Abstract We profiled a large heterogenous cohort of matched diagnostic-relapse tumour tissue and paired plasma-derived cell free DNA (cfDNA) from patients with relapsed and progressive solid tumours of childhood. Tissue and cfDNA sequencing results were concordant, with a wider spectrum of mutant alleles and higher degree of intra-tumour heterogeneity captured by the latter, if sufficient circulating tumour-derived DNA (ctDNA) was present. Serial tumour sequencing identified putative drivers of relapse, with alterations in epigenetic drivers being a common feature. In keeping with epigenetic alterations being a common driver of many childhood cancers, fragmentomics analysis of cfDNA identified tumour-specific epigenetic states and transcription factor binding sites accessible in chromatin. This study leverages a large and well-annotated genomic dataset of aggressive childhood malignancies, identifies genomic and epigenetic drivers of childhood cancer relapse, and highlights the power and practicality of cfDNA analysis to capture both intra-tumoural heterogeneity and the epigenetic state of cancer cells.
Most children requiring radiotherapy receive external beam treatment and few have tumours suitable for brachytherapy. No paediatric radiotherapy centre will treat enough patients from its own normal catchment population for expertise in brachytherapy to be developed and sustained. Following discussion and agreement in the national paediatric radiotherapy group, a service for paediatric brachytherapy in the UK has been developed. We report the process that has evolved over more than 10 years, with survival and functional outcome results.
Ifosfamide and methotrexate are commonly used in the treatment of paediatric sarcoma patients and require careful monitoring of renal function and estimation of glomerular filtration rate (GFR) due to nephrotoxic side effects. Using radiolabelled isotopes to measure GFR is common in paediatric patients due to increased accuracy, reliability and the difficulties of urine collection. However, it is an invasive and expensive test with unavoidable radiation exposure. With no current national guideline on GFR monitoring there is significant variation in practice. This study aims to evaluate frequency of GFR monitoring, across three paediatric oncology centres, and the impact it had on chemotherapy dosing. Recommendations will be made to standardise practice, identify risk factors for renal toxicity and consider frequency of radioisotope GFR measurement
Methods
A retrospective analysis of all paediatric patients diagnosed with Ewing's sarcoma, osteosarcoma or rhabdomyosarcoma, requiring ifosfamide or methotrexate chemotherapy, from January 2019 – January 2020 was conducted. Data collected included; age, diagnosis, baseline renal function, underlying renal conditions, renal function monitoring during treatment (via isotopic GFR or other method) and any chemotherapy dose reduction. Data has also been included from a previous audit of GFR use from the Royal Marsden Hospital collected in 2013. Data was collated from patients' clinical notes and online test portals local to each site
Results
85 patients were eligible for inclusion with 17 patients excluded for incomplete data. The age ranged from 1 month to 21 years, with an average age of 9 years. 62 patients had formal isotope clearance GFR testing and 6 patients had GFR testing via other methods. The 62 patients who received isotope measurement of GFR had a total of 244 GFR tests with an average of 3.9 GFRs per patient (range 1 – 10). Four patients required dose reductions, 2 for bone marrow suppression, 1 for tubulopathy (no change in GFR) and 1 patient for reduction in GFR with no change in baseline creatinine (serum creatinine 41, baseline 60). Two patients had ifosfamide substituted by cyclophosphamide, 1 for acute kidney injury post nephrotoxic antibiotic and 1 for hydronephrosis secondary to mass effect from the primary tumour. 5 patients had delayed methotrexate clearance (>72 hours) but did not have an abnormal GFR. Out of 244 GFRs completed only 1 result led to a change in treatment.
Conclusion
This study demonstrated that despite wide variation in practice between treatment centres there was a very low rate of chemotherapy dose reduction due to abnormal GFR results in the paediatric population. The results suggest fewer formal GFR tests could be performed without compromising patient safety. Instead GFR testing may be best used in the context of risk factors such as known renal disease, a rise in baseline creatinine or concurrent use of nephrotoxic drugs or to complement other less hazardous monitoring tests, such as serial creatinine or creatinine clearance. This would reduce the radiation burden and cost significantly. Data from this study could be used to inform a new guideline for renal monitoring in sarcoma patients which will be discussed at the conference.
National advisory panels (NAPs) have been established for the care of children and young people (CYP) with cancer in the United Kingdom since 2011, with an increase in panel number in recent years. Their practice has not previously been reviewed; therefore, we sought to evaluate the role, practice and impact of six selected NAPs offering expertise in ependymoma, histiocytosis, leukaemia, neuroblastoma, renal tumours and sarcoma.This service evaluation used mixed methodology, including review of NAP documentation, semi-structured interviews with the NAP chairs and an analysis of the cases referred for discussion.Total 1110 referrals were analysed. Results demonstrated the significant scope and amount of work undertaken by the NAPs, largely testament to the commitment of the panel members. Specific roles fulfilled have been highlighted, and NAP recommendations have been shown to influence clinical decision-making and be implemented in the majority of cases. Despite widespread good practice, areas to address have been identified; these include clarity regarding NAP membership, consistency in recommendations, the consideration of holistic information to promote personalised management and the exploration of wider multidisciplinary team roles.In the context of increasing demand and the escalating number of NAPs, it is timely to consider how service improvement can be facilitated. Best practice guidelines have been formulated as a product of this study, to promote a sustainable and effective model for NAPs. Review and benchmarking national panel performance against these guidelines will drive high standards of care going forward and they should be embedded as standard practice.
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