Welcome to SIOP 2022 Interactive Programme
The Congress will officially run on CET time zone (Central European Time, Barcelona)
- Moira Garraus Oneca (Spain)
- Alejandra P. Casanovas (Argentina)
ADHERENCE TO PROTOCOL RECOMMENDATIONS FOR CHILDREN WITH WILMS TUMOUR IN TWO CONSECUTIVE STUDIES IN THE UK AND IRELAND – DOES VARIATION MATTER?
- Suzanne Tugnait (United Kingdom)
Abstract
Background and Aims
Wilms tumour (WT) has excellent event-free and overall survival rates. However, those with advanced disease have more variation in adherence to the treatment protocol. We examined the extent of variation and its possible effects on survival
Methods
Retrospective analysis of all children with unilateral WT treated with pre-operative chemotherapy in the SIOPWT2001 (2002-11) and IMPORT (2012-18) studies in the UK and Ireland. Pre- and post-operative treatments (including radiotherapy) were classified as: per protocol (PP); deviation (PDEV) - variation for specified clinical reasons; violation (PVIOL) - not treated within protocol-defined parameters. Survival analysis was conducted by Kaplan-Meier, to calculate 2 and 5 year OS and EFS.
Results
1130 children with WT were registered by 20 centres. 1044 (92%) had unilateral WT treated with pre-operative chemotherapy. All had centrally reviewed pathology. Case Report Forms allowing categorisation of the whole treatment pathway were available for 752 patients. Survival rates for both studies were identical, with 5-year OS 92% and 5-year EFS 86%. For patients with localised disease (Stage I-III) 5-year EFS was 88% for PP (n=402) and PDEV (n=123) and 84% for PVIOL (n=72), corresponding 5-year OS was 96%, 95% and 93%, respectively. For patients with metastatic disease (Stage IV), 5-year EFS was 80% for PP (n=45) and PDEV (n=50) and 83% for PVIOL (n=54), corresponding 5-year OS was 89%, 78% and 90%, respectively. None of these differences were statistically significant. In SIOPWT2001 33% of PVIOL patients could be categorised as over-treated and 56% as under-treated. In IMPORT, 47% were over-treated and 45% were under-treated.
Conclusions
Variation in adherence to protocol recommendations is more common in Stage IV disease. Whilst variation does not affect 5-year EFS or OS, it comprises both over- and under-treatment, which may affect risks of late effects.
POST-CHEMOTHERAPY BLASTEMAL-PREDOMINANT WILMS TUMOR IN THE CHILDREN’S ONCOLOGY GROUP (COG) CONTEXT: POOLED OUTCOMES DATA FROM STUDIES AREN0532, AREN0533 AND AREN03B2
- Nicholas Evageliou (United States of America)
Abstract
Background and Aims
Blastemal-type histology is a known adverse prognostic finding for Favorable Histology Wilms tumor (FHWT) in the SIOP post-chemotherapy histology classification system. While the majority of patients with unilateral tumors enrolled on COG renal tumor protocols undergo upfront nephrectomy, some have a delayed nephrectomy after preoperative chemotherapy. No alteration of therapy based on post-chemotherapy histology was recommended on the AREN series of trials. We examined the pooled outcomes of patients stratified by COG by post-chemotherapy histology from these trials.
Methods
Histologic classification was assessed for patients with unilateral FHWT enrolled on COG studies AREN0532, AREN0533 and AREN03B2 who underwent nephrectomy after chemotherapy. The classification was determined by COG post-chemotherapy histology guidelines, through central pathology review when available (84%) or by institutional pathology reviews (16%). Patients with anaplastic histology were excluded.
Results
Of 376 patients who underwent delayed nephrectomy, histologic classification was blastemal-predominant in 22 (6%), intermediate-risk in 308 (82%), and low-risk in 46 (12%). Among the blastemal-predominant cohort, 7 (32%) had stage III disease and 15 (68%) had stage IV disease; 14 (64%) were treated with DD4A (vincristine/dactinomycin/doxorubicin) and 8 (36%) were treated with Regimen M (vincristine/dactinomycin/doxorubicin/cyclosphamide/etoposide). Four-year event-free survival (EFS) estimates for the low-risk, intermediate-risk, and blastemal-predominant groups were 89% (95% CI: 81-99%), 84% (95% CI: 80-89%), and 62% (95% CI: 45-87%; p=0.001). Four-year overall survival estimates for the low-risk, intermediate-risk, and blastemal-predominant groups were 93% (95% CI: 87-100%), 93% (95% CI: 90-96%), and 63% (95% CI: 45-90%; p<0.0001). The 4 year EFS of the blastemal-predominant patients treated with DD4A was 70% (95% CI: 49-100%), compared with 50% (95% CI: 25-100%) for those treated with Regimen M.
Conclusions
We confirm the adverse prognostic signifance of post-chemotherapy blastemal-predominant histology in the COG context. The poor outcomes with both Regimens DD4A and M support study of further therapy intensification for these patients in future protocols.
COMPREHENSIVE GERMLINE GENOMICS OF PATIENTS WITH WILMS TUMOR REVEALS A HIGH LEVEL OF PREDISPOSITION IN FEMALES
- Ulrik K. Stoltze (Denmark)
Abstract
Background and Aims
Studies suggest that 5-10% of Wilms tumors (WT) are caused by genetic conditions and that an additional 2-29% of WT are caused by epigenetic conditions, yet investigations incorporating all existing evidence are lacking. Here we combine comprehensive genomics with selective epigenetic testing and deep phenotyping in an unselected national cohort of patients with WT.
Methods
Prospective whole-genome sequencing (WGS) of germline DNA in all children newly diagnosed with WT in Denmark . Deep phenotyping through parent counseling and electronic medical record mining.
Results
Gene panel-based analyses found three (13%) of 24 patients with WT harbored pathogenic variants in genes associated with high risk of WT (FBXW7, WT1 and REST). Epigenetic testing revealed one (4%) patient with uniparental disomy of chromosome 11 and Beckwith-Wiedemann Syndrome (BWS). Another three patients (13%) with bilateral disease and/or features of BWS had higher birth weights (4,780g vs. 3,575g; p=0.002) despite all being female, and the number of females with macrosomia (>4,250g, n=5) was higher than expected (OR 9.98 [CI95% 2.56-34.66]; p<0.001). Finally, constrained gene analysis revealed an additional four patients (17%) with loss-of-function variants in genes evolutionarily intolerant to damage. Both known and novel findings were more common in females (29% vs. 0% and 50% vs. 10%, respectively; p=0.01). Only one patient had a family history indicative of an underlying genetic condition.
Conclusions
In this prospective, nation-wide study, 17% of patients with WT had a causative genetic or epigenetic condition and an additional 33% had either phenotypic traits or loss-function variants possibly linked to WT risk. Interestingly, these percentages were significantly higher in females.
IDENTIFICATION OF NOVEL THERAPEUTICS FOR HEPATOBLASTOMA USING A PATIENT-DERIVED XENOGRAFT IN VITRO DRUG TESTING PLATFORM
- Roland Kappler (Germany)
Abstract
Background and Aims
Treatment of hepatoblastoma, the most common pediatric liver tumor, significantly improved in the last decades thanks to refinements of surgical procedures and clinical risk stratification. However, resistance towards conventional chemotherapy and the severe long-term side effects induced by its cytotoxicity remain a prevalent challenge. The application of computational prediction tools on transcriptomic data presents a promising strategy to identify novel drugs, but their validation in reliable tumor models is inevitably needed.
Methods
We have established an in vitro drug-testing platform comprised of conventional cell lines and cultures from dissociated patient-derived xenografts of pediatric liver cancers. We have used an 11-point dose-response curve to screen standard-of-care drugs used in the current PHITT trial as well as compounds targeting a wide range of different cellular pathways, which were predicted by digital tools on transcriptomic data of primary tumors. Compounds that induced >50% killing after treatment for 48 hours were defined in viability assays.
Results
We identified the ALK inhibitor ceritinib, the CDK9 inhibitors dinaciclib and alvocidib, and the antihelmintic mebendazole to reduce tumor cell growth in a dose-dependent manner. Subsequent in vitro assays showed that the four drugs induced apoptosis, reduced colony formation capability, retarded proliferation, decreased migration, and paused 3-dimensional spheroid growth. Furthermore, the combination of these drugs with cisplatin revealed a strong synergistic effect, comparable to the one of cisplatin and doxorubicin, which is given to high-risk hepatoblastoma patients. Most importantly, these drugs significantly reduced growth of a patient-derived xenograft model when transplanted into nude mice.
Conclusions
We were able to establish a platform for rapid, reproducible and reliable validation of potential drug candidates. Our results strongly suggest that ceritinib, dinaciclib, alvocidib, and mebendazole can be applied as an alternative therapeutic approach for hepatoblastoma.