Maintenance therapy with trofosfamide, idarubicin and etoposide in patients with rhabdomyosarcoma and other high-risk soft tissue sarcomas (CWS-2007-HR): a multicentre, open-label, randomised controlled phase 3 trialResearch in context
Summary: Background: Rhabdomyosarcoma and other soft tissue sarcomas (STS) with high-risk features are still associated with an unsatisfactory outcome. We evaluated the efficacy of oral maintenance therapy added at the end of standard therapy in patients with high-risk rhabdomyosarcoma and STS. Met...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-12-01
|
| Series: | EClinicalMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589537024005364 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846148501390491648 |
|---|---|
| author | Ewa Koscielniak Gustaf Ljungman Bernarda Kazanowska Felix Niggli Monika Sparber-Sauer Rupert Handgretinger Martin Zimmermann Joachim Boos Bernd Blank Erika Hallmen Irene Teichert von Lüttichau Irene Schmid Birgit Fröhlich Hermann L. Müller Wolfgang Behnisch Ruth Ladenstein Monika Scheer Christian Vokuhl Thekla von Kalle Claudia Blattmann Stefan Bielack Thomas Klingebiel |
| author_facet | Ewa Koscielniak Gustaf Ljungman Bernarda Kazanowska Felix Niggli Monika Sparber-Sauer Rupert Handgretinger Martin Zimmermann Joachim Boos Bernd Blank Erika Hallmen Irene Teichert von Lüttichau Irene Schmid Birgit Fröhlich Hermann L. Müller Wolfgang Behnisch Ruth Ladenstein Monika Scheer Christian Vokuhl Thekla von Kalle Claudia Blattmann Stefan Bielack Thomas Klingebiel |
| author_sort | Ewa Koscielniak |
| collection | DOAJ |
| description | Summary: Background: Rhabdomyosarcoma and other soft tissue sarcomas (STS) with high-risk features are still associated with an unsatisfactory outcome. We evaluated the efficacy of oral maintenance therapy added at the end of standard therapy in patients with high-risk rhabdomyosarcoma and STS. Methods: CWS-2007-HR was a multicentre, open-label, randomised controlled, phase 3 trial done at 87 centers in 5 countries. Eligible patients were those aged 6 months to 21 years with non-metastatic incompletely resected embryonal rhabdomyosarcoma occurring in unfavourable sites with unfavourable age (≥10 years) and/or tumour size (>5 cm); all non-metastatic alveolar rhabdomyosarcoma and those with any non-metastatic rhabdomyosarcoma with nodal involvement. A further group was also eligible: patients with non-metastatic undifferentiated sarcoma, extraskeletal Ewing sarcoma and primary unresected synovial sarcoma. Patients in complete remission at the end of standard therapy (nine cycles of ifosfamide, vincristine with doxorubicine or dactinomycin, and surgery or radiotherapy, or both) were randomised to either stop treatment (S-arm) or to receive oral maintenance therapy (M-arm) with eight 10-day courses (25 weeks) of trofosfamide (2 × 75 mg/m2/day) and idarubicin (1 × 5 mg/m2/day 1,4,7,10) alternating with trofosfamide and etoposide (2 × 25 mg/m2/day). The primary outcome was event-free survival (EFS) and the secondary outcome was overall survival (OS) in the intent-to treat population. This trial is registered at ClinicalTrials.gov, NCT00876031, and, EudraCT 2007-0001478-10. Findings: Between July 1st, 2009 and June 30th, 2019, 195 patients were randomly assigned to the M-arm (n = 96) or S-arm (n = 99). In the intent-to-treat population, with a median follow-up of 5.2 years (IQR 3.9–6.1) for surviving patients, the 3-year EFS in the M-arm was 66.9% (95% CI 58.1–77.2) versus 75.6% (67.6–84.6) in the S-arm (hazard ratio, (HR) 1.62, 95% CI 0.98–2.69, p = 0.06). 3-year OS was 82.8% (95% CI 75.4–90.8) in the M-arm versus 84.7% (95% CI 77.8–92.1) in the S-arm (HR 1.55, 95% CI 0.84–2.89, p = 0.17). Grade 3–4 adverse events were haematological in 66% of patients, febrile infections in 6%, gastrointestinal in 10%, and sensory neuropathy in 1%. Interpretation: The addition of 25 weeks of oral maintenance therapy with trofosfamide, etoposide and idarubicin after standard therapy does not improve EFS and OS in patients with high-risk rhabdomyosarcoma and other STS. Funding: Deutsche Kinderkrebsstiftung Grant No.DKS 2009.09, DKS 2012.06, DKS 2015.13, DKS 2018.10 and DKS 2021.04. |
| format | Article |
| id | doaj-art-f4b2c859be764306b03eebde914a77bd |
| institution | Kabale University |
| issn | 2589-5370 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EClinicalMedicine |
| spelling | doaj-art-f4b2c859be764306b03eebde914a77bd2024-12-01T05:07:51ZengElsevierEClinicalMedicine2589-53702024-12-0178102957Maintenance therapy with trofosfamide, idarubicin and etoposide in patients with rhabdomyosarcoma and other high-risk soft tissue sarcomas (CWS-2007-HR): a multicentre, open-label, randomised controlled phase 3 trialResearch in contextEwa Koscielniak0Gustaf Ljungman1Bernarda Kazanowska2Felix Niggli3Monika Sparber-Sauer4Rupert Handgretinger5Martin Zimmermann6Joachim Boos7Bernd Blank8Erika Hallmen9Irene Teichert von Lüttichau10Irene Schmid11Birgit Fröhlich12Hermann L. Müller13Wolfgang Behnisch14Ruth Ladenstein15Monika Scheer16Christian Vokuhl17Thekla von Kalle18Claudia Blattmann19Stefan Bielack20Thomas Klingebiel21Klinikum Stuttgart, Olgahospital, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany; University of Tübingen, Medical Faculty, Germany; Corresponding author. Klinikum Stuttgart, Olgahospital, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany.Department of Women's and Children's Health, Pediatric Oncology, Uppsala University, Uppsala, SwedenDepartment of Pediatric Hematology/Oncology and BMT, University of Wroclaw, Wroclaw, PolandDepartment of Pediatric Oncology, University Children's Hospital, Zurich, SwitzerlandKlinikum Stuttgart, Olgahospital, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany; University of Tübingen, Medical Faculty, GermanyHospital for Children and Adolescents, Department of Pediatric Hematology and Oncology, University of Tübingen, Tübingen, GermanyDepartment of Pediatric Hematology and Oncology, Medical School, Hannover, GermanyMedical Faculty, University of Münster, Albert-Schweitzer-Campus Münster, GermanyKlinikum Stuttgart, Olgahospital, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, GermanyKlinikum Stuttgart, Olgahospital, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, GermanyChildren's Hospital, Hospital Schwabing, Hospital Rechts der Isar, Technical University München, GermanyDr. von Hauner Children's Hospital, Department of Pediatrics, Division of Pediatric Hematology and Oncology, University Hospital Munich, Ludwig Maximilian University München, GermanyDepartment of Pediatric Hematology and Oncology, University Hospital Münster, University of Münster, GermanyUniversity Children's Hospital, Department of Pediatrics and Pediatric Hematology/Oncology, Klinikum Oldenburg AöR, Carl von Ossietzky University, Oldenburg, GermanyDepartment of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, GermanySt Anna Children's Hospital, Children's Cancer Research Institute, Department of Studies and Statistics for Integrated Research and Projects and Medical University of Vienna, Paediatric Department, Vienna, Austria; Department of Pediatric Hematology/Oncology and BMT, University of Wroclaw, Wroclaw, PolandDepartment of Pediatric Oncology and Hematology, Charité-Universitätsmedizin, Berlin, GermanySection of Pediatric Pathology, Department of Pathology, University Bonn, GermanyInstitute of Radiology Olgahospital, Zentrum für Kinder-, Jugend und Frauenmedizin, Klinikum Stuttgart, Stuttgart, GermanyKlinikum Stuttgart, Olgahospital, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany; University of Tübingen, Medical Faculty, GermanyKlinikum Stuttgart, Olgahospital, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany; University Hospital Muenster, Department for Children and Adolescents, Department of Pediatric Hematology and Oncology, Muenster, GermanyUniversity Hospital Frankfurt, Department for Children and Adolescents, Goethe University, Frankfurt am Main, GermanySummary: Background: Rhabdomyosarcoma and other soft tissue sarcomas (STS) with high-risk features are still associated with an unsatisfactory outcome. We evaluated the efficacy of oral maintenance therapy added at the end of standard therapy in patients with high-risk rhabdomyosarcoma and STS. Methods: CWS-2007-HR was a multicentre, open-label, randomised controlled, phase 3 trial done at 87 centers in 5 countries. Eligible patients were those aged 6 months to 21 years with non-metastatic incompletely resected embryonal rhabdomyosarcoma occurring in unfavourable sites with unfavourable age (≥10 years) and/or tumour size (>5 cm); all non-metastatic alveolar rhabdomyosarcoma and those with any non-metastatic rhabdomyosarcoma with nodal involvement. A further group was also eligible: patients with non-metastatic undifferentiated sarcoma, extraskeletal Ewing sarcoma and primary unresected synovial sarcoma. Patients in complete remission at the end of standard therapy (nine cycles of ifosfamide, vincristine with doxorubicine or dactinomycin, and surgery or radiotherapy, or both) were randomised to either stop treatment (S-arm) or to receive oral maintenance therapy (M-arm) with eight 10-day courses (25 weeks) of trofosfamide (2 × 75 mg/m2/day) and idarubicin (1 × 5 mg/m2/day 1,4,7,10) alternating with trofosfamide and etoposide (2 × 25 mg/m2/day). The primary outcome was event-free survival (EFS) and the secondary outcome was overall survival (OS) in the intent-to treat population. This trial is registered at ClinicalTrials.gov, NCT00876031, and, EudraCT 2007-0001478-10. Findings: Between July 1st, 2009 and June 30th, 2019, 195 patients were randomly assigned to the M-arm (n = 96) or S-arm (n = 99). In the intent-to-treat population, with a median follow-up of 5.2 years (IQR 3.9–6.1) for surviving patients, the 3-year EFS in the M-arm was 66.9% (95% CI 58.1–77.2) versus 75.6% (67.6–84.6) in the S-arm (hazard ratio, (HR) 1.62, 95% CI 0.98–2.69, p = 0.06). 3-year OS was 82.8% (95% CI 75.4–90.8) in the M-arm versus 84.7% (95% CI 77.8–92.1) in the S-arm (HR 1.55, 95% CI 0.84–2.89, p = 0.17). Grade 3–4 adverse events were haematological in 66% of patients, febrile infections in 6%, gastrointestinal in 10%, and sensory neuropathy in 1%. Interpretation: The addition of 25 weeks of oral maintenance therapy with trofosfamide, etoposide and idarubicin after standard therapy does not improve EFS and OS in patients with high-risk rhabdomyosarcoma and other STS. Funding: Deutsche Kinderkrebsstiftung Grant No.DKS 2009.09, DKS 2012.06, DKS 2015.13, DKS 2018.10 and DKS 2021.04.http://www.sciencedirect.com/science/article/pii/S2589537024005364RhabdomyosarcomaSoft tissue sarcomaMaintenance therapy |
| spellingShingle | Ewa Koscielniak Gustaf Ljungman Bernarda Kazanowska Felix Niggli Monika Sparber-Sauer Rupert Handgretinger Martin Zimmermann Joachim Boos Bernd Blank Erika Hallmen Irene Teichert von Lüttichau Irene Schmid Birgit Fröhlich Hermann L. Müller Wolfgang Behnisch Ruth Ladenstein Monika Scheer Christian Vokuhl Thekla von Kalle Claudia Blattmann Stefan Bielack Thomas Klingebiel Maintenance therapy with trofosfamide, idarubicin and etoposide in patients with rhabdomyosarcoma and other high-risk soft tissue sarcomas (CWS-2007-HR): a multicentre, open-label, randomised controlled phase 3 trialResearch in context EClinicalMedicine Rhabdomyosarcoma Soft tissue sarcoma Maintenance therapy |
| title | Maintenance therapy with trofosfamide, idarubicin and etoposide in patients with rhabdomyosarcoma and other high-risk soft tissue sarcomas (CWS-2007-HR): a multicentre, open-label, randomised controlled phase 3 trialResearch in context |
| title_full | Maintenance therapy with trofosfamide, idarubicin and etoposide in patients with rhabdomyosarcoma and other high-risk soft tissue sarcomas (CWS-2007-HR): a multicentre, open-label, randomised controlled phase 3 trialResearch in context |
| title_fullStr | Maintenance therapy with trofosfamide, idarubicin and etoposide in patients with rhabdomyosarcoma and other high-risk soft tissue sarcomas (CWS-2007-HR): a multicentre, open-label, randomised controlled phase 3 trialResearch in context |
| title_full_unstemmed | Maintenance therapy with trofosfamide, idarubicin and etoposide in patients with rhabdomyosarcoma and other high-risk soft tissue sarcomas (CWS-2007-HR): a multicentre, open-label, randomised controlled phase 3 trialResearch in context |
| title_short | Maintenance therapy with trofosfamide, idarubicin and etoposide in patients with rhabdomyosarcoma and other high-risk soft tissue sarcomas (CWS-2007-HR): a multicentre, open-label, randomised controlled phase 3 trialResearch in context |
| title_sort | maintenance therapy with trofosfamide idarubicin and etoposide in patients with rhabdomyosarcoma and other high risk soft tissue sarcomas cws 2007 hr a multicentre open label randomised controlled phase 3 trialresearch in context |
| topic | Rhabdomyosarcoma Soft tissue sarcoma Maintenance therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2589537024005364 |
| work_keys_str_mv | AT ewakoscielniak maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT gustafljungman maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT bernardakazanowska maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT felixniggli maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT monikasparbersauer maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT ruperthandgretinger maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT martinzimmermann maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT joachimboos maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT berndblank maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT erikahallmen maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT ireneteichertvonluttichau maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT ireneschmid maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT birgitfrohlich maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT hermannlmuller maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT wolfgangbehnisch maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT ruthladenstein maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT monikascheer maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT christianvokuhl maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT theklavonkalle maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT claudiablattmann maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT stefanbielack maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext AT thomasklingebiel maintenancetherapywithtrofosfamideidarubicinandetoposideinpatientswithrhabdomyosarcomaandotherhighrisksofttissuesarcomascws2007hramulticentreopenlabelrandomisedcontrolledphase3trialresearchincontext |