Improving the outcomes for high-­risk neuroblastoma through the optimisation of radiotherapeutic techniques

Neuroblastoma is a childhood cancer with highly variable clinical behaviour and outcomes. The long-­‐term survival rate for high-­‐risk neuroblastoma remains poor and new therapeutic advances and optimisation of existing therapies is therefore required. Both external beam radiotherapy and molecular radiotherapy have a significant role to play in the multi-­‐modality treatment of high-­‐risk disease. This collection of work examines ways in which the outcome for neuroblastoma may be improved through the introduction of new and enhancement of existing radiotherapeutic techniques. 131I-­‐meta-­‐Iodobenzylguanidine molecular radiotherapy has been used in the treatment of neuroblastoma since the mid 1980’s. Despite this, its role and efficacy remain undefined. A systematic review of 131I-­‐mIBG therapy in neuroblastoma is therefore presented. Radiolabelled somatostatin analogues target a distinct and separate molecular target on neuroblastoma cells to the noradrenaline transporter targeted by 131I-­‐mIBG. This study reports on the use of radiolabelled somatostatin analogues for the imaging and therapy of patients with high-­‐risk neuroblastoma. The expression of the two different molecular targets by immunohistochemistry for the noradrenaline transporter molecule and somatostatin receptor type-­‐2 in archived neuroblastoma tumour samples is also explored. The radiation doses received by comforters and carers providing necessary support to children undergoing molecular radiotherapy over a 10 year period is presented. The gold standard imaging modality for response assessment in neuroblastoma is 123I-­‐mIBG scinitgraphy. The role of other functional imaging techniques such as 18F-­‐ FDG PET/CT remains undefined. This study will look to see if 18F-­‐FDG PET/CT can give additional information with regards to response assessment. External beam radiotherapy is standardly delivered using conventional anterior and posterior parallel opposed beams and this can result in a compromise on target volume coverage to stay within the tolerance of normal tissues. The use of an Intensity Modulated Arc Therapy technique to improve target volume coverage is examined

Immunohistochemical evaluation of molecular radiotherapy target expression in neuroblastoma tissue

Purpose Neuroblastoma may be treated with molecular radiotherapy, 131I meta-Iodobenzylguanidine and 177Lu Lutetium DOTATATE, directed at distinct molecular targets: Noradrenaline Transporter Molecule (NAT) and Somatostatin Receptor (SSTR2), respectively. This study used immunohistochemistry to evaluate target expression in archival neuroblastoma tissue, to determine whether it might facilitate clinical use of molecular radiotherapy. Methods Tissue bank samples of formalin fixed paraffin embedded neuroblastoma tissue from patients for whom clinical outcome data were available were sectioned and stained with haematoxylin and eosin, and monoclonal antibodies directed against NAT and SSTR2. Sections were examined blinded to clinical information and scored for the percentage and intensity of tumour cells stained. These data were analysed in conjunction with clinical data. Results Tissue from 75 patients was examined. Target expression scores varied widely between patients: NAT median 45%, inter-quartile range 25% - 65%; and SSTR2 median 55%, interquartile range 30% – 80%; and in some cases heterogeneity of expression between different parts of a tumour was observed. A weak positive correlation was observed between the expression scores of the different targets: correlation coefficient = 0.23, p = 0.05. MYCN amplified tumours had lower SSTR2 scores: mean difference 23% confidence interval 8% - 39%, p < 0.01. Survival did not differ by scores. Conclusions As expression of both targets is variable and heterogeneous, imaging assessment of both may yield more clinical information than either alone. The clinical value of immunohistochemical assessment of target expression requires prospective evaluation. Variable target expression within a patient may contribute to treatment failure

Parents' responses to prognostic disclosure at diagnosis of a child with a high‐risk brain tumor: Analysis of clinician‐parent interactions and implications for clinical practice

Background: Previous studies have found that parents of children with cancer desire more prognostic information than is often given even when prognosis is poor. We explored in audio‐recorded consultations the kinds of information they seek. / Methods: Ethnographic study including observation and audio recording of consultations at diagnosis. Consultations were transcribed and analyzed using an interactionist perspective including tools drawn from conversation and discourse analysis. / Results: Enrolled 21 parents and 12 clinicians in 13 cases of children diagnosed with a high‐risk brain tumor (HRBT) over 20 months at a tertiary pediatric oncology center. Clinicians presented prognostic information in all cases. Through their questions, parents revealed what further information they desired. Clinicians made clear that no one could be absolutely certain what the future held for an individual child. Explicit communication about prognosis did not satisfy parents’ desire for information about their own child. Parents tried to personalize prognostic information and to apply it to their own situation. Parents moved beyond prognostic information presented and drew conclusions, which could change over time. Parents who were present in the same consultations could form different views of their child's prognosis. / Conclusion: Population level prognostic information left parents uncertain about their child's future. The need parents revealed was not for more such information but rather how to use the information given and how to apply it to their child in the face of such uncertainty. Further research is needed on how best to help parents deal with uncertainty and make prognostic information actionable

The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours

Peptide receptor radionuclide therapy (PRRNT) is a molecularly targeted radiation therapy involving the systemic administration of a radiolabelled peptide designed to target with high affinity and specificity receptors overexpressed on tumours. PRRNT employing the radiotagged somatostatin receptor agonists (90)Y-DOTATOC ([(90)Y-DOTA(0),Tyr(3)]-octreotide) or (177)Lu-DOTATATE ([(177)Lu-DOTA(0),Tyr(3),Thr(8)]-octreotide or [(177)Lu-DOTA(0),Tyr(3)]-octreotate) have been successfully used for the past 15 years to target metastatic or inoperable neuroendocrine tumours expressing the somatostatin receptor subtype 2. Accumulated evidence from clinical experience indicates that these tumours can be subjected to a high absorbed dose which leads to partial or complete objective responses in up to 30 % of treated patients. Survival analyses indicate that patients presenting with high tumour receptor expression at study entry and receiving (177)Lu-DOTATATE or (90)Y-DOTATOC treatment show significantly higher objective responses, leading to longer survival and improved quality of life. Side effects of PRRNT are typically seen in the kidneys and bone marrow. These, however, are usually mild provided adequate protective measures are undertaken. Despite the large body of evidence regarding efficacy and clinical safety, PRRNT is still considered an investigational treatment and its implementation must comply with national legislation, and ethical guidelines concerning human therapeutic investigations. This guidance was formulated based on recent literature and leading experts’ opinions. It covers the rationale, indications and contraindications for PRRNT, assessment of treatment response and patient follow-up. This document is aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRNT and to deliver the treatment in a safe and effective manner. This document is largely based on the book published through a joint international effort under the auspices of the Nuclear Medicine Section of the International Atomic Energy Agency