Prognostic Significance of Age in 5631 Patients with Wilms' Tumour Prospectively Registered in International Society of Pediatric Oncology (SIOP) 93-01 and 2001

Abstract

Background: To enhance risk stratification for Wilms' tumour (WT) in a pre-operative chemotherapy setting, we explored the prognostic significance and optimal age cutoffs in patients treated according to International Society of Paediatric Oncology Renal Tumour Study Group (SIOP-RTSG) protocols. Methods: Patients (6 months-18 years) with unilateral WT, treated with pre-operative chemotherapy, were selected from prospective SIOP 93-01 and 2001 studies (1993-2016). Martingale residual analysis was used to explore optimal age cutoffs. Outcome according to age was analyzed by uni- and multivariable analysis, adjusted for sex, biopsy (yes/no), stage, histological classification and tumour volume at surgery. Findings: 5631 SIOP-registered WT patients were included with a median age of 3·4 years (interquartile range, IQR: 2-5·1). Median follow-up was 6·3 years (IQR: 3·0-8·7). Estimated 5-year event-free survival (EFS) and overall survival (OS) were 85% (95%CI 83·5-85·5) and 93% (95%CI 92·0- 93·4), respectively. Martingale residual plots detected no optimal age cutoffs. Multivariable analysis showed lower EFS with increasing age (linear trend p<0·001). Using previously described age categories, EFS was lower for patients aged 2-4 (HR 1·34, p=0·02), 4-10 (HR 1·83, P<0·0001) and 10-18 years (HR 1·74, p=0·01) as compared to patients aged 6 months-2 years. OS was lower for patients aged 4-10 years (HR 1·67, p=0·01) and 10-18 years (HR 1·87, p=0·04), but not for 2-4 years (HR 1·29, p=0·23). Higher stage, histological risk group and tumour volume were independent adverse prognostic factors for EFS and OS. Interpretation: Although optimal age cutoffs could not be identified, we demonstrated the prognostic significance of age as a linear factor as well as previously described cutoffs for EFS (2 and 4 years) and OS (4 years), in children with WT treated with pre-operative chemotherapy. These findings encourage the consideration of age in the design of future SIOP-RTSG protocols. Funding Statement: Princess Maxima Center for Paediatric Oncology, Foundation KiKa (Children Cancerfree), Great Ormond Street Hospital Children's Charity, Cancer Research UK, the 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 Krebshilfe, Grupo Cooperativo Brasileiro para o Tratamento do Tumour de Wilms' and Sociedade Brasileira de Oncologia Pediatrica, the Spanish Society of Paediatric Haematology and Oncology and the Spanish Association Against Cancer. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: For both protocols ethical approval was obtained by ethical committees of all participating countries, and written informed consent for participation was given by the parents or legal representatives of the patients.