Clinical impact of histologic subtypes in localized non-anaplastic nephroblastoma treated according to the trial and study SIOP-9/GPOH

Weirich, A.; Leuschner, Ivo; Harms, D.; Vujanić, Gordan; Tröger, J.; Abel, Ulrich; Graf, Norbert; Schmidt, Dietmar; Ludwig, R.; Voûte, P. A.

doi:10.1023/a:1011167924230

Cited by 141 publications

(143 citation statements)

References 29 publications

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“…Randomly assigned patients received postoperative chemotherapy for 27 weeks. The treatment including doxorubicin consisted of vincristine 1·5 mg/m² (maximum dose 2 mg) intravenous bolus each week for weeks 1-8, then at weeks 11,12,14,15,17,18,20,21,23,24,26, and 27, combined with actinomycin D 45 μg/kg (maximum dose 2 mg) intravenous bolus every 3 weeks from week 2, and fi ve doses of doxorubicin 50 mg/m² in 4-6 h infusions (total dose 250 mg/m²) given once every 6 weeks from week 2. The treatment excluding doxorubicin omitted doxorubicin entirely and consisted of the identical backbone of vincristine and actinomycin D only (with the same doses and timing).…”

Section: Methodsmentioning

confidence: 99%

“…Tumours are subtyped according to the proportion of necrosis and the cellular composition of the residual viable tumour. 13 Results from a retrospective analysis of the SIOP 9 and 93-01 trials 14,15 showed that patients with blastemal-type Wilms' tumour-of which a high proportion of any surviving viable tumour after preoperative chemotherapy consists of undiff erentiated tumour cells-have a signifi cantly worse chance of event-free survival compared with patients with other subtypes of histologically determined intermediate-risk, non-anaplastic Wilms' tumour. Therefore, we classifi ed the blastemal subtype as high-risk histology, and we excluded patients with this subtype, and the diff use anaplastic subtype, from the randomised trial.…”

Section: Introductionmentioning

confidence: 99%

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Omission of doxorubicin from the treatment of stage II–III, intermediate-risk Wilms' tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial

et al. 2015

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BACKGROUND: Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation. METHODS: For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m(2) at weeks 1-8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 g/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m(2) given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants. FINDINGS: Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8-79·8). 2 year eventfree survival was 92·6% (95% CI 89·6-95·7) for treatment including doxorubicin and 88·2% (84·5-92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4-9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3-98·8) for treatment including doxorubicin and 95·8% (93·3-98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (<1%) of 291 receiving treatment including doxorubicin died of sepsis, three (1%) of 292 receiving treatment excluding doxorubicin died of varicella, metabolic seizure, and sepsis during treatment for relapse. 17 patients (3%) had hepatic veno-occlusive disease. Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin. 12 children receiving treatment including doxorubicin, and ten children receiving treatment excluding doxorubicin, died, with the remaining deaths from tumour recurrence.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Omission of doxorubicin from the treatment of stage II–III, intermediate-risk Wilms' tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial

et al. 2015

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“…A second advantage of preoperative chemotherapy is that response to treatment may provide a valuable prognostic indicator [50,51]. In the absence of a clear choice between up-front nephrectomy and preoperative chemotherapy, it is reasonable to base the timing of resection on factors such as tumor size, the patient's clinical condition, and the experience of the surgeon.…”

Section: Pros and Cons Of The Nwtsg And Siop Approachesmentioning

confidence: 99%

Current Therapy for Wilms’ Tumor

2005

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“…In the SIOP‐9/GPOH (Gesellschaft für Pädiatrische Onkologie und Hämatologie) trial, it was noticed that stromal and epithelial Wilms tumors showed a poor response to preoperative chemotherapy as measured by tumor volume before and after chemotherapy 7. We have previously reported no volume reduction or even enlargement during preoperative chemotherapy in 24 WT1 ‐mutant Wilms tumors 3.…”

Section: Introductionmentioning

confidence: 99%

Chemotherapy and terminal skeletal muscle differentiation in WT1‐mutant Wilms tumors

et al. 2018

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Wilms tumors (WT) with WT1 mutations do not respond well to preoperative chemotherapy by volume reduction, suggesting resistance to chemotherapy. The histologic pattern of this tumor subtype indicates an intrinsic mesenchymal differentiation potential. Currently, it is unknown whether cytotoxic treatments can induce a terminal differentiation state as a direct comparison of untreated and chemotherapy‐treated tumor samples has not been reported so far. We conducted gene expression profiling of 11 chemotherapy and seven untreated WT1‐mutant Wilms tumors and analyzed up‐ and down‐regulated genes with bioinformatic methods. Cell culture experiments were performed from primary Wilms tumors and genetic alterations in WT1 and CTNNB1 analyzed. Chemotherapy induced MYF6 165‐fold and several MYL and MYH genes more than 20‐fold and repressed many genes from cell cycle process networks. Viable tumor cells could be cultivated when patients received less than 8 weeks of chemotherapy but not in two cases with longer treatments. In one case, viable cells could be extracted from a lung metastasis occurring after 6 months of intensive chemotherapy and radiation. Comparison of primary tumor and metastasis cells from the same patient revealed up‐regulation of RELN and TBX2,TBX4 and TBX5 genes and down‐regulation of several HOXD genes. Our analyses demonstrate that >8 weeks of chemotherapy can induce terminal myogenic differentiation in WT1‐mutant tumors, but this is not associated with volume reduction. The time needed for all tumor cells to achieve the terminal differentiation state needs to be evaluated. In contrast, prolonged treatments can result in genetic alterations leading to resistance.

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Clinical impact of histologic subtypes in localized non-anaplastic nephroblastoma treated according to the trial and study SIOP-9/GPOH

Cited by 141 publications

References 29 publications

Omission of doxorubicin from the treatment of stage II–III, intermediate-risk Wilms' tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial

Omission of doxorubicin from the treatment of stage II–III, intermediate-risk Wilms' tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial

Current Therapy for Wilms’ Tumor

Chemotherapy and terminal skeletal muscle differentiation in WT1‐mutant Wilms tumors

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