Gillian A Whitfield

Creating a data exchange strategy for radiotherapy research: towards federated databases and anonymised public datasets.

Disconnected cancer research data management and lack of information exchange about planned and ongoing research are complicating the utilisation of internationally collected medical information for improving cancer patient care. Rapidly collecting/pooling data can accelerate translational research in radiation therapy and oncology. The exchange of study data is one of the fundamental principles behind data aggregation and data mining. The possibilities of reproducing the original study results, performing further analyses on existing research data to generate new hypotheses or developing computational models to support medical decisions (e.g. risk/benefit analysis of treatment options) represent just a fraction of the potential benefits of medical data-pooling. Distributed machine learning and knowledge exchange from federated databases can be considered as one beyond other attractive approaches for knowledge generation within “Big Data”. Data interoperability between research institutions should be the major concern behind a wider collaboration. Information captured in electronic patient records (EPRs) and study case report forms (eCRFs), linked together with medical imaging and treatment planning data, are deemed to be fundamental elements for large multi-centre studies in the field of radiation therapy and oncology. To fully utilise the captured medical information, the study data have to be more than just an electronic version of a traditional (un-modifiable) paper CRF. Challenges that have to be addressed are data interoperability, utilisation of standards, data quality and privacy concerns, data ownership, rights to publish, data pooling architecture and storage. This paper discusses a framework for conceptual packages of ideas focused on a strategic development for international research data exchange in the field of radiation therapy and oncology.

Quantifying motion for pancreatic radiotherapy margin calculation.

BACKGROUND AND PURPOSE Pancreatic radiotherapy (RT) is limited by uncertain target motion. We quantified 3D patient/organ motion during pancreatic RT and calculated required treatment margins. MATERIALS AND METHODS Cone-beam computed tomography (CBCT) and orthogonal fluoroscopy images were acquired post-RT delivery from 13 patients with locally advanced pancreatic cancer. Bony setup errors were calculated from CBCT. Inter- and intra-fraction fiducial (clip/seed/stent) motion was determined from CBCT projections and orthogonal fluoroscopy. RESULTS Using an off-line CBCT correction protocol, systematic (random) setup errors were 2.4 (3.2), 2.0 (1.7) and 3.2 (3.6)mm laterally (left-right), vertically (anterior-posterior) and longitudinally (cranio-caudal), respectively. Fiducial motion varied substantially. Random inter-fractional changes in mean fiducial position were 2.0, 1.6 and 2.6mm; 95% of intra-fractional peak-to-peak fiducial motion was up to 6.7, 10.1 and 20.6mm, respectively. Calculated clinical to planning target volume (CTV-PTV) margins were 1.4 cm laterally, 1.4 cm vertically and 3.0 cm longitudinally for 3D conformal RT, reduced to 0.9, 1.0 and 1.8 cm, respectively, if using 4D planning and online setup correction. CONCLUSIONS Commonly used CTV-PTV margins may inadequately account for target motion during pancreatic RT. Our results indicate better immobilisation, individualised allowance for respiratory motion, online setup error correction and 4D planning would improve targeting.

Automated delineation of radiotherapy volumes: are we going in the right direction?

Rapid and accurate delineation of target volumes and multiple organs at risk, within the enduring International Commission on Radiation Units and Measurement framework, is now hugely important in radiotherapy, owing to the rapid proliferation of intensity-modulated radiotherapy and the advent of four-dimensional image-guided adaption. Nevertheless, delineation is still generally clinically performed with little if any machine assistance, even though it is both time-consuming and prone to interobserver variation. Currently available segmentation tools include those based on image greyscale interrogation, statistical shape modelling and body atlas-based methods. However, all too often these are not able to match the accuracy of the expert clinician, which remains the universally acknowledged gold standard. In this article we suggest that current methods are fundamentally limited by their lack of ability to incorporate essential human clinical decision-making into the underlying models. Hybrid techniques that utilise prior knowledge, make sophisticated use of greyscale information and allow clinical expertise to be integrated are needed. This may require a change in focus from automated segmentation to machine-assisted delineation. Similarly, new metrics of image quality reflecting fitness for purpose would be extremely valuable. We conclude that methods need to be developed to take account of the clinicians expertise and honed visual processing capabilities as much as the underlying, clinically meaningful information content of the image data being interrogated. We illustrate our observations and suggestions through our own experiences with two software tools developed as part of research council-funded projects.

Imaging and Target Volume Delineation in Glioma

Here we review current practices in target volume delineation for radical radiotherapy planning for gliomas. Current radiotherapy planning margins for glioma are informed by historic data of recurrence patterns using radiological imaging or post-mortem studies. Radiotherapy planning for World Health Organization grade II-IV gliomas currently relies predominantly on T1-weighted contrast-enhanced magnetic resonance imaging (MRI) and T2/fluid-attenuated inversion recovery sequences to identify the gross tumour volume (GTV). Isotropic margins are added empirically for each tumour type, usually without any patient-specific individualisation. We discuss novel imaging techniques that have the potential to influence radiotherapy planning, by improving definition of the tumour extent and its routes of invasion, thus modifying the GTV and allowing anisotropic expansion to a clinical target volume better reflecting areas at risk of recurrence. Identifying the relationships of tumour boundaries to important white matter pathways and eloquent areas of cerebral cortex could lead to reduced normal tissue complications. Novel magnetic resonance approaches to identify tumour extent and invasion include: (i) diffusion-weighted magnetic resonance metrics; (ii) diffusion tensor imaging; and (iii) positron emission tomography, using radiolabelled amino acids methyl-11C-L-methionine and 18F-fluoroethyltyrosine. Novel imaging techniques may also have a role together with clinical characteristics and molecular genetic markers in predicting response to therapy. Most significant among these techniques is dynamic contrast-enhanced MRI, which uses dynamic acquisition of images after injection of intravenous contrast. A number of studies have identified changes in diffusion and microvascular characteristics occurring during the early stages of radiotherapy as powerful predictive biomarkers of outcome.

Efficacy and Tolerability of Limited Field Radiotherapy with Concurrent Capecitabine in Locally Advanced Pancreatic Cancer

AIMS Patients with locally advanced pancreatic cancer (LAPC) are most commonly managed with chemotherapy or concurrent chemoradiotherapy (CRT), which may or may not include non-involved regional lymph nodes in the clinical target volume. We present our results of CRT for LAPC using capecitabine and delivering radiotherapy to a limited radiation field that excluded non-involved regional lymph nodes from the clinical target volume. MATERIALS AND METHODS Thirty patients were studied. Patients received 50.4 Gy external beam radiotherapy in 28 fractions, delivered to a planning target volume expanded from the primary tumour and involved nodes only. Capecitabine (500-600 mg/m2) was given twice daily continuously during radiotherapy. Toxicity and efficacy data were prospectively collected. RESULTS Nausea, vomiting and tumour pain were the most common grade 2 toxicities. One patient developed grade 3 nausea. The median time to progression was 8.8 months, with 20% remaining progression free at 1 year. The median overall survival was 9.7 months with a 1 year survival of 30%. Of 21 patients with imaged progression, 13 (62%) progressed systemically, three (14%) had local progression, two (10%) had locoregional progression and three (14%) progressed with both local/locoregional and systemic disease. CONCLUSION CRT using capecitabine and limited field radiotherapy is a well-tolerated, relatively efficacious treatment for LAPC. The low toxicity and low regional progression rates support the use of limited field radiotherapy, allowing evaluation of this regimen with other anti-cancer agents.

New Developments in Intracranial Stereotactic Radiotherapy for Metastases

Brain metastases are common and the prognosis for patients with multiple brain metastases treated with whole brain radiotherapy is limited. As systemic disease control continues to improve, the expectations of radiotherapy for brain metastases are growing. Stereotactic radiosurgery (SRS) as a high precision localised irradiation given in a single fraction prolongs survival in patients with a single brain metastasis and functional independence in those with up to three brain metastases. SRS technology has become commonplace and is available in many radiation oncology and neurosurgery departments. With increasing use there is a need for appropriate patient selection, refinement of dose-fractionation and safe integration of SRS with other treatment modalities. We review the evidence for current practice and new developments in the field, with a specific focus on patient-relevant outcomes.

Neurocognitive Effects Following Cranial Irradiation for Brain Metastases

About 90% of patients with brain metastases have impaired neurocognitive function at diagnosis and up to two-thirds will show further declines within 2-6 months of whole brain radiotherapy. Distinguishing treatment effects from progressive disease can be challenging because the prognosis remains poor in many patients. Omitting whole brain radiotherapy after local therapy in good prognosis patients improves verbal memory at 4 months, but the effect of higher intracranial recurrence and salvage therapy rates on neurocognitive function beyond this time point is unknown. Hippocampal-sparing whole brain radiotherapy and postoperative stereotactic radiosurgery are investigational techniques intended to reduce toxicity. Here we describe the changes that can occur and review technological, pharmacological and practical approaches used to mitigate their effect in clinical practice.

FISHing Tips: What Every Clinician Should Know About 1p19q Analysis in Gliomas Using Fluorescence in situ Hybridisation

1p19q co-deletion is a chromosomal alteration associated with primary brain tumours of oligodendroglial histology. It is an established predictive and prognostic biomarker that informs whether patients are offered radiotherapy, chemotherapy or both. In the near future, 1p19q co-deletion status may also be incorporated into the reclassification of gliomas. Analysis is commonly carried out using fluorescence in situ hybridisation (FISH) because it is a reliable and validated laboratory technique. The result is generally considered to be dichotomous (1p19q co-deletion present or absent), but there are subtleties in interpretation that are of clinical relevance. Separate centres may interpret certain chromosome deletion patterns differently. Pivotal trials in mixed and pure anaplastic oligodendrogliomas have used slightly different FISH probe ratios as the cut-off for chromosome deletion. Here we review the clinical implications of this variability and review the process of 1p19q co-deletion assessment using FISH in gliomas from a clinicians perspective. We also consider common alternative methods of analysis.

Radical chemoradiotherapy for adenocarcinoma of the distal oesophagus and oesophagogastric junction: what planning margins should we use?

Distal oesophageal and Type I-II oesophagogastric junctional adenocarcinomas have a poor prognosis. In radical chemoradiotherapy, consensus is lacking on radiotherapy margins. Here, we review the effect of common imaging modalities on the extent of the gross tumour volume (GTV) and the evidence for margins. To do this, papers were identified from PubMed, and geometric uncertainties were combined using the British Institute of Radiology formula. CT and endoscopic ultrasound were best for GTV delineation, but the role of positron emission tomography is uncertain. Evidence suggests 3 cm proximal and 5 cm distal GTV-CTV (clinical target volume) margins (along the mucosa) for advanced tumours, but is lacking for early tumours and radial margins. Nodal spread, present in most pT2 tumours, is strongly prognostic and is initially to regional nodes (not wholly covered by typical radiotherapy). Calculated CTV-PTV (planning target volume) margins for three-dimensional conformal radiotherapy using literature estimates of tumour motion and set-up errors with bony online set-up correction, ignoring delineation errors, are 2.2 cm superiorly (sup) and inferiorly (inf) and 1.2-1.3 cm radially (1.3 cm sup-inf; 0.8 cm radially if the tumours mid-position is known). As these margins may risk excessive toxicity, we propose treating microscopic disease for potentially curable tumours (cT2N0, some cT3N0), but gross disease only for advanced tumours. Recommended GTV-CTV margins are a maximum of 3 cm proximally and 5 cm distally up to cT2N0; 3 cm proximally and 5 cm distally for cT3N0 if anticipated toxicity allows; and 0 cm for cT4 and most node-positive tumours. The CTV-PTV margins above must be added to this for all stages. Methods of including elective nodal areas close to the GTV should be researched, e.g. nodal maps and intensity-modulated radiotherapy.

The EPTN consensus-based atlas for CT- and MR-based contouring in neuro-oncology

PURPOSE To create a digital, online atlas for organs at risk (OAR) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging. METHODS CT and 3 Tesla (3T) MR images (slice thickness 1 mm with intravenous contrast agent) were obtained from the same patient and subsequently fused. In addition, a 7T MR without intravenous contrast agent was obtained from a healthy volunteer. Based on discussion between experienced radiation oncologists, the clinically relevant organs at risk (OARs) to be included in the atlas for neuro-oncology were determined, excluding typical head and neck OARs previously published. The draft atlas was delineated by a senior radiation oncologist, 2 residents in radiation oncology, and a senior neuro-radiologist incorporating relevant available literature. The proposed atlas was then critically reviewed and discussed by European radiation oncologists until consensus was reached. RESULTS The online atlas includes one CT-scan at two different window settings and one MR scan (3T) showing the OARs in axial, coronal and sagittal view. This manuscript presents the three-dimensional descriptions of the fifteen consensus OARs for neuro-oncology. Among these is a new OAR relevant for neuro-cognition, the posterior cerebellum (illustrated on 7T MR images). CONCLUSION In order to decrease inter- and intra-observer variability in delineating OARs relevant for neuro-oncology and thus derive consistent dosimetric data, we propose this atlas to be used in photon and particle therapy. The atlas is available online at www.cancerdata.org and will be updated whenever required.