Image guidance and inter-fractional anatomical variation in paediatric abdominal radiotherapy

OBJECTIVES: To identify variables predicting inter fractional anatomical variationsmeasured with cone-beam CT (CBCT) throughout abdominal paediatric radiotherapy, and to assess the potential of surface-guided radiotherapy (SGRT) to monitor these changes. METHODS: Metrics of variation in gastrointestinal (GI) gas volume andseparation of the body contour and abdominal wallwere calculated from 21 planning CTs and 77 weekly CBCTs for 21 abdominal neuroblastoma patients (median 4y, range: 2 -19y). Age, sex, feeding tubes, and general anaesthesia (GA) were explored as predictive variables for anatomical variation. Furthermore,GI gas variationwas correlated with changes in body and abdominal wall separation, as well as simulated SGRT metrics of translational and rotationalcorrections between CT/CBCT. RESULTS: GI gas volumes varied 74 ± 54 ml across all scans, while body and abdominal wall separationvaried 2.0 ± 0.7 mm and4.1±1.5mmfrom planning, respectively. Patients < 3.5y (p = 0.04) and treated under GA (p < 0.01) experienced greater GI gas variation; GA was the strongest predictor in multivariate analysis (p < 0.01). Absence of feeding tubes was linked to greater body contour variation (p = 0.03). GI gas variation correlated with body (R = 0.53) and abdominal wall (R = 0.63) changes. The strongest correlations with SGRT metrics were found for anteroposterior translation (R = 0.65) androtation of the left-right axis (R = -0.36). CONCLUSIONS: Young age, GA, and absence of feeding tubes were linked to stronger inter fractional anatomical variation and are likely indicative of patients benefiting from adaptive/robust planning pathways.Our data suggests a role for SGRT toinformthe need for CBCT at each treatment fractionin this patient group. ADVANCES IN KNOWLEDGE: This is the first study to suggest the potential role of SGRT for the management of internal inter fractional anatomical variation in paediatric abdominal radiotherapy

Deep learning based synthetic CT from cone beam CT generation for abdominal paediatric radiotherapy

Objective: Adaptive radiotherapy workflows require images with the quality of computed tomography (CT) for re-calculation and re-optimisation of radiation doses. In this work we aim to improve quality of cone beam CT (CBCT) images for dose calculation using deep learning. / Approach: We propose a novel framework for CBCT-to-CT synthesis using cycle-consistent Generative 10 Adversarial Networks (cycleGANs). The framework was tailored for paediatric abdominal patients, a challenging application due to the inter-fractional variability in bowel filling and smaller patient numbers. We introduced the concept of global residuals only learning to the networks and modified the cycleGAN loss function to explicitly promote structural consistency between source and synthetic images. Finally, to compensate for the anatomical variability and address the difficulties in collecting large datasets in the 15 paediatric population, we applied a smart 2D slice selection based on the common field-of-view across the dataset (abdomen). This acted as a weakly paired data approach that allowed us to take advantage of scans from patients treated for a variety of malignancies (thoracic-abdominal-pelvic) for training purposes. We first optimised the proposed framework and benchmarked its performance on a development dataset. Later, a comprehensive quantitative evaluation was performed on an unseen 20 dataset, which included calculating global image similarity metrics, segmentation-based measures and proton therapy-specific metrics. / Main results: We found improved performance, compared to a baseline implementation, on imagesimilarity metrics such as Mean Absolute Error calculated for a matched virtual CT (55.0±16.6 proposed vs 58.9±16.8 baseline). There was also a higher level of structural agreement for gastrointestinal gas 25 between source and synthetic images measured through dice similarity overlap (0.872±0.053 proposed vs 0.846±0.052 baseline). Differences found in water-equivalent thickness metrics were also smaller for our method (3.3±2.4% proposed vs 3.7±2.8% baseline). / Significance: Our findings indicate that our innovations to the cycleGAN framework improved the quality and structure consistency of the synthetic CTs generated

Developing a framework for CBCT-to-CT synthesis in paediatric abdominal radiotherapy

We proposed a CBCT-to-CT synthesis framework tailored for paediatric abdominal patients. Our approach was based on the cycle-consistent generative adversarial network (cycleGAN) modified to preserve structural consistency. To adjust for differences in field-of-view and body size from different patient groups, our training data was spatially co-registered to a common field-of-view and normalised to a fixed size. The proposed framework showed improvements in generating synthetic CTs from CBCTs compared to the original implementation of cycleGAN without field-of-view adjustments and structural consistency constrain

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

BackgroundPrevious 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.MethodsEthnographic 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.ResultsEnrolled 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.ConclusionPopulation 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

Impact of cyclic changes in pharmacokinetics and absorbed dose in pediatric neuroblastoma patients receiving [177Lu]Lu-DOTATATE

Purpose Recent reports personalizing the administered activity (AA) of each cycle of peptide receptor radionuclide therapy based on the predicted absorbed dose (AD) to the kidneys (dose-limiting organ) have been promising. Assuming identical renal pharmacokinetics for each cycle is pragmatic, however it may lead to over- or under-estimation of the optimal AA. Here, we investigate the influence that earlier cycles of [177Lu]Lu-DOTATATE had on the biokinetics and AD of subsequent cycles in a recent clinical trial that evaluated the safety and activity of [177Lu]Lu-DOTATATE in pediatric neuroblastoma (NBL). We investigated whether predictions based on an assumption of unchanging AD per unit AA (Gy/GBq) prove robust to cyclical changes in biokinetics. Methods A simulation study, based on dosimetry data from six children with NBL who received four-cycles of [177Lu]Lu-DOTATATE in the LuDO trial (ISRCTN98918118), was performed to explore the effect of variable biokinetics on AD. In the LuDO trial, AA was adapted to the patient’s weight and SPECT/CT-based dosimetry was performed for the kidneys and tumour after each cycle. The largest tumour mass was selected for dosimetric analysis in each case. Results The median tumour AD per cycle was found to decrease from 15.6 Gy (range 8.12–26.4) in cycle 1 to 11.4 Gy (range 9.67–28.8), 11.3 Gy (range 2.73–32.9) and 4.3 Gy (range 0.72–20.1) in cycles 2, 3 and 4, respectively. By the fourth cycle, the median of the ratios of the delivered AD (ADD) and the predicted (or “expected”) AD (ADE) (which was based on an assumption of stable biokinetics from the first cycle onwards) were 0.16 (range 0.02–0.92, p = 0.013) for the tumour and 1.08 (range 0.84–1.76, p > 0.05) for kidney. None of the patients had an objective response at 1 month follow up. Conclusion This study demonstrates variability in Gy/GBq and tumour AD per cycle in children receiving four administrations of [177Lu]Lu-DOTATATE treatment for NBL. NBL is deemed a radiation sensitive tumour; therefore, dose-adaptive treatment planning schemes may be appropriate for some patients to compensate for decreasing tumour uptake as treatment progresses. Trial registration ISRCTN ISRCTN98918118. Registered 20 December 2013 (retrospectively registered)