Neuroendocrine morbidity after pediatric optic gliomas: a longitudinal analysis of 166 children over 30 years

Context: 50% of pediatric low-grade gliomas affect the optic pathway, hypothalamus and suprasellar areas (OP/HSGs) resulting in significant long-term neuroendocrinopathy. Objective: To dissect tumor- from treatment-related risk factors for OP/HSG-associated neuroendocrinopathy. Design: Retrospective case notes analysis of 166 children with newly-diagnosed OP/HSGs at our quaternary center between 1980 –2010 by multivariate Cox, linear and logistic regression. Results: Patients were of median (range) age 4.9 (0.2–15.4) years at diagnosis and followed up for 8.3 (0.04 –26.8) years. Despite high 20-year overall survival (81.0%), progression-free and endocrine event-free (EEFS) survival were 47.2% and 20.8% respectively. EEFS declined up to 15 years postdiagnosis, with hypothalamic involvement (p0.001) being implicated more than radiotherapy (p0.008) in earlier endocrinopathy; the reverse being true of its density (radiotherapy p0.001; hypothalamic involvement p0.006). GH deficiency (GHD) was commonest (40.3%), followed by central precocious puberty (CPP, 26.0%), gonadotropin (GnD, 20.4%), TSH (13.3%), and ACTH (13.3%) deficiencies. GHD increased with later treatment eras (p0.01), but replacement did not increase progression. CPP was associated with future GnD (p0.05). Posterior pituitary dysfunction (PPD, 7.2%) occurred in 57.9% after only biopsies or shunt procedures, and was associated with 6/13 deaths. 50.2% became obese. Tumor extent, surgery and increased endocrinopathy, rather than radiotherapy, predicted visuo-cognitive morbidity. Conclusions: This first longitudinal OP/HSG-specific study demonstrates that hypothalamo-pituitary dysfunction evolves hierarchically over decades. Tumor location predicts its speed of onset and radiotherapy its density. GnD can evolve from previous CPP, whilst life-threatening PPD can occur after any surgery. Our data suggest that recent radiation-avoiding chemotherapeutic strategies have increased GHD without improving survival

Identifying Surrogates for Heart and Ipsilateral Lung Dose to Guide Field Placement and Treatment Modality Selection during Virtual Simulation of Breast Radiotherapy

AIMS: Virtual simulation (VSim) of tangential photon fields is a common method of field localisation for breast radiotherapy. Heart and ipsilateral lung dose is unknown until the dosimetric plan is produced. If heart and ipsilateral lung tolerance doses are exceeded, this can prolong the pre-treatment pathway, particularly if a change of technique is required. The aim of this study was to identify predictive surrogates for heart and ipsilateral lung dose during VSim to aid optimum field placement and treatment modality selection. MATERIALS AND METHODS: Computed tomography data from 50 patients referred for left breast/chest wall radiotherapy were retrospectively analysed (model-building cohort). The prescribed dose was 40.05 Gy in 15 fractions using a tangential photon technique. The heart and ipsilateral lung contours were duplicated, cropped to within the field borders and labelled heart-in-field (HIF) and ipsilateral lung-in-field (ILF). The percentage of HIF (%HIF) and ILF (%ILF) was calculated and correlated with mean heart dose (MHD) and volume of the ipsilateral lung receiving 18 Gy (V18Gy). Linear regression models were calculated. A validation cohort of 10 left- and 10 right-sided cases with an anterior supraclavicular fossa (SCF) field, and 10 left- and 10 right-sided cases including the internal mammary nodes using a wide tangential technique and anterior SCF field, tested the predictive model. Threshold values for %HIF and %ILF were calculated for clinically relevant MHD and ipsilateral lung V18Gy tolerance doses. RESULTS: For the model-building cohort, the median %HIF and MHD were 2.6 (0.4-16.7) and 2.3 (1.2-8) Gy. The median %ILF and ipsilateral lung V18Gy were 12.1 (2.8-33.6) and 12.6 (3.3-35) %. There was a statistically significant strong positive correlation of %HIF with MHD (r2 = 0.97, P < 0.0001) and of %ILF with ipsilateral lung V18Gy (r2 = 0.99, P < 0.0001). For the validation cohort, the median %HIF and MHD were 3.9 (0.6-8) and 2.5 (1.4-4.7) Gy. The median %ILF and ipsilateral lung V18Gy were 20.1 (12.4-32.0) and 20.9 (12.4-34.4) %. The validation cohort confirmed that %HIF and %ILF continue to be predictive surrogates for heart and ipsilateral lung dose during VSim of left- and right-sided cases when including the SCF ± internal mammary nodes with a three-field photon technique. DISCUSSION: The ability to VSim breast radiotherapy (±nodal targets) and accurately predict the heart and ipsilateral lung doses on the dosimetric plan will ensure that tolerance doses are not exceeded, and identify early in the pre-treatment pathway those cases where alternative techniques or modalities should be considered

Radiomics-Based Texture Analysis of Ga-68-DOTATATE Positron Emission Tomography and Computed Tomography Images as a Prognostic Biomarker in Adults With Neuroendocrine Cancers Treated With Lu-177-DOTATATE

Purpose: Neuroendocrine tumors (NET) are rare cancers with variable behavior. A better understanding of prognosis would aid individualized management. The aim of this hypothesis-generating pilot study was to investigate the prognostic potential of tumor heterogeneity and tracer avidity in NET using texture analysis (TA) of 68Ga-DOTATATE positron emission tomography (PET) and non-enhanced computed tomography (CT) performed at baseline in patients treated with 177Lu-DOTATATE. It aims to justify a larger-scale study to evaluate its clinical value. Methods: The pretherapy 68Ga-DOTATATE PET-CT scans of 44 patients with metastatic NET (carcinoid, pancreatic, thyroid, head and neck, catecholamine-secreting, and unknown primary NET) treated with 177Lu-DOTATATE were analyzed retrospectively using commercially available texture analysis research software. Image filtration extracted and enhanced objects of different sizes (fine, medium, coarse), then quantified heterogeneity by statistical and histogram-based parameters (mean intensity, standard deviation, entropy, mean of positive pixels, skewness, and kurtosis). Regions of interest were manually drawn around up to five of the most 68Ga-DOTATATE avid lesions for each patient. 68Gallium uptake on PET was quantified as SUVmax and SUVmean. Associations between imaging and clinical markers with progression-free (PFS) and overall survival (OS) were assessed using univariate Kaplan-Meier analysis. Independence of the significant univariate markers of survival was tested using multivariate Cox regression analysis. Results: Measures of heterogeneity (higher kurtosis, higher entropy, and lower skewness) on coarse-texture scale CT and unfiltered PET images predicted shorter PFS (CT coarse kurtosis: p=0.05, PET entropy: p=0.01, PET skewness: p=0.03) and shorter OS (CT coarse kurtosis: p=0.05, PET entropy: p=0.01, PET skewness p=0.02). Conventional PET parameters such as SUVmax and SUVmean showed trends towards predicting outcome but were not statistically significant. Multivariate analysis identified that CT-TA (coarse kurtosis: HR=2.57, 95% CI=1.22–5.38, p=0.013) independently predicted PFS, and PET-TA (unfiltered skewness: HR=9.05, 95% CI=1.19–68.91, p=0.033) independently predicted OS. Conclusion: These preliminary data generate a hypothesis that radiomic analysis of neuroendocrine cancer on 68Ga-DOTATATE PET-CT may be of prognostic value and a valuable addition to the assessment of patients

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

Assessment of the impact of CT calibration procedures for proton therapy planning on paediatric treatments

PURPOSE: Relative stopping powers (RSP) for proton therapy are estimated using single-energy CT (SECT), calibrated with standardised tissues of the adult male. It is assumed that those tissues are representative of tissues of all age and sex. Female, male and paediatric tissues differ from one another in density and composition. In this study, we use tabulated paediatric tissues and computational phantoms to investigate the impact of this assumption on paediatric proton therapy. The potential of dual-energy CT (DECT) to improve the accuracy of these calculations is explored. METHODS: We study 51 human body tissues, categorised into male/female for the age groups newborn, 1-, 5-, 10-, 15-year old and adult, with given compositions and densities. CT numbers are simulated and RSPs are estimated using SECT and DECT methods. Estimated tissue RSPs from each method are compared to theoretical RSP. The dose and range errors of each approach is evaluated on 3 computational phantoms (Ewing's sarcoma, salivary sarcoma, glioma) derived from paediatric proton therapy patients. RESULTS: With SECT, soft tissues have mean estimation errors and standard deviation up to (1.96 ± 4.18)% observed in newborns, compared to (0.20 ± 1.15)% in adult males. Mean estimation errors for bones are up to (-3.35 ± 4.76)% in paediatrics as opposed to (0.10 ± 0.66)% in adult males. With DECT, mean errors reduce to (0.17 ± 0.13)% and (0.23 ± 0.22)% in newborns (soft tissues/bones). With SECT, dose errors in a Ewing's sarcoma phantom are exceeding 5 Gy (10% of prescribed dose) at the distal end of the treatment field, with volumes of dose errors >5 Gy of Vdiff> 5 = 4630.7mm3 . Similar observations are made in the head and neck phantoms, with overdoses to healthy tissue exceeding 2 Gy (4%). A systematic Bragg peak shift resulting in either over- or underdosage of healthy tissues and target volumes depending on the crossed tissues RSP prediction errors is observed. Water equivalent range errors of single beams are between -1.53mm and 5.50mm (min, max) (Ewing's sarcoma phantom), -0.78mm and 3.62mm (salivary sarcoma phantom), and -0.43mm and 1.41mm (glioma phantom). DECT can reduce dose errors to <1 Gy and range errors to <1 mm. CONCLUSION: SECT estimates RSPs for paediatric tissues with systematic shifts. DECT improves the accuracy of RSPs and dose distributions in paediatric tissues compared to the SECT calibration curve based on adult males tissues

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

Brachytherapy for rhabdomyosarcoma: Survey of international clinical practice and development of guidelines.

BACKGROUND AND PURPOSE: The purpose of this study was to address the lack of published data on the use of brachytherapy in pediatric rhabdomyosarcoma by describing current practice as starting point to develop consensus guidelines. MATERIALS AND METHODS: An international expert panel on the treatment of pediatric rhabdomyosarcoma comprising 24 (pediatric) radiation oncologists, brachytherapists and pediatric surgeons met for a Brachytherapy Workshop hosted by the European paediatric Soft tissue Sarcoma Study Group (EpSSG). The panel's clinical experience, the results of a previously distributed questionnaire, and a review of the literature were presented. RESULTS: The survey indicated the most common use of brachytherapy to be in combination with tumor resection, followed by brachytherapy as sole local therapy modality. HDR was increasingly deployed in pediatric practice, especially for genitourinary sites. Brachytherapy planning was mostly by 3D imaging based on CT. Recommendations for patient selection, treatment requirements, implant technique, delineation, dose prescription, dose reporting and clinical management were defined. CONCLUSIONS: Consensus guidelines for the use of brachytherapy in pediatric rhabdomyosarcoma have been developed through multicenter collaboration establishing the basis for future work. These have been adopted for the open EpSSG overarching study for children and adults with Frontline and Relapsed RhabdoMyoSarcoma (FaR-RMS)

Radiotherapy fractionation for the palliation of uncomplicated painful bone metastases – an evidence-based practice guideline

BACKGROUND: This practice guideline was developed to provide recommendations to clinicians in Ontario on the preferred standard radiotherapy fractionation schedule for the treatment of painful bone metastases. METHODS: A systematic review and meta-analysis was performed and published elsewhere. The Supportive Care Guidelines Group, a multidisciplinary guideline development panel, formulated clinical recommendations based on their interpretation of the evidence. In addition to evidence from clinical trials, the panel also considered patient convenience and ease of administration of palliative radiotherapy. External review of the draft report by Ontario practitioners was obtained through a mailed survey, and final approval was obtained from the Practice Guidelines Coordinating Committee. RESULTS: Meta-analysis did not detect a significant difference in complete or overall pain relief between single treatment and multifraction palliative radiotherapy for bone metastases. Fifty-nine Ontario practitioners responded to the mailed survey (return rate 62%). Forty-two percent also returned written comments. Eighty-three percent of respondents agreed with the interpretation of the evidence and 75% agreed that the report should be approved as a practice guideline. Minor revisions were made based on feedback from the external reviewers and the Practice Guidelines Coordinating Committee. The Practice Guidelines Coordinating Committee approved the final practice guideline report. CONCLUSION: For adult patients with single or multiple radiographically confirmed bone metastases of any histology corresponding to painful areas in previously non-irradiated areas without pathologic fractures or spinal cord/cauda equine compression, we conclude that: • Where the treatment objective is pain relief, a single 8 Gy treatment, prescribed to the appropriate target volume, is recommended as the standard dose-fractionation schedule for the treatment of symptomatic and uncomplicated bone metastases. Several factors frequently considered in clinical practice when applying this evidence such as the effect of primary histology, anatomical site of treatment, risk of pathological fracture, soft tissue disease and cord compression, use of antiemetics, and the role of retreatment are discussed as qualifying statements. Our systematic review and meta-analysis provided high quality evidence for the key recommendation in this clinical practice guideline. Qualifying statements addressing factors that should be considered when applying this recommendation in clinical practice facilitate its clinical application. The rigorous development and approval process result in a final document that is strongly endorsed by practitioners as a practice guideline