Omitting Doxorubicin From Postoperative Chemotherapy Has No Significant Survival Effect in Intermediate-Risk Wilms Tumor
In a phase III noninferiority trial (SIOP WT 2001) reported in The Lancet, Pritchard-Jones et al in the SIOP (International Society of Paediatric Oncology) Renal Tumours Study Group found that omission of doxorubicin from postoperative chemotherapy for stage II to III histologic intermediate-risk Wilms tumor, excluding the high-risk blastemal subtype, did not have a significant adverse impact on event-free or overall survival.
Study Details
In this open-label trial, 583 children from 26 countries aged 6 months to 18 years at diagnosis with histologic intermediate-risk stage II (n = 341) or III (n = 242) disease assessed after delayed nephrectomy were randomly assigned between November 2001 and December 2009 to receive postoperative chemotherapy with vincristine and actinomycin D with (n = 291) or without (n = 292) doxorubicin. Patients had to have received preoperative chemotherapy with 4 weeks of vincristine and actinomycin D. Patients with high-risk blastemal or diffuse anaplastic subtypes or evidence of metastases were excluded.
Vincristine was given at 1.5 mg/m2 at weeks 1 to 8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, and actinomycin D was given at 45 μg/kg every 3 weeks from week 2. Doxorubicin was given in five doses at 50 mg/m2 every 6 weeks from week 2. The primary endpoint was noninferiority of event-free survival at 2 years, with a margin of 10% in the intent-to-treat population.
Event-Free and Overall Survival
Median follow-up was 60.8 months. Two-year event-free survival was 92.6% (95% confidence interval [CI] = 89.6%–95.7%) in the doxorubicin group vs 88.2% (95% CI = 84.5%–92.1%) in the no-doxorubicin group, with the difference of 4.4% (95% CI = 0.4%–9.3%) not exceeding the 10% noninferiority margin. Five-year overall survival was 96.5% (95% CI = 94.3%–98.8%) vs 95.8% (95% CI = 93.3%–98.4%), respectively.
Among patients with stage II disease, 2-year event-free survival was 92.5% vs 88.1%, and 5-year overall survival was 97.6% vs 95.5%. Among patients with stage III disease, 2-year event-free survival was 91.5% vs 86.9%, and 5-year overall survival was 93.8% vs 96.0%.
Cardiotoxic effects, all grade 1 or 2, were reported in 15 children (5%) receiving doxorubicin, with none observed in the no-doxorubicin group.
The investigators concluded: “Doxorubicin does not need to be included in treatment of stage II–III intermediate risk Wilms’ tumour when the histological response to preoperative chemotherapy is incorporated into the risk stratification."
Kathy Pritchard-Jones, MD, of University College London Institute of Child Health, is the corresponding author of The Lancet article.
The study was funded by Cancer Research UK, UK National Cancer Research Network and Children’s Cancer and Leukaemia Group, Societe Francaise des Cancers de l’Enfant and Association Leon Berard Enfant Cancereux and Enfant et Sante, Gesellschaft fur Padiatrische Onkologie und Hamatologie and Deutsche Krebschilfe, Grupo Cooperativo Brasileiro para o Tratamento do Tumor de Wilms and Sociedade Brasileira de Oncologia Pediatrica, Spanish Society of Pediatric Haematology and Oncology and Spanish Association Against Cancer, and SIOP.
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