics ; FOXO1 protein ; Histology ; Humans ; Hyperglycemia ; Infant ; Inhibitor drugs ; Intravenous administration ; Irinotecan ; Irinotecan - administration & dosage ; Irinotecan - therapeutic use ; Leukopenia ; Lymphopenia ; Male ; Metastases ; Metastasis ; Mucositis ; Neutropenia ; Oncology ; Patients ; Pediatrics ; Progression-Free Survival ; Radiation therapy ; Rhabdomyosarcoma ; Rhabdomyosarcoma - drug therapy ; Rhabdomyosarcoma - mortality ; Rhabdomyosarcoma - pathology ; Sarcoma ; Sirolimus - administration & dosage ; Sirolimus - analogs & derivatives ; Sirolimus - therapeutic use ; Survival ; Targeted cancer therapy ; Teenagers ; Toxicity ; Vincristine ; Vincristine - administration & dosage ; Vincristine - adverse effects ; Vinorelbine ; Young Adult ; Young adults]]></subject><ispartof>The lancet oncology, 2024-07, Vol.25 (7), p.912-921</ispartof><rights>2024 Elsevier Ltd</rights><rights>Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.</rights><rights>2024. Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c323t-ad5ef7a45302d8652d851cc2d7a06d9c214e50cdd84d320129675a868918c5f33</citedby><cites>FETCH-LOGICAL-c323t-ad5ef7a45302d8652d851cc2d7a06d9c214e50cdd84d320129675a868918c5f33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/3071775060?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976,64364,64366,64368,72218</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38936378$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gupta, Abha A</creatorcontrib><creatorcontrib>Xue, Wei</creatorcontrib><creatorcontrib>Harrison, Douglas J</creatorcontrib><creatorcontrib>Hawkins, Douglas S</creatorcontrib><creatorcontrib>Dasgupta, Roshni</creatorcontrib><creatorcontrib>Wolden, Suzanne</creatorcontrib><creatorcontrib>Shulkin, Barry</creatorcontrib><creatorcontrib>Qumseya, Amira</creatorcontrib><creatorcontrib>Routh, Jonathan C</creatorcontrib><creatorcontrib>MacDonald, Tamara</creatorcontrib><creatorcontrib>Feinberg, Shari</creatorcontrib><creatorcontrib>Crompton, Brian</creatorcontrib><creatorcontrib>Rudzinski, Erin R</creatorcontrib><creatorcontrib>Arnold, Michael</creatorcontrib><creatorcontrib>Venkatramani, Raj</creatorcontrib><title>Addition of temsirolimus to chemotherapy in children, adolescents, and young adults with intermediate-risk rhabdomyosarcoma (ARST1431): a randomised, open-label, phase 3 trial from the Children's Oncology Group</title><title>The lancet oncology</title><addtitle>Lancet Oncol</addtitle><description>The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic FOXO1 fusion-positive disease. Temsirolimus in combination with chemotherapy has shown promising activity in patients with relapsed or refractory rhabdomyosarcoma. We aimed to compare event-free survival in patients with intermediate-risk rhabdomyosarcoma treated with vincristine, actinomycin, and cyclophosphamide alternating with vincristine and irinotecan (VAC/VI) combined with temsirolimus followed by maintenance therapy versus VAC/VI alone with maintenance therapy.
ARST1431 was a randomised, open-label, phase 3 trial conducted across 210 institutions in Australia, Canada, New Zealand, and the USA. Eligible patients were those aged 40 years or younger with non-metastatic FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1-negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1-negative disease with distant metastases. Eligible patients had to have a Lansky performance status score of 50 or higher if 16 years or younger and a Karnofsky performance status score of 50 or higher if older than 16 years; all patients were previously untreated. Patients were randomised (1:1) in blocks of four and stratified by histology, stage, and group. Patients received intravenous VAC/VI chemotherapy with a cyclophosphamide dose of 1·2 g/m2 per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m2 or 0·5 mg/kg per dose for those who weighed less than 10 kg. The total duration of therapy was 42 weeks followed by 6 months of maintenance therapy with oral cyclophosphamide plus intravenous vinorelbine for all patients. Temsirolimus was withheld during radiotherapy and for 2 weeks before any major surgical procedure. The primary endpoint was 3-year event-free survival. Data were analysed with a revised intention-to-treat approach. The study is registered with ClinicalTrials.gov (NCT02567435) and is complete.
Between May 23, 2016, and Jan 1, 2022, 325 patients were enrolled. In 297 evaluable patients (148 assigned to VAC/VI alone and 149 assigned to VAC/VI with temsirolimus), the median age was 6·3 years (IQR 3·0–11·3); 33 (11%) patients were aged 18 years or older; 179 (60%) of 297 were male. 113 (77%) of 148 patients were FOXO1 negative in the VAC/VI group, and 108 (73%) of 149 were FOXO1 negative in the VAC/VI with temsirolimus group. With a median follow-up of 3·6 years (IQR 2·8–4·5), 3-year event-free survival did not differ significantly between the two groups (64·8% [95% CI 55·5–74·1] in the VAC/VI group vs 66·8% [57·5–76·2] in the VAC/VI plus temsirolimus group (hazard ratio 0·86 [95% CI 0·58–1·26]; log-rank p=0·44). The most common grade 3–4 adverse events were anaemia (62 events in 60 [41%] of 148 patients in the VAC/VI group vs 89 events in 87 [58%] of 149 patients in the VAC/VI with temsirolimus group), lymphopenia (83 events in 65 [44%] vs 99 events in 71 [48%]), neutropenia (160 events in 99 [67%] vs 164 events in 105 [70%]), and leukopenia (121 events in 86 [58%] vs 132 events in 93 [62%]). There was one treatment-related death in the VAC/VI with temsirolimus group, categorised as not otherwise specified.
Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population.
The Children's Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health).</description><subject>Adolescent</subject><subject>Adult</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Chemotherapy</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Children</subject><subject>Children & youth</subject><subject>Cyclophosphamide</subject><subject>Cyclophosphamide - administration & dosage</subject><subject>Dactinomycin - administration & dosage</subject><subject>Female</subject><subject>Forkhead Box Protein O1 - genetics</subject><subject>FOXO1 protein</subject><subject>Histology</subject><subject>Humans</subject><subject>Hyperglycemia</subject><subject>Infant</subject><subject>Inhibitor drugs</subject><subject>Intravenous administration</subject><subject>Irinotecan</subject><subject>Irinotecan - administration & dosage</subject><subject>Irinotecan - therapeutic use</subject><subject>Leukopenia</subject><subject>Lymphopenia</subject><subject>Male</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mucositis</subject><subject>Neutropenia</subject><subject>Oncology</subject><subject>Patients</subject><subject>Pediatrics</subject><subject>Progression-Free Survival</subject><subject>Radiation therapy</subject><subject>Rhabdomyosarcoma</subject><subject>Rhabdomyosarcoma - drug therapy</subject><subject>Rhabdomyosarcoma - mortality</subject><subject>Rhabdomyosarcoma - pathology</subject><subject>Sarcoma</subject><subject>Sirolimus - administration & dosage</subject><subject>Sirolimus - analogs & derivatives</subject><subject>Sirolimus - therapeutic use</subject><subject>Survival</subject><subject>Targeted cancer therapy</subject><subject>Teenagers</subject><subject>Toxicity</subject><subject>Vincristine</subject><subject>Vincristine - administration & dosage</subject><subject>Vincristine - adverse effects</subject><subject>Vinorelbine</subject><subject>Young Adult</subject><subject>Young adults</subject><issn>1470-2045</issn><issn>1474-5488</issn><issn>1474-5488</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNqFkd1u1DAQhSMEoj_wCKCRuGArbcCO4yTLDVqtoCBVqkTLteW1J10Xx05th2pfkyfC-wMX3HBje0afzxzNKYpXlLyjhDbvb2jdkrIiNZ9V9QUhFefl4klxmtt1yeuue7p_H5CT4izGe0JoSwl_XpywbsEa1nanxa-l1iYZ78D3kHCIJnhrhilC8qA2OPi0wSDHLRiXa2N1QDcHqb3FqNClmAunYesnd5fbk00RHk3aZD5hGFAbmbAMJv6AsJFr7YetjzIoP0iYLb_d3NKa0YsPICFkHT-YiHoOfkRXWrlGO4dxIyMCgxSMtNAHP0D2BKujmbcRrp3y1t9t4TL4aXxRPOuljfjyeJ8X3z9_ul19Ka-uL7-ullelYhVLpdQc-1bWnJFKdw3PB6dKVbqVpNELVdEaOVFad7VmFaHVomm57JpuQTvFe8bOi9lBdwz-YcKYRDav0Frp0E9RMNLmQTR_zOibf9B7PwWX3e0o2racNCRT_ECp4GMM2IsxmEGGraBE7EIX-9DFLlFR1WIfutipvz6qT-u88L-__qScgY8HAPM6fhoMIiqDTuVwAqoktDf_GfEbtMm9nA</recordid><startdate>202407</startdate><enddate>202407</enddate><creator>Gupta, Abha A</creator><creator>Xue, Wei</creator><creator>Harrison, Douglas J</creator><creator>Hawkins, Douglas S</creator><creator>Dasgupta, Roshni</creator><creator>Wolden, Suzanne</creator><creator>Shulkin, Barry</creator><creator>Qumseya, Amira</creator><creator>Routh, Jonathan C</creator><creator>MacDonald, Tamara</creator><creator>Feinberg, Shari</creator><creator>Crompton, Brian</creator><creator>Rudzinski, Erin R</creator><creator>Arnold, Michael</creator><creator>Venkatramani, Raj</creator><general>Elsevier Ltd</general><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>0TZ</scope><scope>3V.</scope><scope>7RV</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8C2</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>202407</creationdate><title>Addition of temsirolimus to chemotherapy in children, adolescents, and young adults with intermediate-risk rhabdomyosarcoma (ARST1431): a randomised, open-label, phase 3 trial from the Children's Oncology Group</title><author>Gupta, Abha A ; Xue, Wei ; Harrison, Douglas J ; Hawkins, Douglas S ; Dasgupta, Roshni ; Wolden, Suzanne ; Shulkin, Barry ; Qumseya, Amira ; Routh, Jonathan C ; MacDonald, Tamara ; Feinberg, Shari ; Crompton, Brian ; Rudzinski, Erin R ; Arnold, Michael ; Venkatramani, Raj</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c323t-ad5ef7a45302d8652d851cc2d7a06d9c214e50cdd84d320129675a868918c5f33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Chemotherapy</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Children</topic><topic>Children & youth</topic><topic>Cyclophosphamide</topic><topic>Cyclophosphamide - administration & dosage</topic><topic>Dactinomycin - administration & dosage</topic><topic>Female</topic><topic>Forkhead Box Protein O1 - genetics</topic><topic>FOXO1 protein</topic><topic>Histology</topic><topic>Humans</topic><topic>Hyperglycemia</topic><topic>Infant</topic><topic>Inhibitor drugs</topic><topic>Intravenous administration</topic><topic>Irinotecan</topic><topic>Irinotecan - administration & dosage</topic><topic>Irinotecan - therapeutic use</topic><topic>Leukopenia</topic><topic>Lymphopenia</topic><topic>Male</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Mucositis</topic><topic>Neutropenia</topic><topic>Oncology</topic><topic>Patients</topic><topic>Pediatrics</topic><topic>Progression-Free Survival</topic><topic>Radiation therapy</topic><topic>Rhabdomyosarcoma</topic><topic>Rhabdomyosarcoma - drug therapy</topic><topic>Rhabdomyosarcoma - mortality</topic><topic>Rhabdomyosarcoma - pathology</topic><topic>Sarcoma</topic><topic>Sirolimus - administration & dosage</topic><topic>Sirolimus - analogs & derivatives</topic><topic>Sirolimus - therapeutic use</topic><topic>Survival</topic><topic>Targeted cancer therapy</topic><topic>Teenagers</topic><topic>Toxicity</topic><topic>Vincristine</topic><topic>Vincristine - administration & dosage</topic><topic>Vincristine - adverse effects</topic><topic>Vinorelbine</topic><topic>Young Adult</topic><topic>Young adults</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gupta, Abha A</creatorcontrib><creatorcontrib>Xue, Wei</creatorcontrib><creatorcontrib>Harrison, Douglas J</creatorcontrib><creatorcontrib>Hawkins, Douglas S</creatorcontrib><creatorcontrib>Dasgupta, Roshni</creatorcontrib><creatorcontrib>Wolden, Suzanne</creatorcontrib><creatorcontrib>Shulkin, Barry</creatorcontrib><creatorcontrib>Qumseya, Amira</creatorcontrib><creatorcontrib>Routh, Jonathan C</creatorcontrib><creatorcontrib>MacDonald, Tamara</creatorcontrib><creatorcontrib>Feinberg, Shari</creatorcontrib><creatorcontrib>Crompton, Brian</creatorcontrib><creatorcontrib>Rudzinski, Erin R</creatorcontrib><creatorcontrib>Arnold, Michael</creatorcontrib><creatorcontrib>Venkatramani, Raj</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Pharma and Biotech Premium PRO</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Complete (ProQuest Database)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest Public Health Database</collection><collection>Lancet Titles</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>The lancet oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gupta, Abha A</au><au>Xue, Wei</au><au>Harrison, Douglas J</au><au>Hawkins, Douglas S</au><au>Dasgupta, Roshni</au><au>Wolden, Suzanne</au><au>Shulkin, Barry</au><au>Qumseya, Amira</au><au>Routh, Jonathan C</au><au>MacDonald, Tamara</au><au>Feinberg, Shari</au><au>Crompton, Brian</au><au>Rudzinski, Erin R</au><au>Arnold, Michael</au><au>Venkatramani, Raj</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Addition of temsirolimus to chemotherapy in children, adolescents, and young adults with intermediate-risk rhabdomyosarcoma (ARST1431): a randomised, open-label, phase 3 trial from the Children's Oncology Group</atitle><jtitle>The lancet oncology</jtitle><addtitle>Lancet Oncol</addtitle><date>2024-07</date><risdate>2024</risdate><volume>25</volume><issue>7</issue><spage>912</spage><epage>921</epage><pages>912-921</pages><issn>1470-2045</issn><issn>1474-5488</issn><eissn>1474-5488</eissn><abstract>The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic FOXO1 fusion-positive disease. Temsirolimus in combination with chemotherapy has shown promising activity in patients with relapsed or refractory rhabdomyosarcoma. We aimed to compare event-free survival in patients with intermediate-risk rhabdomyosarcoma treated with vincristine, actinomycin, and cyclophosphamide alternating with vincristine and irinotecan (VAC/VI) combined with temsirolimus followed by maintenance therapy versus VAC/VI alone with maintenance therapy.
ARST1431 was a randomised, open-label, phase 3 trial conducted across 210 institutions in Australia, Canada, New Zealand, and the USA. Eligible patients were those aged 40 years or younger with non-metastatic FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1-negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1-negative disease with distant metastases. Eligible patients had to have a Lansky performance status score of 50 or higher if 16 years or younger and a Karnofsky performance status score of 50 or higher if older than 16 years; all patients were previously untreated. Patients were randomised (1:1) in blocks of four and stratified by histology, stage, and group. Patients received intravenous VAC/VI chemotherapy with a cyclophosphamide dose of 1·2 g/m2 per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m2 or 0·5 mg/kg per dose for those who weighed less than 10 kg. The total duration of therapy was 42 weeks followed by 6 months of maintenance therapy with oral cyclophosphamide plus intravenous vinorelbine for all patients. Temsirolimus was withheld during radiotherapy and for 2 weeks before any major surgical procedure. The primary endpoint was 3-year event-free survival. Data were analysed with a revised intention-to-treat approach. The study is registered with ClinicalTrials.gov (NCT02567435) and is complete.
Between May 23, 2016, and Jan 1, 2022, 325 patients were enrolled. In 297 evaluable patients (148 assigned to VAC/VI alone and 149 assigned to VAC/VI with temsirolimus), the median age was 6·3 years (IQR 3·0–11·3); 33 (11%) patients were aged 18 years or older; 179 (60%) of 297 were male. 113 (77%) of 148 patients were FOXO1 negative in the VAC/VI group, and 108 (73%) of 149 were FOXO1 negative in the VAC/VI with temsirolimus group. With a median follow-up of 3·6 years (IQR 2·8–4·5), 3-year event-free survival did not differ significantly between the two groups (64·8% [95% CI 55·5–74·1] in the VAC/VI group vs 66·8% [57·5–76·2] in the VAC/VI plus temsirolimus group (hazard ratio 0·86 [95% CI 0·58–1·26]; log-rank p=0·44). The most common grade 3–4 adverse events were anaemia (62 events in 60 [41%] of 148 patients in the VAC/VI group vs 89 events in 87 [58%] of 149 patients in the VAC/VI with temsirolimus group), lymphopenia (83 events in 65 [44%] vs 99 events in 71 [48%]), neutropenia (160 events in 99 [67%] vs 164 events in 105 [70%]), and leukopenia (121 events in 86 [58%] vs 132 events in 93 [62%]). There was one treatment-related death in the VAC/VI with temsirolimus group, categorised as not otherwise specified.
Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population.
The Children's Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health).</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>38936378</pmid><doi>10.1016/S1470-2045(24)00255-9</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1470-2045 |
| ispartof | The lancet oncology, 2024-07, Vol.25 (7), p.912-921 |
| issn | 1470-2045 1474-5488 1474-5488 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_3073231129 |
| source | MEDLINE; Elsevier ScienceDirect Journals; ProQuest Central |
| subjects | Adolescent Adult Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - therapeutic use Chemotherapy Child Child, Preschool Children Children & youth Cyclophosphamide Cyclophosphamide - administration & dosage Dactinomycin - administration & dosage Female Forkhead Box Protein O1 - genetics FOXO1 protein Histology Humans Hyperglycemia Infant Inhibitor drugs Intravenous administration Irinotecan Irinotecan - administration & dosage Irinotecan - therapeutic use Leukopenia Lymphopenia Male Metastases Metastasis Mucositis Neutropenia Oncology Patients Pediatrics Progression-Free Survival Radiation therapy Rhabdomyosarcoma Rhabdomyosarcoma - drug therapy Rhabdomyosarcoma - mortality Rhabdomyosarcoma - pathology Sarcoma Sirolimus - administration & dosage Sirolimus - analogs & derivatives Sirolimus - therapeutic use Survival Targeted cancer therapy Teenagers Toxicity Vincristine Vincristine - administration & dosage Vincristine - adverse effects Vinorelbine Young Adult Young adults |
| title | Addition of temsirolimus to chemotherapy in children, adolescents, and young adults with intermediate-risk rhabdomyosarcoma (ARST1431): a randomised, open-label, phase 3 trial from the Children's Oncology Group |
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