BACKGROUND:Retinoblastoma is the most common intra-ocular malignancy in children and frequently presents in very young patients who commonly require intravenous carboplatin. Delivering this is challenging due to a lack of uniform dosing recommendations, rapid changes in physiological function and the risk of side-effects. METHODS:We conducted a retrospective review of neonates and infants in the UK with retinoblastoma, who have undergone carboplatin therapeutic drug monitoring (TDM). We report on the pharmacokinetic, treatment efficacy and toxicity data. RESULTS:In total, 29 patients (median age 5 weeks at treatment onset) underwent a total of 74 TDM guided cycles of chemotherapy, involving real time sampling and dose adjustment. An additional 13 patients underwent TDM sampling to modify doses between cycles. Without the adoption of TDM guided dosing, carboplatin exposures would have been ≥20% outside the target AUC in 38/78 (49%) of treatment cycles. Excellent responses and a reassuringly low incidence of toxicities were observed following dose adjustment, despite the young patient age and the implementation of dose increases in the majority of cases. CONCLUSIONS:Real time TDM is safe, effective and deliverable for neonates and infants receiving carboplatin for retinoblastoma and should be considered standard of care up to the age of 6 months.

Background Children with cancer are not at increased risk of severe SARS-CoV-2 infection; however, adults with haematological malignancies have increased risk of severe infections compared with non-haematological malignancies. Methods We compared patients with haematological and non-haematological malignancies enrolled in the UK Paediatric Coronavirus Cancer Monitoring Project between 12 March 2020 and 16 February 2021. Children who received stem cell transplantation were excluded. Results Only 2/62 patients with haematological malignancy had severe/critical infections, with an OR of 0.5 for patients with haematological compared with non-haematological malignancies. Interpretation Children with haematological malignancies are at no greater risk of severe SARS-CoV-2 infection than those with non-haematological malignancies.

The COVID-19 pandemic has considerably changed health services for children with cancer worldwide by creating barriers throughout the care continuum. Reports available at this time suggest that asymptomatic and mild upper and lower respiratory tract syndromes are the most common presentation of COVID-19 in children with cancer. Nonetheless, severe cases of COVID-19 and deaths secondary to the infection have been reported. In addition to the direct effects of the severe acute respiratory syndrome coronavirus 2, children with cancer have suffered from the collateral consequences of the pandemic, including decreased access to diagnosis and cancer-directed therapy. The COVID-19 pandemic has presented unprecedented challenges to safe and effective care of children with cancer, including their enrollment in therapeutic clinical trials. Data from the Children’s Oncology Group and Cancer Research U.K. Clinical Trials Unit show variability in the enrollment of children with cancer in clinical trials during the COVID-19 pandemic. However, the overall effects on outcomes for children with cancer undergoing care during the pandemic remain largely unknown. In this article, we review the current knowledge about the direct and collateral effects of the COVID-19 pandemic, including on clinical trial enrollment and operations.

Early phase trials provide crucial information about new medicines that allow them to be taken forward into larger confirmatory studies. Paediatric early phase studies are becoming more common, particularly in the era of precision therapy. There are almost 600 active paediatric phase I/II trials listed on clinicaltrials.gov. Conventionally, early phase dose-escalation trials use rule-based designs such as the 3+3 to guide dose decisions. A trial is considered to have a rule-based design if predefined rules are used to guide decisions to escalate, continue or de-escalate based on the observed toxicities at the current dose. Though it is well established that model-based design is generally superior to rule-based design, its uptake remains low. Trials with a model-based design use statistical models to guide decisions on which dose levels to give the next patient(s), based on the targeted toxicity level and previous information. In this article, we review one of the most commonly used model-based designs, the continual reassessment method. The goal of any phase I study is to find a recommended dose of a new therapy to advance in subsequent studies. This can be defined in different ways; one of the most common being the maximum tolerated dose (MTD). One key question is: ‘What level of toxicity is acceptable based on the expected benefits of treatment?’ The MTD is defined as the dose expected to cause a degree of medically undesirable dose-limiting toxicity (DLT) in an acceptable specified proportion of participants . The latter is referred to as the target toxicity level (TTL). This level will differ depending on the expected benefits of the treatment as well as the severity of the expected toxicity for the specific intervention. This relationship is illustrated in figure 1. Figure 1 An illustration of the relationship between dose …

BACKGROUND:Children with cancer are frequently immunocompromised. While children are generally thought to be at less risk of severe SARS-CoV-2 infection than adults, comprehensive population-based evidence for the risk in children with cancer is unavailable. We aimed to produce evidence of the incidence and outcomes from SARS-CoV-2 in children with cancer attending all hospitals treating this population across the UK. METHODS:Retrospective and prospective observational study of all children in the UK under 16 diagnosed with cancer through data collection from all hospitals providing cancer care to this population. Eligible patients tested positive for SARS-CoV-2 on reverse transcription polymerase chain reaction (RT-PCR). The primary end-point was death, discharge or end of active care for COVID-19 for those remaining in hospital. RESULTS:Between 12 March 2020 and 31 July 2020, 54 cases were identified: 15 (28%) were asymptomatic, 34 (63%) had mild infections and 5 (10%) moderate, severe or critical infections. No patients died and only three patients required intensive care support due to COVID-19. Estimated incidence of hospital identified SARS-CoV-2 infection in children with cancer under 16 was 3%. CONCLUSIONS:Children with cancer with SARS-CoV-2 infection do not appear at increased risk of severe infection compared to the general paediatric population. This is reassuring and supports the continued delivery of standard treatment.

Clinical trials can be separated into phase I (dose finding and safety), phase II (activity or early efficacy), phase III (efficacy compared with current standard of care) and occasionally phase IV (postmarketing studies). A new compound would usually have to go through phase I–III studies sequentially with all of the financial and regulatory hurdles this poses. A recent study has estimated that only 13.8% of compounds tested will be successful in achieving a marketing license.1 Adaptive designs are an extensive class of flexible tools which use accumulated data in the trial to make preplanned adaptations to the trial’s course. They can be used in all trial phases. The adaptations can include stopping an arm early for futility or safety, closing recruitment to an arm early if there is strong evidence of efficacy, changing of target sample size or allocation ratios. They are usually more efficient, informative and ethical than traditional fixed designs (where no interim adaptations are permitted). They can often offer savings in resources and even number of patients (figure 1).2 Figure 1 Benefits of adaptive trial designs. Adapted from: adaptive designs in clinical trials: why use them, and how to run and report them. A novel paradigm for conducting adaptive trials, which allows several treatments to be assessed concurrently with preplanned interim adaptations, is the so-called multiarm, …

Intracranial germ cell tumors are a heterogeneous group of tumors, broadly classified into germinomatous, nongerminomatous, or teratoma subtypes. Treatment has evolved over recent decades to include multimodal therapy combining surgery, radiotherapy, and chemotherapy. Although the majority of intracranial germs cell tumors are treated successfully, management can be fraught with complexities and present significant clinical challenges. Bifocal disease is well described, but rare, and therefore its behavior is not well characterized, particularly in nongerminomatous disease. This case report presents an interesting case, with both rare and common complications, in particular, to emphasize the challenges of germ cell tumor management. With a focus on bifocal disease, we review the published cases and highlight how advanced imaging and magnetic resonance spectroscopy can be used in management. Advances in biology, targeted agents, and novel diagnostic tools are also discussed.

We read with interest the recent article by Martin and Kneyber: Is there a role for high-flow nasal cannula oxygen therapy to prevent endotracheal intubation in children with viral bronchiolitis?1 Respiratory support using high flow nasal cannula oxygen (HFNCO) in severe bronchiolitis has been used in various settings including a general paediatric ward.2 We would like to share our experience of using HFNCO for the last 3 years (2010–2011, 2011–2012 and 2012–2013) in a paediatric ward, working to a strict protocol. Infants with bronchiolitis …