Multi-centre evaluation of variation in cumulative dose assessment in reirradiation scenarios.

BACKGROUND AND PURPOSE: Safe reirradiation relies on assessment of cumulative doses to organs at risk (OARs) across multiple treatments. Different clinical pathways can result in inconsistent estimates. Here, we quantified the consistency of cumulative dose to OARs across multi-centre clinical pathways. MATERIAL AND METHODS: We provided DICOM planning CT, structures and doses for two reirradiation cases: head & neck (HN) and lung. Participants followed their standard pathway to assess the cumulative physical and EQD2 doses (with provided α/ß values), and submitted DVH metrics and a description of their pathways. Participants could also submit physical dose distributions from Course 1 mapped onto the CT of Course 2 using their best available tools. To assess isolated impact of image registrations, a single observer accumulated each submitted spatially mapped physical dose for every participating centre. RESULTS: Cumulative dose assessment was performed by 24 participants. Pathways included rigid (n = 15), or deformable (n = 5) image registration-based 3D dose summation, visual inspection of isodose line contours (n = 1), or summation of dose metrics extracted from each course (n = 3). Largest variations were observed in near-maximum cumulative doses (25.4 - 41.8 Gy for HN, 2.4 - 33.8 Gy for lung OARs), with lower variations in volume/dose metrics to large organs. A standardised process involving spatial mapping of the first course dose to the second course CT followed by summation improved consistency for most near-maximum dose metrics in both cases. CONCLUSION: Large variations highlight the uncertainty in reporting cumulative doses in reirradiation scenarios, with implications for outcome analysis and understanding of published doses. Using a standardised workflow potentially including spatially mapped doses improves consistency in determination of accumulated dose in reirradiation scenarios.

Review and recommendations on deformable image registration uncertainties for radiotherapy applications.

Deformable image registration (DIR) is a versatile tool used in many applications in radiotherapy (RT). DIR algorithms have been implemented in many commercial treatment planning systems providing accessible and easy-to-use solutions. However, the geometric uncertainty of DIR can be large and difficult to quantify, resulting in barriers to clinical practice. Currently, there is no agreement in the RT community on how to quantify these uncertainties and determine thresholds that distinguish a good DIR result from a poor one. This review summarises the current literature on sources of DIR uncertainties and their impact on RT applications. Recommendations are provided on how to handle these uncertainties for patient-specific use, commissioning, and research. Recommendations are also provided for developers and vendors to help users to understand DIR uncertainties and make the application of DIR in RT safer and more reliable.

Voxel-based analysis: Roadmap for clinical translation.

Voxel-based analysis (VBA) allows the full, 3-dimensional, dose distribution to be considered in radiotherapy outcome analysis. This provides new insights into anatomical variability of pathophysiology and radiosensitivity by removing the need for a priori definition of organs assumed to drive the dose response associated with patient outcomes. This approach may offer powerful biological insights demonstrating the heterogeneity of the radiobiology across tissues and potential associations of the radiotherapy dose with further factors. As this methodological approach becomes established, consideration needs to be given to translating VBA results to clinical implementation for patient benefit. Here, we present a comprehensive roadmap for VBA clinical translation. Technical validation needs to demonstrate robustness to methodology, where clinical validation must show generalisability to external datasets and link to a plausible pathophysiological hypothesis. Finally, clinical utility requires demonstration of potential benefit for patients in order for successful translation to be feasible. For each step on the roadmap, key considerations are discussed and recommendations provided for best practice.

Dose outside of the prostate is associated with improved outcomes for high-risk prostate cancer patients treated with brachytherapy boost.

Background: One in three high-risk prostate cancer patients treated with radiotherapy recur. Detection of lymph node metastasis and microscopic disease spread using conventional imaging is poor, and many patients are under-treated due to suboptimal seminal vesicle or lymph node irradiation. We use Image Based Data Mining (IBDM) to investigate association between dose distributions, and prognostic variables and biochemical recurrence (BCR) in prostate cancer patients treated with radiotherapy. We further test whether including dose information in risk-stratification models improves performance. Method: Planning CTs, dose distributions and clinical information were collected for 612 high-risk prostate cancer patients treated with conformal hypo-fractionated radiotherapy, intensity modulated radiotherapy (IMRT), or IMRT plus a single fraction high dose rate (HDR) brachytherapy boost. Dose distributions (including HDR boost) of all studied patients were mapped to a reference anatomy using the prostate delineations. Regions where dose distributions significantly differed between patients that did and did-not experience BCR were assessed voxel-wise using 1) a binary endpoint of BCR at four-years (dose only) and 2) Cox-IBDM (dose and prognostic variables). Regions where dose was associated with outcome were identified. Cox proportional-hazard models with and without region dose information were produced and the Akaike Information Criterion (AIC) was used to assess model performance. Results: No significant regions were observed for patients treated with hypo-fractionated radiotherapy or IMRT. Regions outside the target where higher dose was associated with lower BCR were observed for patients treated with brachytherapy boost. Cox-IBDM revealed that dose response was influenced by age and T-stage. A region at the seminal vesicle tips was identified in binary- and Cox-IBDM. Including the mean dose in this region in a risk-stratification model (hazard ratio=0.84, p=0.005) significantly reduced AIC values (p=0.019), indicating superior performance, compared with prognostic variables only. The region dose was lower in the brachytherapy boost patients compared with the external beam cohorts supporting the occurrence of marginal misses. Conclusion: Association was identified between BCR and dose outside of the target region in high-risk prostate cancer patients treated with IMRT plus brachytherapy boost. We show, for the first-time, that the importance of irradiating this region is linked to prognostic variables.

Dysphagia at 1 Year is Associated With Mean Dose to the Inferior Section of the Brain Stem.

PURPOSE: Dysphagia is a common toxicity after head and neck (HN) radiation therapy that negatively affects quality of life. We explored the relationship between radiation therapy dose to normal HN structures and dysphagia 1 year after treatment using image-based datamining (IBDM), a voxel-based analysis technique. METHODS AND MATERIALS: We used data from 104 patients with oropharyngeal cancer treated with definitive (chemo)radiation therapy. Swallow function was assessed pretreatment and 1 year posttreatment using 3 validated measures: MD Anderson Dysphagia Inventory (MDADI), performance status scale for normalcy of diet (PSS-HN), and water swallowing test (WST). For IBDM, we spatially normalized all patients' planning dose matrices to 3 reference anatomies. Regions where the dose was associated with dysphagia measures at 1 year were found by performing voxel-wise statistics and permutation testing. Clinical factors, treatment variables, and pretreatment measures were used in multivariable analysis to predict each dysphagia measure at 1 year. Clinical baseline models were found using backward stepwise selection. Improvement in model discrimination after adding the mean dose to the identified region was quantified using the Akaike information criterion. We also compared the prediction performance of the identified region with a well-established association: mean doses to the pharyngeal constrictor muscles. RESULTS: IBDM revealed highly significant associations between dose to distinct regions and the 3 outcomes. These regions overlapped around the inferior section of the brain stem. All clinical models were significantly improved by including mean dose to the overlap region (P ≤ .006). Including pharyngeal dosimetry significantly improved WST (P = .04) but not PSS-HN or MDADI (P ≥ .06). CONCLUSIONS: In this hypothesis-generating study, we found that mean dose to the inferior section of the brain stem is strongly associated with dysphagia 1 year posttreatment. The identified region includes the swallowing centers in the medulla oblongata, providing a possible mechanistic explanation. Further work including validation in an independent cohort is required.

Probabilistic evaluation of plan quality for time-dependent anatomical deformations in head and neck cancer patients.

PURPOSE: In addition to patient set-up uncertainties, anatomical deformations, e.g., weight loss, lead to time-dependent differences between the planned and delivered dose in a radiotherapy course that currently cannot easily be predicted. The aim of this study was to create time-varying prediction models to describe both the average and residual anatomical deformations. METHODS: Weekly population-based principal component analysis models were generated from on-treatment cone-beam CT scans (CBCTs) of 30 head and neck cancer patients, with additional data of 35 patients used as a validation cohort. We simulated treatment courses accounting for a) anatomical deformations, b) set-up uncertainties and c) a combination of both. The dosimetric effects of the simulated deformations were compared to a direct dose accumulation based on deformable registration of the CBCT data. RESULTS: Set-up uncertainties were seen to have a larger effect on the organ at risk (OAR) doses than anatomical deformations for all OARs except the larynx and the primary CTV. Distributions from simulation results were in good agreement with those of the accumulated dose. CONCLUSIONS: We present a novel method of modelling time-varying organ deformations in head and neck cancer. The effect on the OAR doses from these deformations are smaller than the effect of set-up uncertainties for most OARs. These models can, for instance, be used to predict which patients could benefit from adaptive radiotherapy, prior to commencing treatment.

Analytic calculations and synthetic shapes for validation of quantitative contour comparison software.

A high level of variability in reported values was observed in a recent survey of contour similarity measures (CSMs) calculation tools. Such variations in the output measurements prevent meaningful comparison between studies. The purpose of this study was to develop a dataset with analytically calculated gold standard values to facilitate standardization and ensure accuracy of CSM implementations. The dataset was generated in the Digital Imaging and Communications in Medicine (DICOM) format. Both the dataset and the software used for its generation are made publicly available to encourage robust testing of CSM implementations for accuracy, improving consistency between different implementations.

Accurate segmentation of head and neck radiotherapy CT scans with 3D CNNs: consistency is key.

Objective.Automatic segmentation of organs-at-risk in radiotherapy planning computed tomography (CT) scans using convolutional neural networks (CNNs) is an active research area. Very large datasets are usually required to train such CNN models. In radiotherapy, large, high-quality datasets are scarce and combining data from several sources can reduce the consistency of training segmentations. It is therefore important to understand the impact of training data quality on the performance of auto-segmentation models for radiotherapy.Approach.In this study, we took an existing 3D CNN architecture for head and neck CT auto-segmentation and compare the performance of models trained with a small, well-curated dataset (n= 34) and then a far larger dataset (n= 185) containing less consistent training segmentations. We performed 5-fold cross-validations in each dataset and tested segmentation performance using the 95th percentile Hausdorff distance and mean distance-to-agreement metrics. Finally, we validated the generalisability of our models with an external cohort of patient data (n= 12) with five expert annotators.Main results.The models trained with a large dataset were greatly outperformed by models (of identical architecture) trained with a smaller, but higher consistency set of training samples. Our models trained with a small dataset produce segmentations of similar accuracy as expert human observers and generalised well to new data, performing within inter-observer variation.Significance.We empirically demonstrate the importance of highly consistent training samples when training a 3D auto-segmentation model for use in radiotherapy. Crucially, it is the consistency of the training segmentations which had a greater impact on model performance rather than the size of the dataset used.

Applicability and usage of dose mapping/accumulation in radiotherapy.

Dose mapping/accumulation (DMA) is a topic in radiotherapy (RT) for years, but has not yet found its widespread way into clinical RT routine. During the ESTRO Physics workshop 2021 on "commissioning and quality assurance of deformable image registration (DIR) for current and future RT applications", we built a working group on DMA from which we present the results of our discussions in this article. Our aim in this manuscript is to shed light on the current situation of DMA in RT and to highlight the issues that hinder consciously integrating it into clinical RT routine. As a first outcome of our discussions, we present a scheme where representative RT use cases are positioned, considering expected anatomical variations and the impact of dose mapping uncertainties on patient safety, which we have named the DMA landscape (DMAL). This tool is useful for future reference when DMA applications get closer to clinical day-to-day use. Secondly, we discussed current challenges, lightly touching on first-order effects (related to the impact of DIR uncertainties in dose mapping), and focusing in detail on second-order effects often dismissed in the current literature (as resampling and interpolation, quality assurance considerations, and radiobiological issues). Finally, we developed recommendations, and guidelines for vendors and users. Our main point include: Strive for context-driven DIR (by considering their impact on clinical decisions/judgements) rather than perfect DIR; be conscious of the limitations of the implemented DIR algorithm; and consider when dose mapping (with properly quantified uncertainties) is a better alternative than no mapping.

Gender-related and geographic trends in interactions between radiotherapy professionals on Twitter.

Background and purpose: Twitter presence in academia has been linked to greater research impact which influences career progression. The purpose of this study was to analyse Twitter activity of the radiotherapy community around ESTRO congresses with a focus on gender-related and geographic trends. Materials and methods: Tweets, re-tweets and replies, here designated as interactions, around the ESTRO congresses held in 2012-2021 were collected. Twitter activity was analysed temporally and, for the period 2016-2021, the geographical span of the ESTRO Twitter network was studied. Tweets and Twitter users collated during the 10 years analysed were ranked based on number of 'likes', 're-tweets' and followers, considered as indicators of leadership/influence. Gender representation was assessed for the top-end percentiles. Results: Twitter activity around ESTRO congresses was multiplied by 60 in 6 years growing from 150 interactions in 2012 to a peak of 9097 in 2018. In 2020, during the SARS-CoV-2 pandemic, activity dropped by 60 % to reach 2945 interactions and recovered to half the pre-pandemic level in 2021. Europe, North America and Oceania were strongly connected and remained the main contributors. While overall, 58 % of accounts were owned by men, this proportion increased towards top liked/re-tweeted tweets and most-followed profiles to reach up to 84 % in the top-percentiles. Conclusion: During the SARS-CoV-2 pandemic, Twitter activity around ESTRO congresses substantially decreased. Men were over-represented on the platform and in most popular tweets and influential accounts. Given the increasing importance of social media presence in academia the gender-based biases observed may help in understanding the gender gap in career progression.

Multicenter comparison of measures for quantitative evaluation of contouring in radiotherapy.

Background and Purpose: A wide range of quantitative measures are available to facilitate clinical implementation of auto-contouring software, on-going Quality Assurance (QA) and interobserver contouring variation studies. This study aimed to assess the variation in output when applying different implementations of the measures to the same data in order to investigate how consistently such measures are defined and implemented in radiation oncology. Materials and Methods: A survey was conducted to assess if there were any differences in definitions of contouring measures or their implementations that would lead to variation in reported results between institutions. This took two forms: a set of computed tomography (CT) image data with "Test" and "Reference" contours was distributed for participants to process using their preferred tools and report results, and a questionnaire regarding the definition of measures and their implementation was completed by the participants. Results: Thirteen participants completed the survey and submitted results, with one commercial and twelve in-house solutions represented. Excluding outliers, variations of up to 50% in Dice Similarity Coefficient (DSC), 50% in 3D Hausdorff Distance (HD), and 200% in Average Distance (AD) were observed between the participant submitted results. Collaborative investigation with participants revealed a large number of bugs in implementation, confounding the understanding of intentional implementation choices. Conclusion: Care must be taken when comparing quantitative results between different studies. There is a need for a dataset with clearly defined measures and ground truth for validation of such tools prior to their use.

Suitability of propagated contours for adaptive replanning for head and neck radiotherapy.

PURPOSE: Adaptive radiotherapy relies on rapid recontouring for replanning. Contour propagation offers workflow efficiencies, but the impact of using unedited propagated OAR contours directly during re-optimisation is unclear. METHODS: Plans for ten head and neck patients were created on the planning CT scan. OAR contours for the spinal cord, brainstem, parotids and larynx were then propagated to five shading-corrected CBCTs equally spaced throughout treatment using five commercial packages. Two reference contours were created on the CBCTs by (1) a clinician and (2) a geometric consensus from the propagated contours. Treatment plans were re-optimised on each CBCT for each set of contours, and the DVH statistic differences to the reference contours were calculated. The spread of DVH statistic differences between the 5th and 95th percentiles was quantified. RESULTS: The spread of DVH statistic differences was 3.7 Gy compared to the clinician contour and 3.3 Gy compared to the consensus contour for the brainstem (and PRV) and 2.4 Gy and 2 Gy for the spinal cord (and PRV), across all 5 auto-contouring solutions. The parotids and larynx showed differences of 3.7 Gy compared to the clinician and 0.9 Gy to the consensus contour, with the larger difference for the clinician possibly caused by uncertainty in the clinician standard due to poor image quality on the CBCTs. CONCLUSIONS: Propagated OAR contours can be used safely for adaptive radiotherapy replanning, however, where organ doses are close to clinical tolerance then the contours should be reviewed for accuracy regardless of the propagation software used.

Evaluating principal component analysis models for representing anatomical changes in head and neck radiotherapy.

Background and purpose: Anatomical changes during radiotherapy pose a challenge to robustness of plans. Principal component analysis (PCA) is commonly used to model such changes. We propose a toolbox to evaluate how closely a given PCA model can represent actual deformations seen in the patient and highlight regions where the model struggles to capture these changes. Materials and methods: We propose to calculate a residual error map from the difference between an actual displacement vector field (DVF) and the closest DVF that the PCA model can produce. This was done by taking the inner product of the DVF with the PCA components from the model. As a global measure of error, the 90th percentile of the residual errors ( M res 90 ) across the whole scan was used. As proof of principle, we demonstrated this approach on both patient-specific cases and a population-based PCA in head and neck (H&N) cancer patients. These models were created using deformation data from deformable registrations between the planning computed tomography and cone-beam computed tomography (CBCTs), and were evaluated against DVFs from registrations of CBCTs not used to create the model. Results: For our example cases, the oropharyngeal and the nasal cavity regions showed the largest local residual error, indicating the PCA models struggle to predict deformations seen in these regions. M res 90 ranged from 0.4 mm to 6.3 mm across the different models. Conclusions: A method to quantitatively evaluate how well PCA models represent observed anatomical changes was proposed. We demonstrated our approach on H&N PCA models, but it can be applied to other sites.

Optimising a 3D convolutional neural network for head and neck computed tomography segmentation with limited training data.

Background and purpose: Convolutional neural networks (CNNs) are increasingly used to automate segmentation for radiotherapy planning, where accurate segmentation of organs-at-risk (OARs) is crucial. Training CNNs often requires large amounts of data. However, large, high quality datasets are scarce. The aim of this study was to develop a CNN capable of accurate head and neck (HN) 3D auto-segmentation of planning CT scans using a small training dataset (34 CTs). Materials and Method: Elements of our custom CNN architecture were varied to optimise segmentation performance. We tested and evaluated the impact of: using multiple contrast channels for the CT scan input at specific soft tissue and bony anatomy windows, resize vs. transpose convolutions, and loss functions based on overlap metrics and cross-entropy in different combinations. Model segmentation performance was compared with the inter-observer deviation of two doctors' gold standard segmentations using the 95th percentile Hausdorff distance and mean distance-to-agreement (mDTA). The best performing configuration was further validated on a popular public dataset to compare with state-of-the-art (SOTA) auto-segmentation methods. Results: Our best performing CNN configuration was competitive with current SOTA methods when evaluated on the public dataset with mDTA of ( 0.81 ± 0.31 ) mm for the brainstem, ( 0.20 ± 0.08 ) mm for the mandible, ( 0.77 ± 0.14 ) mm for the left parotid and ( 0.81 ± 0.28 ) mm for the right parotid. Conclusions: Through careful tuning and customisation we trained a 3D CNN with a small dataset to produce segmentations of HN OARs with an accuracy that is comparable with inter-clinician deviations. Our proposed model performed competitively with current SOTA methods.

Image-based data mining applies to data collected from children.

PURPOSE: Image-based data mining (IBDM) is a novel voxel-based method for analyzing radiation dose responses that has been successfully applied in adult data. Because anatomic variability and side effects of interest differ for children compared to adults, we investigated the feasibility of IBDM for pediatric analyses. METHODS: We tested IBDM with CT images and dose distributions collected from 167 children (aged 10 months to 20 years) who received proton radiotherapy for primary brain tumors. We used data from four reference patients to assess IBDM sensitivity to reference selection. We quantified spatial-normalization accuracy via contour distances and deviations of the centers-of-mass of brain substructures. We performed dose comparisons with simplified and modified clinical dose distributions with a simulated effect, assessing their accuracy via sensitivity, positive predictive value (PPV) and Dice similarity coefficient (DSC). RESULTS: Spatial normalizations and dose comparisons were insensitive to reference selection. Normalization discrepancies were small (average contour distance < 2.5 mm, average center-of-mass deviation < 6 mm). Dose comparisons identified differences (p < 0.01) in 81% of simplified and all modified clinical dose distributions. The DSCs for simplified doses were high (peak frequency magnitudes of 0.9-1.0). However, the PPVs and DSCs were low (maximum 0.3 and 0.4, respectively) in the modified clinical tests. CONCLUSIONS: IBDM is feasible for childhood late-effects research. Our findings may inform cohort selection in future studies of pediatric radiotherapy dose responses and facilitate treatment planning to reduce treatment-related toxicities and improve quality of life among childhood cancer survivors.

Dual-energy computed tomography: Survey results on current uses and barriers to further implementation.

OBJECTIVE: To gauge the current availability of dual-energy computed tomography (DECT) scanners in the UK, establish available technologies, look broadly at current clinical uses in adults and paediatrics, and identify barriers to implementation and potential ways to increase use. METHODS: A survey was distributed amongst 10 radiology departments and shared on two national professional co-operation mail bases; the survey ran from 20th July to 9th December 2020. It explored current DECT utilisation in adults and paediatrics as well as barriers to use and suggestions to overcome those barriers. RESULTS: The survey demonstrated DECT availability on 39 (40%) of the 98 CT scanners, but there was limited clinical use in adults and paediatrics. Eighteen (72%) of the 25 respondents had access to at least one DECT scanner, with 14 (56%) having adult DECT protocols in clinical use; <10% head examinations and <50% for other anatomical areas. Only two (8%) respondents had DECT paediatric protocols in clinical use; <10% examinations for all anatomical areas.The main barriers to implementation identified were lack of experience with DECT (8 (44%) users (adult) and 10 (56%) users (paediatric)) and no clinical protocols available (6 (33%) users (adult and paediatric)).Understanding DECT benefits and establishing suitable protocols were the most popular suggestions for increased implementation (10 (40%) of 25 respondents). CONCLUSION: DECT scanners are available, but clinical use is limited for both adults and paediatrics. The main barriers identified were lack of experience with DECT and the availability of suitable protocols. Further work identified to help implementation included better education on the benefits of DECT, provision of clinical protocols and ensuring a multidisciplinary approach. ADVANCES IN KNOWLEDGE: Barriers to implementation of clinical DECT protocols were identified, together with potential solutions to overcome these and enable further implementation.

Novel methodology to assess the effect of contouring variation on treatment outcome.

PURPOSE: Contouring variation is one of the largest systematic uncertainties in radiotherapy, yet its effect on clinical outcome has never been analyzed quantitatively. We propose a novel, robust methodology to locally quantify target contour variation in a large patient cohort and find where this variation correlates with treatment outcome. We demonstrate its use on biochemical recurrence for prostate cancer patients. METHOD: We propose to compare each patient's target contours to a consistent and unbiased reference. This reference was created by auto-contouring each patient's target using an externally trained deep learning algorithm. Local contour deviation measured from the reference to the manual contour was projected to a common frame of reference, creating contour deviation maps for each patient. By stacking the contour deviation maps, time to event was modeled pixel-wise using a multivariate Cox proportional hazards model (CPHM). Hazard ratio (HR) maps for each covariate were created, and regions of significance found using cluster-based permutation testing on the z-statistics. This methodology was applied to clinical target volume (CTV) contours, containing only the prostate gland, from 232 intermediate- and high-risk prostate cancer patients. The reference contours were created using ADMIRE® v3.4 (Elekta AB, Sweden). Local contour deviations were computed in a spherical coordinate frame, where differences between reference and clinical contours were projected in a 2D map corresponding to sampling across the coronal and transverse angles every 3°. Time to biochemical recurrence was modeled using the pixel-wise CPHM analysis accounting for contour deviation, patient age, Gleason score, and treated CTV volume. RESULTS: We successfully applied the proposed methodology to a large patient cohort containing data from 232 patients. In this patient cohort, our analysis highlighted regions where the contour variation was related to biochemical recurrence, producing expected and unexpected results: (a) the interface between prostate-bladder and prostate-seminal vesicle interfaces where increase in the manual contour relative to the reference was related to a reduction of risk of biochemical recurrence by 4-8% per mm and (b) the prostate's right, anterior and posterior regions where an increase in the manual contour relative to the reference contours was related to an increase in risk of biochemical recurrence by 8-24% per mm. CONCLUSION: We proposed and successfully applied a novel methodology to explore the correlation between contour variation and treatment outcome. We analyzed the effect of contour deviation of the prostate CTV on biochemical recurrence for a cohort of more than 200 prostate cancer patients while taking basic clinical variables into account. Applying this methodology to a larger dataset including additional clinically important covariates and externally validating it can more robustly identify regions where contour variation directly relates to treatment outcome. For example, in the prostate case we use to demonstrate our novel methodology, external validation will help confirm or reject the counter-intuitive results (larger contours resulting in higher risk). Ultimately, the results of this methodology could inform contouring protocols based on actual patient outcomes.

The role of computational methods for automating and improving clinical target volume definition.

Treatment planning in radiotherapy distinguishes three target volume concepts: the gross tumor volume (GTV), the clinical target volume (CTV), and the planning target volume (PTV). Over time, GTV definition and PTV margins have improved through the development of novel imaging techniques and better image guidance, respectively. CTV definition is sometimes considered the weakest element in the planning process. CTV definition is particularly complex since the extension of microscopic disease cannot be seen using currently available in-vivo imaging techniques. Instead, CTV definition has to incorporate knowledge of the patterns of tumor progression. While CTV delineation has largely been considered the domain of radiation oncologists, this paper, arising from a 2019 ESTRO Physics research workshop, discusses the contributions that medical physics and computer science can make by developing computational methods to support CTV definition. First, we overview the role of image segmentation algorithms, which may in part automate CTV delineation through segmentation of lymph node stations or normal tissues representing anatomical boundaries of microscopic tumor progression. The recent success of deep convolutional neural networks has also enabled learning entire CTV delineations from examples. Second, we discuss the use of mathematical models of tumor progression for CTV definition, using as example the application of glioma growth models to facilitate GTV-to-CTV expansion for glioblastoma that is consistent with neuroanatomy. We further consider statistical machine learning models to quantify lymphatic metastatic progression of tumors, which may eventually improve elective CTV definition. Lastly, we discuss approaches to incorporate uncertainty in CTV definition into treatment plan optimization as well as general limitations of the CTV concept in the case of infiltrating tumors without natural boundaries.