Dose to organs at risk for total body irradiation: Single-institution data using the modulated arc total body irradiation technique.

BACKGROUND: Organs at risk (OAR) dose reporting for total body irradiation (TBI) patients is limited, and standardly reported only as mean doses to the lungs and kidneys. Consequently, dose received and effects on other OAR remain unexplored. To remedy this gap, this study reports dose data on an extensive list of OAR for patients treated at a single institution using the modulated arc total body irradiation (MATBI) technique. METHOD: An audit was undertaken of all patients treated with MATBI between January 2015 and March 2021 who had completed their course of treatment. OAR were contoured on MATBI patient treatment plans, with 12 Gy in six fraction prescription. OAR dose statistics and dose volume histogram data are reported for the whole body, lungs, kidneys, bones, brain, lens, heart, liver and bowel bag. RESULTS: The OAR dose data for 29 patients are reported. Mean dose results are body 11.77 Gy, lungs 9.86 Gy, kidneys 11.84 Gy, bones 12.03 Gy, brain 12.12 Gy, right lens 12.31 Gy, left lens 12.64 Gy, heart 11.07 Gy, liver 11.81 Gy and bowel bag 12.06 Gy. Dose statistics at 1-Gy intervals of V6-V13 for lungs and V10-V13 for kidneys are also included. CONCLUSION: This is the first time an extensive list of OAR data has been reported for any TBI technique. Due to the paucity of reporting, this information could be used by centres implementing the MATBI technique, in addition to aiding comparison between TBI techniques, with the potential for greater understanding of the relationship between dose volume data and toxicity.

Early myocardial injury in children on doxorubicin for cancer chemotherapy: a cross-sectional study in a tertiary referral centre in Kenya.

INTRODUCTION: Use of doxorubicin, an anthracycline chemotherapeutic agent has been associated with late-occurring cardiac toxicities. Detection of early-occurring cardiac effects of cancer chemotherapy is essential to prevent occurrence of adverse events including toxicity, myocardial dysfunction, and death. OBJECTIVE: To investigate the prevalence of elevated cardiac troponin T (cTnT) and associated factors of myocardial injury in children on doxorubicin cancer chemotherapy. METHODS: Design: A cross-sectional study. SETTING AND SUBJECTS: A hospital-based study conducted on children aged 1-month to 12.4-years who had a diagnosis of cancer and were admitted at Kenyatta National Hospital (KNH). INTERVENTIONS AND OUTCOMES: The patients underwent Echocardiography (ECHO) before their scheduled chemotherapy infusion. Twenty-four (24) hours after the chemotherapy infusion the patients had an evaluation of the serum cardiac troponin T (cTnT) and a repeat ECHO. Myocardial injury was defined as cTnT level > 0.014 ng/ml or a Fractional Shortening (FS) of < 29% on ECHO. RESULTS: One hundred (100) children were included in the final analysis. Thirty-two percent (32%) of the study population had an elevated cTnT. A cumulative doxorubicin dose of > 175 mg/m2 was significantly associated with and elevated cTnT (OR, 10.76; 95% CI, 1.18-97.92; p = 0.035). Diagnosis of nephroblastoma was also associated with an elevated cTnT (OR, 3.0; 95% CI, 1.23-7.26) but not statistically significant (p = 0.105). Nine percent (9%) of the participants had echocardiographic evidence of myocardial injury. CONCLUSION: When compared to echocardiography, elevated levels of cTnT showed a higher association with early-occurring chemotherapy-induced myocardial injury among children on cancer treatment at a tertiary teaching and referral hospital in Kenya.

An evaluation of ankle and foot bolus in paediatric modulated arc total body irradiation (MATBI).

INTRODUCTION: This retrospective planning study aimed to evaluate the role of bolus in achieving dose uniformity in the ankles and feet in paediatric patients undergoing Modulated Arc Total Body Irradiation (MATBI) treatment and to identify patient factors that may negate or warrant its use. METHODS: The clinically treated plans of 20 paediatric patients who received MATBI treatment utilising ankle and foot bolus (Bolus plan) were compared with two retrospectively generated plans; a plan with bolus removed and no re-optimisation (No Bolus plan), and a re-optimised plan without bolus attempting to achieve equal dosimetry to the clinical plan via monitor unit adjustment (MU plan). Descriptive statistics were used to evaluate the dose uniformity criteria of ±10% coverage of the reference dose (RD) for each subregion of the ankle and foot for the three plans. The impact of patient height, weight, and age at the time of treatment was evaluated using Spearman's correlation. RESULTS: Variation in doses >10% RD was minimal across the three plans, with an average D1cc difference < 0.4Gy. For the ankle and foot regions in the Bolus plans, the volume receiving at least 90% of the RD (V90) was on average > 92%. In No Bolus and MU plans, there was an average reduction of 24.5% and 23.2% V90 coverage respectively in the toes. Spearman's correlation suggests height has the strongest relationship to D1cc. CONCLUSION: This study validated the continued use of ankle and foot bolus to achieve dosimetric goals for paediatric MATBI treatments, particularly V90 coverage across all heights.

Radiotherapy management of paediatric cancers with synchronous metastasis.

Cancer in childhood represent 1% of all the new diagnosed cancers. About 30% of children with cancer receive radiation therapy, representing about 600 to 700 patients per year in France. As a consequence, paediatric cancers with synchronous metastasis is a very rare situation in oncology, with usually poor standard of care. However, considerable efforts are made by paediatric oncology scientific societies to offer trials or treatment consensus despite these rare situations. The article proposes to synthesize the radiotherapy management of both primary tumour and synchronous metastasis in the most "common" childhood or adolescent cancers.

Metastasis in Neuroblastoma and Its Link to Autophagy.

Neuroblastoma is a paediatric malignancy originating from the neural crest that commonly occurs in the abdomen and adrenal gland, leading to cancer-related deaths in children. Distant metastasis can be encountered at diagnosis in greater than half of these neuroblastoma patients. Autophagy, a self-degradative process, plays a key role in stress-related responses and the survival of cells and has been studied in neuroblastoma. Accordingly, in the early stages of metastasis, autophagy may suppress cancer cell invasion and migration, while its role may be reversed in later stages, and it may facilitate metastasis by enhancing cancer cell survival. To that end, a body of literature has revealed the mechanistic link between autophagy and metastasis in neuroblastoma in multiple steps of the metastatic cascade, including cancer cell invasion and migration, anoikis resistance, cancer cell dormancy, micrometastasis, and metastatic outbreak. This review aims to take a step forward and discuss the significance of multiple molecular players and compounds that may link autophagy to metastasis and map their function to various metastatic steps in neuroblastoma.

Immune contexture of paediatric cancers.

BACKGROUND: The clinical development of immune checkpoint-targeted immunotherapies has been disappointing so far in paediatric solid tumours. However, as opposed to adults, very little is known about the immune contexture of paediatric malignancies. METHODS: We investigated by gene expression and immunohistochemistry (IHC) the immune microenvironment of five major paediatric cancers: Ewing sarcoma (ES), osteosarcoma (OS), rhabdomyosarcoma (RMS), medulloblastoma (MB) and neuroblastoma (NB; 20 cases each; n = 100 samples total), and correlated them with overall survival. RESULTS: NB and RMS tumours had high immune cell gene expression values and high T-cell counts but were low for antigen processing cell (APC) genes. OS and ES tumours showed low levels of T-cells but the highest levels of APC genes. OS had the highest levels of macrophages (CSF1R, CD163 and CD68), whereas ES had the lowest. MB appeared as immune deserts. Tregs (FOXP3 staining) were higher in both RMS and OS. Most tumours scored negative for PD-L1 in tumour and immune cells, with only 11 of 100 samples positive for PD-L1 staining. PD-L1 and OX40 levels were generally low across all five indications. Interestingly, NB had comparable levels of CD8 by IHC and by gene expression to adult tumours. However, by gene expression, these tumours were low for T-cell cytotoxic molecules GZMB, GZMA and PRF1. Surprisingly, the lower the level of tumour infiltrative CD8 T-cells, the better the prognosis was in NB, RMS and ES. Gene expression analyses showed that MYCN-amplified NB have higher amounts of immune suppressive cells such as macrophages, myeloid-derived suppressor cells and Tregs, whereas the non-MYCN-amplified tumours were more infiltrated and had higher expression levels of Teff. CONCLUSIONS: Our results describe the quality and quantity of immune cells across five major paediatric cancers and provide some key features differentiating these tumours from adult tumour types. These findings explain why anti-PD(L)1 might not have had single agent success in paediatric cancers. These results provides the rationale for the development of biologically stratified and personalised immunotherapy strategies in children with relapsing/refractory cancers.

Phase II and biomarker study of programmed cell death protein 1 inhibitor nivolumab and metronomic cyclophosphamide in paediatric relapsed/refractory solid tumours: Arm G of AcSé-ESMART, a trial of the European Innovative Therapies for Children With Cancer Consortium.

PURPOSE: AcSé-ESMART is a European multicentre, proof-of-concept multiarm phase I/II platform trial in paediatric patients with relapsed/refractory cancer. Arm G assessed the activity and safety of nivolumab in combination with metronomic cyclophosphamide +/- irradiation. EXPERIMENTAL DESIGN: Following a Phase II Simon two-stage design, nivolumab was administered intravenously at 3 mg/kg every 2 weeks of a 28-day cycle, oral cyclophosphamide at 25 mg/m2 twice a day, 1 week on/1 week off. The primary endpoint was objective response rate. Irradiation/radioablation of primary tumour or metastasis could be administered as per physician's choice. Biomarker evaluation was performed by tumour immunohistochemistry, whole exome and RNA sequencing, and immunophenotyping of peripheral blood by flow cytometry. RESULTS: Thirteen patients were treated with a median age of 15 years (range: 5.5-19.4). The main histologies were high-grade glioma, neuroblastoma, and desmoplastic small round cell tumour (DSRCT). The safety profile was similar to those of single-agent nivolumab, albeit haematologic toxicity, mainly lymphocytopenia, was commonly reported with the addition of cyclophosphamide +/- irradiation. Two patients with DSRCT and ependymoma presented unconfirmed partial response and prolonged disease stabilisation. Low mutational load with modest intratumour CD3+ T-cell infiltration and immunosuppressive tumour microenvironment were observed in the tumour samples. Under combined treatment, no positive modulation of circulating T cells was displayed, while derived neutrophil-to-lymphocyte ratio increased. CONCLUSIONS: Nivolumab in combination with cyclophosphamide was well tolerated but had limited activity in this paediatric setting. Metronomic cyclophosphamide did not modulate systemic immune response that could compensate limited T-cell infiltration and the immunosuppressive tumour microenvironment. CLINICALTRIALS. GOV IDENTIFIER: NCT2813135.

Neurocognitive impairment following proton therapy for paediatric brain tumour: a systematic review of post-therapy assessments.

BACKGROUND: Proton therapy (PT), frequently utilised to treat paediatric brain tumour (PBT) patients, eliminates exit dose and minimises dose to healthy tissues that theoretically can mitigate treatment-related effects including cognitive deficits. As clinical outcome data are emerging, we aimed to systematically review current evidence of cognitive changes following PT of PBT. MATERIALS AND METHODS: We searched PubMed and Scopus electronic databases to identify eligible reports on cognitive changes following PT of PBT according to PRISMA guidelines. Reports were extracted for information on demographics and cognitive outcomes. Then, they were systematically reviewed based on three themes: (1) comparison with photon therapy, (2) comparison with baseline cognitive measures, to population normative mean or radiotherapy-naïve PBT patients and (3) effects of dose distribution to cognition. RESULTS: Thirteen reports (median size (range): 70 (12-144)) were included. Four reports compared the cognitive outcome between PBT patients treated with proton to photon therapy and nine compared with baseline/normative mean/radiotherapy naïve from which two reported the effects of dose distribution. Reports found significantly poorer cognitive outcome among patients treated with photon therapy compared with proton therapy especially in general cognition and working memory. Craniospinal irradiation (CSI) was consistently associated with poorer cognitive outcome while focal therapy was associated with minor cognitive change/difference. In limited reports available, higher doses to the hippocampus and temporal lobes were implicated to larger cognitive change. CONCLUSION: Available evidence suggests that PT causes less cognitive deficits compared with photon therapy. Children who underwent focal therapy with proton were consistently shown to have low risk of cognitive deficit suggesting the need for future studies to separate them from CSI. Evidence on the effect of dose distribution to cognition in PT is yet to mature.

Evaluating anthracycline cardiotoxicity associated single nucleotide polymorphisms in a paediatric cohort with early onset cardiomyopathy.

BACKGROUND: Anthracyclines are a mainstay of chemotherapy. However, a relatively frequent adverse outcome of anthracycline treatment is cardiomyopathy. Multiple genetic studies have begun to dissect the complex genetics underlying cardiac sensitivity to the anthracycline drug class. A number of single nucleotide polymorphisms (SNPs) have been identified to be in linkage disequilibrium with anthracycline induced cardiotoxicity in paediatric populations. METHODS: Here we screened for the presence of SNPs resulting in a missense coding change in a cohort of children with early onset chemotherapy related cardiomyopathy. The SNP identity was evaluated by Sanger sequencing of PCR amplicons from genomic DNA of patients with anthracycline related cardiac dysfunction. RESULTS: All of the published SNPs were observed within our patient group. There was no correlation between the number of missense variants an individual carried with severity of disease. Furthermore, the time to cardiac disease onset post-treatment was not greater in those individuals carrying a high load of SNPs resulting from missense variants. CONCLUSIONS: We conclude that previously identified missense SNPs are present within a paediatric cohort with early onset heart damage induced by anthracyclines. However, these SNPs require further replication cohorts and functional validation before being deployed to assess anthracycline cardiotoxicity risk in the clinic.

Considerations and adaptions to the modulated arc total body irradiation technique: dosimetry description.

Total body irradiation (TBI) is a complex treatment technique, which has been slow to transition to a three-dimensional (3D) planning approach. There is limited literature available providing a detailed description on methods to plan TBI on a 3D planning system. 3D planning using the modulated arc TBI (MATBI) technique is a complex process involving a significant number of quality assurance processes and scripts, due to more than 40 treatment beams and two patient positions. This article will focus on the workflow and technical planning aspects of our institution's MATBI technique and identify reasons for modifications made to the developing institution's original MATBI approach. Included is a description of specific simulation equipment, detailed explanation of the four-stage computing process including the role of scripting to standardise and streamline what is otherwise a complex number of steps. The information provided is specific to one centre's approach but shows the fundamental planning process and demonstrates a streamlined method, which can be adapted to other planning systems. Overall, the ability to accurately represent the TBI technique in 3D on a planning system will be shown.

Mapping evidence on the distribution of paediatric cancers in sub-Saharan Africa: a scoping review protocol.

BACKGROUND: Paediatric cancers account for a minor fraction of deaths and hence receive little attention from policymakers. In low-income countries, the absence of comprehensive national paediatric strategies results in a lack of access for a majority of children with cancer. In sub-Saharan Africa (SSA), the burden of childhood cancers is underestimated due to a lack of paediatric cancer registries, poor health care systems and competing healthcare needs. The objective of this study is to map evidence on the distribution of paediatric cancers in the SSA region. METHOD: A scoping review will be conducted to map literature on the distribution of paediatric cancers in SSA. An electronic literature search will be conducted from the following databases: PubMed, Google Scholar, EBSCOhost (CINAHL and Health Source) and World Health Organization (WHO)/International Agency for Research in Cancer (IARC) (GLOBOCAN databases). We will also search the reference lists of included studies to source relevant literature. A pilot search was conducted to determine the feasibility of the study. Study selection will be guided by the inclusion and exclusion criteria. After charting the data, a descriptive overview of the studies will be presented in a narrative format. An account of the study characteristics will be described in this narrative. The analysis will be mainly based on mapping the country-specific outcomes emerging from the studies, and a numerical summary of these outcomes will be conducted. Tables, maps and charts will be produced and presented in the result section. DISCUSSION: This review study will identify existing research gaps for future research to influence policy implementation and to improve the availability of diagnosis and treatment of paediatric cancers in SSA.

Are further studies needed to justify the use of proton therapy for paediatric cancers of the central nervous system? A review of current evidence.

Clinical implementation of proton therapy demonstrated its potential to overcome some limitations of the more traditional, photon-based radiotherapy, due to physical and radiobiological advantages of protons. However, questions concerning the long-term effects of protons on paediatric patients need outcome analysis of the reported literature in order to be answered. The current paper has analysed the available clinical trials and comparative studies (protons vs photons) for paediatric cancers of the central nervous system (CNS) analysing the reported outcomes and follow-up times in order to evaluate the safety of proton therapy for this patient group. Based on the literature analysis, proton therapy for treatment of paediatric cancers of the CNS was found to provide survival and tumour control outcomes comparable, and frequently superior, to photon therapy. Furthermore, the use of protons was shown to decrease the incidence of severe acute and late toxicities, including reduced severity of endocrine, neurological, IQ and QoL deficits. Most commonly, the reported median follow-up time was up to 5 years. Only a few studies reported promising, longer follow-up results. Considering that these patients are likely to survive many of the malignancies reported on, the incidence of long term sequellae impacting growth, development and quality of life into adulthood, should be viewed longitudinally for completeness. The evidence surrounding proton therapy in paediatric tumour management supports its effectiveness and potential benefits in reducing the incidence of late-onset toxicities and second malignancies. For stronger evidence, it is highly desired for future studies to improve current reporting by (1) highlighting the paediatric patient cohort's outcome (in mixed patient groups), (2) reporting the follow-up time, (3) clearly indicating the toxicity criteria used in their evaluation, and (4) identifying the risk group. With this suggested clarity of future reporting, meaningful data to support treatment choice may then be available.

Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors.

Although all tumours are rare in childhood, there are some particularly rare paediatric cancers which have not benefited from advances made by the international paediatric oncology network. To establish a shared definition and produce a list of these entities, the European Union Joint Action on Rare Cancers (JARC) promoted a consensus effort. The definition was based on the incidence rates estimated using the information network on rare cancers (RARECAREnet) database, pooling data from 94 population-based cancer registries and 27 countries. The RARECAREnet list of cancers was used to estimate the incidence rates. This list groups cancers by combining the International Classification of Diseases for Oncology, third edition, morphology and topography codes. According to the consensus, very rare paediatric cancers were identified as those with an annual incidence <2/1000000 and corresponded to 11% of all cancers in patients aged 0-14 years. Two subgroups were identified: tumour types typical of childhood (i.e. hepatoblastoma, pleuropulmonary blastoma, pancreatoblastoma) and those typical of adult age (i.e. carcinomas, melanoma). The threshold of 2/1000000 could also be adopted in populations aged 0-19 years: in this case, three tumour types had an incidence rate which was >2/1000000 (i.e. thyroid and testicular cancers and skin melanoma), but the consensus experts considered them as 'very rare' according to their clinical needs (e.g. shortage of knowledge and clinical expertise as the other rare paediatric cancers). The JARC consensus produced a definition and a list of very rare paediatric cancers which may represent a starting point for prioritising research on these tumours, based on data and patients' clinical needs.

Current status of proton therapy outcome for paediatric cancers of the central nervous system - Analysis of the published literature.

INTRODUCTION: The most common solid tumours that develop in children are cancers of the central nervous system. Due to the increased rate of survival over the past decades, greater focus has been placed on the minimisation of long term side effects. In childhood cancer survivors, over 60% report one or more radiation-related late toxicities while half of these adverse events are graded as life-threatening or severe. Proton therapy enables high conformity with the planning target volume and a reduction in dose to areas beyond the target. Owing to the unique nature of dose delivery with proton therapy a reduction of low doses to normal tissues is achievable, and is believed to allow for a decrease in long-term treatment-related side effects. This paper aims to review the published literature around the effectiveness of proton therapy for the treatment of paediatric cancers of the central nervous system, with a focus on treatment outcomes and treatment-related toxicities. METHODS: A search strategy utilising the Medline database was created with the intent of including all articles reporting on proton therapy, paediatric cancers, CNS tumours and treatment outcomes. The final search strategy included the following limitations: limited to humans, English, published from 2000 onwards. The final article count total was 74. RESULTS AND CONCLUSIONS: Proton therapy for the treatment of paediatric cancers of the central nervous system was found to provide survival and tumour control outcomes comparable to photon therapy. Reduced incidence of severe acute and late toxicities was also reported with the use of proton therapy. This includes reduced severity of endocrine, neurological, IQ and QoL deficits. Currently, extensive follow-up of proton patient populations still needs to be made to determine incidences of late-onset toxicities and secondary malignancies. Current evidence surrounding proton therapy use in paediatric patients supports its effectiveness and potential benefits in reducing the incidence of severe toxicities in later life.

Modification of a modulated arc total body irradiation technique: Implementation and first clinical experience for paediatric patients.

INTRODUCTION: To implement the modulated arc total body irradiation (MATBI) technique within the existing infrastructure of a radiation oncology department. The technique needed to treat paediatric patients of all ages, some of whom would require general anaesthesia (GA). METHODS: The MATBI technique required minor modifications to be incorporated within existing departmental infrastructure. Ancillary equipment essential to the technique were identified and in some cases custom designed to meet health and safety criteria. GA equipment was also considered. To evaluate the effectiveness of the implemented technique, an audit of the cases clinically treated was conducted. RESULTS: A motorised treatment couch was designed to allow the patient to be positioned in stabilisation equipment at a height, then lowered to the floor to accommodate source-to-skin-distances from 180 cm to 198 cm to treat the fixed 40 cm × 40 cm field size. Treatment couch design also facilitated positioning of the bespoke two-part spoiler. While organ at risk dose is limited using a beam weight optimisation technique, the dose is further reduced using compensators placed close to the patient's skin on a 3D printed custom-made support bridge. A digital radiography system is used to verify compensator position. Fifteen patients have been treated to date for various diseases using a variety of dose fractionations ranging from 2 Gy in a single fraction to 12 Gy in 6 fractions. Five patients have required GA due to age or behavioural issues. CONCLUSION: The modified MATBI technique and the equipment required for treatment delivery has been found to be well tolerated by all patients.