A National Referral Service for Paediatric Brachytherapy: An Evolving Practice and Outcomes Over 13 Years.

AIMS: 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. MATERIALS AND METHODS: Since 2009, potential patients have been referred to the central paediatric oncology multidisciplinary team meeting, where imaging, pathology and treatment options are discussed. Since 2013, the National Soft Tissue Sarcoma Advisory Panel has also reviewed most patients, with the principal aim of advising on the most suitable primary tumour management for complex patients. Clinical assessment and examination under anaesthetic with biopsies may be undertaken to confirm the appropriateness of brachytherapy, either alone or following conservative surgery. Fractionated high dose rate brachytherapy was delivered to a computed tomography planned volume after implantation of catheters under ultrasound imaging guidance. Since 2019, follow-up has been in a dedicated multidisciplinary clinic. RESULTS: From 2009 to 2021 inclusive, 35 patients (16 female, 19 male, aged 8 months to 17 years 6 months) have been treated. Histology was soft-tissue sarcoma in 33 patients and carcinoma in two. The treated site was pelvic in 31 patients and head and neck in four. With a median follow-up of 5 years, the local control and overall survival rates are 100%. Complications have been few, and functional outcome is good. CONCLUSION: Brachytherapy is effective for selected paediatric patients, resulting in excellent tumour control and good functional results. It is feasible to deliver paediatric brachytherapy at a single centre within a national referral service.

Paediatric Molecular Radiotherapy: Challenges and Opportunities.

The common contemporary indications for paediatric molecular radiotherapy (pMRT) are differentiated thyroid cancer and neuroblastoma. It may also have value in neuroendocrine cancers, and it is being investigated in clinical trials for other diseases. pMRT is the prototypical biomarker-driven, precision therapy, with a unique mode of delivery and mechanism of action. It is safe and well tolerated, compared with other treatments. However, its full potential has not yet been achieved, and its wider use faces a number of challenges and obstacles. Paradoxically, the success of radioactive iodine as a curative treatment for metastatic thyroid cancer has led to a 'one size fits all' approach and limited academic enquiry into optimisation of the conventional treatment regimen, until very recently. Second, the specialised requirements for the delivery of pMRT are available in only a very limited number of centres. This limited capacity and geographical coverage results in reduced accessibility. With few enthusiastic advocates for this treatment modality, investment in research to improve treatments and broaden indications from both industry and national and charitable research funders has historically been suboptimal. Nonetheless, there is now an increasing interest in the opportunities offered by pMRT. Increased research funding has been allocated, and technical developments that will permit innovative approaches in pMRT are available for exploration. A new portfolio of clinical trials is being assembled. These studies should help to move at least some paediatric treatments from simply palliative use into potentially curative protocols. Therapeutic strategies require modification and optimisation to achieve this. The delivery should be personalised and tailored appropriately, with a comprehensive evaluation of tumour and organ-at-risk dosimetry, in alignment with the external beam model of radiotherapy. This article gives an overview of the current status of pMRT, indicating the barriers to progress and identifying ways in which these may be overcome.

Efficacy, acceptability and tolerability of the new oral phosphate binder Lenziaren® in healthy cats fed a standard diet.

BACKGROUND: The efficacy, acceptability and tolerability of the new oral phosphate binder Lenziaren® (SBR759) were evaluated in a randomized parallel-group design study in 36 healthy cats (n = 6 per group). Five groups were fed once daily with a commercial diet containing 0.2% phosphorus ("standard diet") into which was mixed Lenziaren® at 0.25, 0.5, 1.0 or 2.0 g/day or no treatment (control group) daily for 30 days. A sixth group was fed a commercial diet containing lower amounts (0.12%) of phosphorus ("renal diet") and no treatment. RESULTS: When compared to the control group, Lenziaren® produced significant dose-related reductions in urine phosphate concentrations, urine phosphate excretion and fractional urinary phosphate excretion. Significant effects versus the control group were observed at the 0.5, 1.0 and 2.0 g/day dosages. Lenziaren® was well tolerated and was associated with higher food consumption and serum iron concentrations versus the control. When compared to the control group, the renal diet was associated with significantly lower urine phosphate concentrations and loss of body weight. Lenziaren® had similar effects on urine phosphate concentrations compared to the renal diet, but was not associated with loss of body weight. CONCLUSIONS: Lenziaren® was effective as an oral phosphate binder in cats fed with a standard diet containing 0.2% phosphorus. The acceptability and tolerability were good. Dosages of 0.5-1.0 g/cat per day are recommended for clinical testing in cats fed with a standard diet.

Tolerability and efficacy of the intestinal phosphate binder Lantharenol® in cats.

BACKGROUND: Tolerability and efficacy of the intestinal phosphate binder Lantharenol® (lanthanum carbonate octahydrate) were tested in two prospective, randomized and negative controlled laboratory studies with healthy adult cats fed commercial maintenance diets non-restricted in phosphorus. In the first study, the maximal tolerated dose was determined. Starting from a dose of 0.125 g/kg body weight mixed with the daily feed ration, the dose of Lantharenol® was doubled every other week until signs of intolerability were observed (N=10 cats compared to 5 untreated controls). In the second study, the effects of feed supplementation for two weeks with approximately 2, 6, and 20% of the maximal tolerated dose on phosphorus excretion patterns and balance were assessed (N=8 cats per group). RESULTS: Lantharenol® was found to be safe and well tolerated up to the dose of 1 g/kg bodyweight, corresponding to a concentration of 84 g Lantharenol®/kg complete feed, defined as dry matter with a standard moisture content of 12%. Feed supplementation for two weeks with approximately 2-20% of this dosage (i.e., 1.6, 4.8, and 16 g/kg complete feed) resulted in a shift from urinary to faecal phosphorus excretion. Apparent phosphorus digestibility was dose-dependently reduced compared to the control group fed with diet only (N=8). CONCLUSIONS: The feed additive was well accepted and tolerated by all cats. Therefore, Lantharenol® presents a well tolerated and efficacious option to individually tailor restriction of dietary phosphorus as indicated, for instance, in feline chronic kidney disease.

Identification of enzymes involved in phase I metabolism of ciclesonide by human liver microsomes.

Ciclesonide, a novel inhaled corticosteroid, is currently being developed for the treatment of asthma. Here, the enzymes catalysing the human hepatic metabolism of ciclesonide were investigated. When incubated with human liver microsomes (HLM), [14C]ciclesonide was first metabolised to the active metabolite M1 (des-isobutyryl-ciclesonide, des-CIC) and to at least two additional metabolites, M2 and M3. M3 comprises a 'family' of structurally similar metabolites that are inactive. 16-Hydroxyprednisolone was also formed in microsomal incubations of [14C]des-CIC, but at approximately one-tenth the amount of both M2 and M3. bis-p-Nitrophenylphosphate and SKF 525-A respectively inhibited des-CIC formation from [14C]ciclesonide by 82% and 49% and M2/M3 formation by 82-84% and 87-89%. Regression analysis showed significant negative correlations (r = -0.96, -0.79 and -0.71, respectively) of M2 formation with CYP3A4/5, CYP2B6 and CYP2C8 activities; M3 formation significantly correlated with CYP4A9/11 (r = 0.47). Troleandomycin and diethyldithiocarbamate inhibited M2 and M3 formation by 85% and 45%, respectively. Sulphaphenazole and quinidine had no inhibitory effects. CYP3A4 Supersomes catalysed notable formation of both M2 and M3 from [14C]des-CIC; CYP2C8 and CYP2D6, but not CYP4A11 formed smaller amounts. It is concluded that the human hepatic metabolism of ciclesonide is primarily catalysed by one or more esterases and, subsequently, by CYP3A4.