Complications after proton radiotherapy in children, focusing on severe late complications. A complete Swedish cohort 2008-2019.

BACKGROUND: Proton radiotherapy (RT) is an attractive tool to deliver local therapy with minimal dose to uninvolved tissue, however, not suitable for all patients. The aim was to explore complications, especially severe late complications (grades 3-4), following proton RT delivered to a complete Swedish cohort of paediatric patients aged <18 years treated 2008-2019. MATERIAL AND METHODS: Data was downloaded from a national registry. Complications with a possible causation with RT are reported. Proton treatments until July 2015 was performed with a fixed horizontal 172 MeV beam (The Svedberg Laboratory (TSL), Uppsala) in a sitting position and thereafter with gantry-based pencil-beam scanning technique (Skandion Clinic, Uppsala) in a supine position. RESULTS: 219 courses of proton RT (77 at TSL and 142 at Skandion) were delivered to 212 patients (mean age 9.2 years) with various tumour types (CNS tumours 58%, sarcomas 26%, germ cell tumours 7%). Twenty-five patients had severe acute complications (skin, mucous membrane, pharynx/oesophagus, larynx, upper gastrointestinal canal, lower gastrointestinal canal, eyes, ears). Fifteen patients had severe late complications; with increased proportion over time: 4% at 1-year follow-up (FU), 5% at 3-year, 11% at 5-year. Organs affected were skin (1 patient), subcutaneous tissue (4), salivary glands (1), upper GI (1), bone (7), joints (2), CNS (2), PNS (1), eyes (1) and ears (5). Twenty-one of the 28 patients with 10-year FU had at least one late complication grades 1-4 and fourteen of them had more than one (2-5 each). CONCLUSION: The most important result of our study is the relatively low proportion of severe late complications, comparable with other proton studies on various tumours. Furthermore, the numbers of late complications are lower than our own data set on a mixed population of photon and proton treated paediatric patients, assuring the safety of using proton therapy also in the clinical practice.

Assessment of volume segmentation in radiotherapy of adolescents; a treatment planning study by the Swedish Workgroup for Paediatric Radiotherapy.

BACKGROUND AND PURPOSE: The variability in target delineation for similar cases between centres treating paediatric and adolescent patients, and the apparent differences in interpretation of radiotherapy guidelines in the treatment protocols encouraged us to perform a dummy-run study as a part of our quality assurance work. The aim was to identify and quantify differences in the segmentation of target volumes and organs at risk (OARs) and to analyse the treatment plans and dose distributions. MATERIALS AND METHODS: Four patient cases were selected: Wilm's tumour, Hodgkin's disease, rhabdomyosarcoma of the prostate and chordoma of the skull base. The five participating centres received the same patient-related material. They introduced the cases in their treatment planning system, delineated target volumes and OARs and created treatment plans. Dose-volume histograms were retrieved for relevant structures and volumes and dose metrics were derived and compared, e.g. target volumes and their concordance, dose homogeneity index (HI), treated and irradiated volumes, remaining volume at risk and relevant Vx and Dx values. RESULTS: We found significant differences in target segmentation in the majority of the cases. The planning target volumes (PTVs) varied two- to four-fold and conformity indices were in the range of 0.3-0.6. This resulted in large variations in dose distributions to OARs as well as in treated and irradiated volumes even though the treatment plans showed good conformity to the PTVs. Potential reasons for the differences in target delineation were analysed. CONCLUSION: Considerations of the growing child and difficulties in interpretation of the radiotherapy information in the treatment protocols were identified as reasons for the variation. As a result, clarified translated detailed radiotherapy guidelines for paediatric/adolescent patients have been recognised as a way to reduce this variation.

Neurocognition and mean radiotherapy dose to vulnerable brain structures: new organs at risk?

BACKGROUND: Children with brain tumors are at high risk of neurocognitive decline after radiotherapy (RT). However, there is a lack of studies on how RT doses to organs at risk (OARs) impacts neurocognition. The aim of this study was to examine dose-risk relationships for mean RT dose to different brain structures important for neurocognitive networks. We explored previously established OARs and potentially new OARs. METHODS: A sample of 44 pediatric brain tumor survivors who had received proton and/or photon RT were included. Correlations between mean RT doses to OARs and IQ were analyzed. Previously established OARs were cochleae, optic chiasm, optic nerve, pituitary gland, hypothalamus, hippocampus and pons. Potential new OARs for RT-induced neurocognitive decline were cerebellum, vermis and thalamus. RESULTS: Mean RT dose to different OARs correlated with several IQ subtests. Higher mean RT dose to cochleae, optic nerve, cerebellum, vermis and pons was correlated with lower performance on particularly full-scale IQ (FIQ), Perceptual Reasoning (PRI), Working Memory (WMI) and Processing Speed Index (PSI). Higher mean RT dose to hippocampus correlated with lower performance on processing speed and working memory. For those receiving whole brain RT (WBRT), higher mean RT dose to the pituitary gland correlated with lower performance on working memory. CONCLUSION: A high dose-risk correlation was found between IQ subtests and mean RT dose in established and potential new OARs. Thus, in the lack of validated dose constraints for vulnerable brain structures, a parsimonious approach in RT planning should be considered to preserve neurocognitive networks.

Neurocognitive Functions Before and After Radiotherapy in Pediatric Brain Tumor Survivors.

BACKGROUND: The numbers of pediatric brain tumor survivors are increasing due to improved treatment protocols and multimodal treatments. Many survivors have neurocognitive sequelae, especially after radiotherapy. Neuropsychologic assessment is therefore essential to interpret clinical outcome, evaluate treatments protocol, and implement rehabilitation interventions. The overall aim of this study was to describe neurocognitive functions before and after radiotherapy. We also aimed to explore potential confounding risk factors that could affect the interpretation of radiotherapy-induced neurocognitive decline. METHODS: Fifty pediatric brain tumor survivors who had received radiotherapy (five years or more ago) were included. Clinical characteristics, potential confounding risk factors, radiotherapy plans, and neurocognitive functions on intelligence quotient (IQ) and neuropsychologic measurements were analyzed before and after radiotherapy. RESULTS: Neurocognitive functions were affected before radiotherapy and were progressively aggravated thereafter. The last neuropsychologic assessment after radiotherapy varied between two and 139 months. Nineteen patients were tested five years after radiotherapy, and 90% of them performed ≥1 S.D. below the normative mean on IQ measurements. Several potential confounding risk factors including those induced by radiotherapy were associated with lower performance on perceptual function, working memory, and processing speed. Longer time after radiotherapy was particularly associated with lower performance on working memory and processing speed. Importantly, the neuropsychologic assessments revealed more comprehensive problems than could be inferred from IQ measurements alone. CONCLUSIONS: Our study underpins the importance of systematic and structured neuropsychologic assessment before and after radiotherapy. The timing of the assessment is important, and potential confounding risk factors need to be identified to better evaluate radiotherapy-induced neurocognitive decline.

Coronary artery disease surveillance among childhood, adolescent and young adult cancer survivors: A systematic review and recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

BACKGROUND: Coronary artery disease (CAD) is a concerning late outcome for cancer survivors. However, uniform surveillance guidelines are lacking. AIM: To harmonise international recommendations for CAD surveillance for survivors of childhood, adolescent and young adult (CAYA) cancers. METHODS: A systematic literature review was performed and evidence graded using the Grading of Recommendations, Assessment, Development and Evaluation criteria. Eligibility included English language studies, a minimum of 20 off-therapy cancer survivors assessed for CAD, and 75% diagnosed prior to age 35 years. All study designs were included, and a multidisciplinary guideline panel formulated and graded recommendations. RESULTS: 32 of 522 identified articles met eligibility criteria. The prevalence of CAD ranged from 0 to 72% and was significantly increased compared to control populations. The risk of CAD was increased among survivors who received radiotherapy exposing the heart, especially at doses ≥15 Gy (moderate-quality evidence). The guideline panel agreed that healthcare providers and CAYA cancer survivors treated with radiotherapy exposing the heart should be counselled about the increased risk for premature CAD. While the evidence is insufficient to support primary screening, monitoring and early management of modifiable cardiovascular risk factors are recommended. Initiation and frequency of surveillance should be based on the intensity of treatment exposures, family history, and presence of co-morbidities but at least by age 40 years and at a minimum of every 5 years. All were strong recommendations. CONCLUSION: These systematically assessed and harmonised recommendations for CAD surveillance will inform care and guide research concerning this critical outcome for CAYA cancer survivors.

Together we can: experiences from 7 years of cross-sectional studies in a Swedish palliative care clinical research network.

During recent years, research networks and collaboratives focusing on palliative care research have been established both nationally and internationally resulting in several ongoing projects. In 2002, a clinician-based research network, the Palliative Care Research Network in Sweden (PANIS), was established to stimulate research and development of palliative care in Sweden. The growing network, which today includes 60 specialized palliative care units, has used a web-based survey generator to collect data on symptom prevalence, treatment traditions and important issues in palliative care. Eleven different studies involving almost 11,000 patients have been performed within the network including studies on prevalence of antitumoral treatment, the use of opioids, corticosteroids, blood transfusions, parenteral nutrition and prevalence of palliative sedation therapy in specialized palliative care. The working method of the research network is described, and demographic data from 9,298 patients in six cross-sectional studies are presented. Using a relatively simple research methodology, the network has succeeded in addressing key clinical questions and in this article we share experiences and challenges met during the journey.

Lung toxicity after radiation in childhood: Results of the International Project on Prospective Analysis of Radiotoxicity in Childhood and Adolescence.

BACKGROUND AND PURPOSE: This study presents the evaluation of acute and late toxicities of the lung in children and adolescents after irradiation in terms of dose-volume effects. MATERIALS AND METHODS: Irradiated children and adolescents in Germany have prospectively been documented since 2001 in the "Registry for the Evaluation of Side-Effects after Radiotherapy in Childhood and Adolescence (RiSK)"; in Sweden since 2008 in the RADTOX registry. RESULTS: Up to April 2012, 1,392 children were recruited from RiSK, and up to June 2013, 485 from the RADTOX-registry. Of these patients, 295 were irradiated to the lung. Information about acute toxicity was available for 228 patients. 179 patients have been documented concerning late toxicity (≥grade 1: n = 28). The acute toxicity rate was noticeably higher in children irradiated with 5-20Gy (p < 0.05). In the univariate analysis, a shorter time until late toxicity was noticeably associated with irradiation with 5-15Gy (p < 0.05). CONCLUSION: Acute and late toxicities appear to be correlated with higher irradiation volumes and low doses. Our data indicate that similar to the situation in adult patients, V5, V10, V15 and V20 should be kept as low as possible (e.g., at least V5 < 50%, V10 and V15 < 35% and V20 < 30%) in children and adolescents to lower the risk of toxicity.

Acute Toxicity Grade 3 and 4 After Irradiation in Children and Adolescents: Results From the IPPARCA Collaboration.

PURPOSE: In the context of oncologic therapy for children, radiation therapy is frequently indicated. This study identified the frequency of and reasons for the development of high-grade acute toxicity and possible sequelae. MATERIALS AND METHODS: Irradiated children have been prospectively documented since 2001 in the Registry for the Evaluation of Side Effects After Radiation in Childhood and Adolescence (RiSK) database in Germany and since 2008 in the registry for radiation therapy toxicity (RADTOX) in Sweden. Data were collected using standardized, published forms. Toxicity classification was based on Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. RESULTS: As of June 2013, 1500 children have been recruited into the RiSK database and 485 into the RADTOX registry leading to an analysis population of 1359 patients (age range 0-18). A total of 18.9% (n=257) of all investigated patients developed high-grade acute toxicity (grades 3/4). High-grade toxicity of the bone marrow was documented for 63.8% (n=201) of those patients, oral mucositis for 7.6% (n=24), and dermatitis for 7.6% (n=24). Patients with high-grade acute toxicity received concomitant chemotherapy more frequently (56%) than patients with no or lower acute toxicity (31.5%). In multivariate analyses, concomitant chemotherapy, diagnosis of Ewing sarcoma, and total radiation dose showed a statistically noticeable effect (P≤.05) on acute toxicity, whereas age, concomitant chemotherapy, Hodgkin lymphoma, Ewing sarcoma, total radiation dose, and acute toxicity influenced the time until maximal late toxicity. CONCLUSIONS: Generally, high-grade acute toxicity after irradiation in children and adolescence occurs in a moderate proportion of patients (18.9%). As anticipated, the probability of acute toxicity appeared to depend on the prescribed dose as well as concomitant chemotherapy. The occurrence of chronic toxicity correlates with the prior acute toxicity grade. Age seems to influence the time until maximal late toxicity but not the development of acute toxicity.

[Palliative medicine network promotes research and development]. / Nätverksarbete inom palliativ medicin främjar forskning och utveckling.

Research in palliative medicine is often rendered difficult because of limited patient materials. It's important to find new solutions to this problem. In 2002, the palliative research network in Sweden - PANIS - was established, and now comprises 43 palliative units with over 1,700 patients enrolled. So far, we have conducted five surveys and collected data from over 3,700 patients. The subjects have been: The occurrence of hiccups in terminal cancer patients, the occurrence of antitumoral treatments among cancer patients in palliative care, the use of opioids in palliative care, treatment with blood transfusion and erythropoietin in palliative care and the use of corticosteroids in palliative care. A web-based survey generator simplifies the handling of the results and enables the participating units to get instant feedback. We hope to be able to identify adequate and interesting research questions and facilitate the recruitment of patients into palliative studies.

Rapid, reproducible pain relief with [131I]iodine-meta-iodobenzylguanidine in a boy with disseminated neuroblastoma.

[131I]Iodine-meta-iodobenzylguanidine ([131I]MIBG) is a radioactively labelled substance which is incorporated intracellularly by cells with neuroendocrine differentiation and used in the treatment of neuroendocrine malignancies. The agent was systemically administered on three occasions during a period of 16 weeks to a 4-year-old boy afflicted with disseminated neuroblastoma and suffering from severe pain caused by the disease. Initially, during the weeks immediately prior to radionuclide therapy, the boy required continuous intravenous infusions of morphine. On the 3rd day after each treatment, morphine administration could be discontinued and the boy appeared to be pain free. His appetite returned to normal and he became more mobile. The therapy had a good effect on his pain on each of the three occasions. Recurrent side effects were thrombocytopenia and cystitis. It is concluded that treatment with systemic radiotherapy in the form of [131I]MIBG was easy to perform and effective in this case of disseminated neuroblastoma and illustrates that this primary therapy can be used for palliative purposes.

The use of blood transfusions and erythropoietin-stimulating agents in Swedish palliative care.

GOALS OF WORK: To outline the use of blood transfusions and erythropoietin-stimulating agents (ESAs) in palliative care in Sweden and to get an idea of whether or not these usually very sick patients benefit from the treatment. PATIENTS AND METHODS: An internet-based questionnaire was sent out to 24 specialized palliative care units within the Swedish palliative research network. All data were registered by each member directly into a web-based survey generator from which the results were extracted and analyzed. MAIN RESULTS: Twenty-two units registered 1,046 patients (median age 68 years, 87% had a cancer diagnosis). Among these patients, 900 were enrolled in advanced home care and the others were treated in in-patient units. Erythrocyte transfusions were given to 174 patients (17%) during the month before registration with a mean amount of 2.9 units (range 1-18) given to each patient. Erythrocyte transfusions were given to 18% of the patients with a malignancy and to 11% of the patients with a non-malignant disease. Six patients also received thrombocyte transfusions. One hundred seventeen patients (68%) were judged to benefit from the erythrocyte transfusions. Eighty-two (58%) of the 141 transfused patients enrolled in advanced home care received their transfusions in their homes. ESAs was given to 127 patients (12%). CONCLUSIONS: Transfusions are not uncommon in Swedish palliative care. A majority seemed to benefit from the transfusions. Since they are expensive and time consuming, the effect should, however, be carefully evaluated in every individual in order to avoid ineffective treatment.