An in-silico planning study of stereotactic body radiation therapy for polymetastatic patients with more than ten extra-cranial lesions.

Background and purpose: Limited data is available about the feasibility of stereotactic body radiation therapy (SBRT) for treating more than five extra-cranial metastases, and almost no data for treating more than ten. The aim of this study was to investigate the feasibility of SBRT in this polymetatstatic setting. Materials and methods: Consecutive metastatic melanoma patients with more than ten extra-cranial metastases and a maximum lesion diameter below 11 cm were selected from a single-center prospective registry for this in-silico planning study. For each patient, SBRT plans were generated to treat all metastases with a prescribed dose of 5x7Gy, and dose-limiting organs (OARs) were analyzed. A cell-kill based inverse planning approach was used to automatically determine the maximum deliverable dose to each lesion individually, while respecting all OARs constraints. Results: A total of 23 polymetastatic patients with a medium of 17 metastases (range, 11-51) per patient were selected. SBRT plans with sufficient target coverage and respected OARs dose constraints were achieved in 16 out of 23 patients. In the remaining seven patients, the lungs V5Gy < 80 % and the liver D700 cm3 < 15Gy were most frequently the dose-limiting constraints. The cell-kill based planning approach allowed optimizing the dose administration depending on metastases total volume and location. Conclusion: This retrospective planning study shows the feasibility of definitive SBRT for 70% of polymetastatic patients with more than ten extra-cranial lesions and proposes the cell-killing planning approach as an approach to individualize treatment planning in polymetastatic patients'.

A multi-centric dataset on patient-individual pathological lymph node involvement in head and neck squamous cell carcinoma.

Dataset: We provide a dataset on lymph node metastases in 968 patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC). All patients received neck dissection and we report the number of metastatic versus investigated lymph nodes per lymph node level (LNL) for every individual patient. Additionally, clinicopathological factors including T-category, primary tumor subsite (ICD-O-3 code), age, and sex are reported for all patients. The data is provided as three datasets: Dataset 1 contains 373 HNSCC patients treated at Centre Léon Bérard (CLB), France, with primary tumor location in the oral cavity, oropharynx, hypopharynx, and larynx. Dataset 2 contains 332 HNSCC patients treated at the Inselspital, Bern University Hospital (ISB), Switzerland with primary tumor location in the oral cavity, oropharynx, hypopharynx, and larynx. For these patients, additional information is provided including lateralization of the primary tumor, size and location of the largest metastases, and clinical involvement based on computed tomography (CT), magnetic resonance imaging (MRI), and/or 18FDG-positron emission tomography (PET/CT) imaging. Dataset 3 consists of 263 oropharyngeal SCC patients underlying a previous publication by Bauwens et al. [1], which were treated at CLB. For these patients, additional information including HPV status, lateralization of the primary tumor and clinically diagnosed lymph node involvement is provided. Reuse Potential: The data may be used to quantify the probability of occult lymph node metastases in each LNL, depending on an individual patient's characteristics of the primary tumor and the location of clinically diagnosed lymph node metastases. As such, the data may contribute to further personalize the elective treatment of the neck for HNSCC patients, i.e. definition of the elective clinical target volume (CTV-N) in radiotherapy (RT) and the extent of neck dissection (ND) in surgery. There exists only one similar publicly available dataset that reports clinical involvement per LNL in 287 oropharyngeal SCC patients [2]. The data presented in this article substantially extends the available data, it additionally includes pathologically assessed involvement per LNL, and it provides data for multiple subsites in the head and neck region.

Treatment planning comparison for head and neck cancer between photon, proton, and combined proton-photon therapy - From a fixed beam line to an arc.

BACKGROUND AND PURPOSE: This study investigates whether combined proton-photon therapy (CPPT) improves treatment plan quality compared to single-modality intensity-modulated radiation therapy (IMRT) or intensity-modulated proton therapy (IMPT) for head and neck cancer (HNC) patients. Different proton beam arrangements for CPPT and IMPT are compared, which could be of specific interest concerning potential future upright-positioned treatments. Furthermore, it is evaluated if CPPT benefits remain under inter-fractional anatomical changes for HNC treatments. MATERIAL AND METHODS: Five HNC patients with a planning CT and multiple (4-7) repeated CTs were studied. CPPT with simultaneously optimized photon and proton fluence, single-modality IMPT, and IMRT treatment plans were optimized on the planning CT and then recalculated and reoptimized on each repeated CT. For CPPT and IMPT, plans with different degrees of freedom for the proton beams were optimized. Fixed horizontal proton beam line (FHB), gantry-like, and arc-like plans were compared. RESULTS: The target coverage for CPPT without adaptation is insufficient (average V95%=88.4 %), while adapted plans can recover the initial treatment plan quality for target (average V95%=95.5 %) and organs-at-risk. CPPT with increased proton beam flexibility increases plan quality and reduces normal tissue complication probability of Xerostomia and Dysphagia. On average, Xerostomia NTCP reductions compared to IMRT are -2.7 %/-3.4 %/-5.0 % for CPPT FHB/CPPT Gantry/CPPT Arc. The differences for IMPT FHB/IMPT Gantry/IMPT Arc are + 0.8 %/-0.9 %/-4.3 %. CONCLUSION: CPPT for HNC needs adaptive treatments. Increasing proton beam flexibility in CPPT, either by using a gantry or an upright-positioned patient, improves treatment plan quality. However, the photon component is substantially reduced, therefore, the balance between improved plan quality and costs must be further determined.

Quantitative Study on the Breast Density and the Volume of the Mammary Gland According to the Patient's Age and Breast Quadrant.

OBJECTIVES: Breast density is considered an independent risk factor for the development of breast cancer. This study aimed to quantitatively assess the percent breast density (PBD) and the mammary glands volume (MGV) according to the patient's age and breast quadrant. We propose a regression model to estimate PBD and MGV as a function of the patient's age. METHODS: The breast composition in 1027 spiral breast CT (BCT) datasets without soft tissue masses, calcifications, or implants from 517 women (57 ± 8 years) were segmented. The breast tissue volume (BTV), MGV, and PBD of the breasts were measured in the entire breast and each of the four quadrants. The three breast composition features were analyzed in the seven age groups, from 40 to 74 years in 5-year intervals. A logarithmic model was fitted to the BTV, and a multiplicative inverse model to the MGV and PBD as a function of age was established using a least-squares method. RESULTS: The BTV increased from 545 ± 345 to 676 ± 412 cm3, and the MGV and PBD decreased from 111 ± 164 to 57 ± 43 cm3 and from 21 ± 21 to 11 ± 9%, respectively, from the youngest to the oldest group (p < 0.05). The average PBD over all ages were 14 ± 13%. The regression models could predict the BTV, MGV, and PBD based on the patient's age with residual standard errors of 386 cm3, 67 cm3, and 13%, respectively. The reduction in MGV and PBD in each quadrant followed the ones in the entire breast. CONCLUSIONS: The PBD and MGV computed from BCT examinations provide important information for breast cancer risk assessment in women. The study quantified the breast mammary gland reduction and density decrease over the entire breast. It established mathematical models to estimate the breast composition features-BTV, MGV, and PBD, as a function of the patient's age.

Spatiotemporal fractionation schemes for stereotactic radiosurgery of multiple brain metastases.

BACKGROUND: Stereotactic radiosurgery (SRS) is an established treatment for patients with brain metastases (BMs). However, damage to the healthy brain may limit the tumor dose for patients with multiple lesions. PURPOSE: In this study, we investigate the potential of spatiotemporal fractionation schemes to reduce the biological dose received by the healthy brain in SRS of multiple BMs, and also demonstrate a novel concept of spatiotemporal fractionation for polymetastatic cancer patients that faces less hurdles for clinical implementation. METHODS: Spatiotemporal fractionation (STF) schemes aim at partial hypofractionation in the metastases along with more uniform fractionation in the healthy brain. This is achieved by delivering distinct dose distributions in different fractions, which are designed based on their cumulative biologically effective dose ( BED α / ß ${\rm{BED}}_{{{\alpha}}/{{\beta}}}$ ) such that each fraction contributes with high doses to complementary parts of the target volume, while similar dose baths are delivered to the normal tissue. For patients with multiple brain metastases, a novel constrained approach to spatiotemporal fractionation (cSTF) is proposed, which is more robust against setup and biological uncertainties. The approach aims at irradiating entire metastases with possibly different doses, but spatially similar dose distributions in every fraction, where the optimal dose contribution of every fraction to each metastasis is determined using a new planning objective to be added to the BED-based treatment plan optimization problem. The benefits of spatiotemporal fractionation schemes are evaluated for three patients, each with >25 BMs. RESULTS: For the same tumor BED10 and the same brain volume exposed to high doses in all plans, the mean brain BED2 can be reduced compared to uniformly fractionated plans by 9%-12% with the cSTF plans and by 13%-19% with the STF plans. In contrast to the STF plans, the cSTF plans avoid partial irradiation of the individual metastases and are less sensitive to misalignments of the fractional dose distributions when setup errors occur. CONCLUSION: Spatiotemporal fractionation schemes represent an approach to lower the biological dose to the healthy brain in SRS-based treatments of multiple BMs. Although cSTF cannot achieve the full BED reduction of STF, it improves on uniform fractionation and is more robust against both setup errors and biological uncertainties related to partial tumor irradiation.

Patient-specific quality assurance for deformable IMRT/IMPT dose accumulation: Proposition and validation of energy conservation based validation criterion.

BACKGROUND: Deformable image registration (DIR)-based dose accumulation (DDA) is regularly used in adaptive radiotherapy research. However, the applicability and reliability of DDA for direct clinical usage are still being debated. One primary concern is the validity of DDA, particularly for scenarios with substantial anatomical changes, for which energy-conservation problems were observed in conceptual studies. PURPOSE: We present and validate an energy-conservation (EC)-based DDA validation workflow and further investigate its usefulness for actual patient data, specifically for lung cancer cases. METHODS: For five non-small cell lung cancer (NSCLC) patients, DDA based on five selective DIR methods were calculated for five different treatment plans, which include one intensity-modulated photon therapy (IMRT), two intensity-modulated proton therapy (IMPT), and two combined proton-photon therapy (CPPT) plans. All plans were optimized on the planning CT (planCT) acquired in deep inspiration breath-hold (DIBH) and were re-optimized on the repeated DIBH CTs of three later fractions. The resulting fractional doses were warped back to the planCT using each DIR. An EC-based validation of the accumulation process was implemented and applied to all DDA results. Correlations between relative organ mass/volume variations and the extent of EC violation were then studied using Bayesian linear regression (BLR). RESULTS: For most OARs, EC violation within 10% is observed. However, for the PTVs and GTVs with substantial regression, severe overestimation of the fractional energy was found regardless of treatment type and applied DIR method. BLR results show that EC violation is linearly correlated to the relative mass variation (R^2 > 0.95) and volume variation (R^2 > 0.60). CONCLUSION: DDA results should be used with caution in regions with high mass/volume variation for intensity-based DIRs. EC-based validation is a useful approach to provide patient-specific quality assurance of the validity of DDA in radiotherapy.

Automatic and standardized quality assurance of digital mammography and tomosynthesis with deep convolutional neural networks.

OBJECTIVES: The aim of this study was to develop and validate a commercially available AI platform for the automatic determination of image quality in mammography and tomosynthesis considering a standardized set of features. MATERIALS AND METHODS: In this retrospective study, 11,733 mammograms and synthetic 2D reconstructions from tomosynthesis of 4200 patients from two institutions were analyzed by assessing the presence of seven features which impact image quality in regard to breast positioning. Deep learning was applied to train five dCNN models on features detecting the presence of anatomical landmarks and three dCNN models for localization features. The validity of models was assessed by the calculation of the mean squared error in a test dataset and was compared to the reading by experienced radiologists. RESULTS: Accuracies of the dCNN models ranged between 93.0% for the nipple visualization and 98.5% for the depiction of the pectoralis muscle in the CC view. Calculations based on regression models allow for precise measurements of distances and angles of breast positioning on mammograms and synthetic 2D reconstructions from tomosynthesis. All models showed almost perfect agreement compared to human reading with Cohen's kappa scores above 0.9. CONCLUSIONS: An AI-based quality assessment system using a dCNN allows for precise, consistent and observer-independent rating of digital mammography and synthetic 2D reconstructions from tomosynthesis. Automation and standardization of quality assessment enable real-time feedback to technicians and radiologists that shall reduce a number of inadequate examinations according to PGMI (Perfect, Good, Moderate, Inadequate) criteria, reduce a number of recalls and provide a dependable training platform for inexperienced technicians.

Radiation dose estimates based on Monte Carlo simulation for spiral breast computed tomography imaging in a large cohort of patients.

BACKGROUND: Spiral breast computed tomography (BCT) equipped with a photon-counting detector (PCD) is a new radiological modality allowing for the compression-free acquisition of high-resolution 3-D datasets of the breast. Optimized dose exposu04170/re setups according to breast size were previously proposed but could not effectively be applied in a clinical environment due to ambiguity in measuring breast size. PURPOSE: This study aims to report the standard radiation dose values in a large cohort of patients examined with BCT, and to provide a mathematical model to estimate radiation dose based on morphological features of the breast. METHODS: This retrospective study was conducted on 1657 BCT examinations acquired between 2018 and 2021 from 829 participants (57 ± 10 years, all female). Applying a dedicated breast tissue segmentation algorithm and Monte Carlo (MC) simulation, mean absorbed dose (MAD), mean glandular dose (MGD), mean skin dose (MSD), maximum glandular dose (maxGD), and maximum skin dose (maxSD) were calculated and related to morphological features such as breast volume, effective diameter, breast length, skin volume, and glandularity. Effective dose (ED) was calculated by applying the corresponding beam and tissue weighting factors, 1 Sv/Gy and 0.12 per breast. Relevant morphological features predicting dose values were identified based on the Spearman's rank correlation coefficient. Exponential or bi-exponential models predicting the dose values as a function of morphological features were fitted by using a non-linear least squares (LS) method. The models were validated by assessing R2 and residual standard error (RSE). RESULTS: The most relevant morphological features for radiation dose estimation were the breast volume (correlation coefficient: -0.8), diameter (-0.7), and length (-0.6). The glandularity presented a weak-positive correlation (0.4) with MGD and maxGD due to the inhomogeneous distribution of the glandularity and absorbed dose in the 3-D breast volume. The standard MGDs were calculated to be 7.3 ± 0.7, 6.5 ± 0.3, and 5.9 ± 0.3 mGy, MADs to 7.6 ± 0.8, 6.8 ± 0.3, and 6.2 ± 0.3 mGy, maxSDs to 19.9 ± 1.6, 19.5 ± 0.5, and 18.9 ± 0.5 mGy, and EDs to 0.88 ± 0.08, 0.78 ± 0.04, and 0.72 ± 0.04 mSv for small, medium, and large breasts with average breast lengths of 5.9 ± 1.6, 8.7 ± 1.3, and 12.2 ± 2.0 cm, respectively. The estimated glandularity - 23.1 ± 16.9, 12.5 ± 11.4, and 6.9 ± 7.3% from small to large breasts. The mathematical models were able to estimate the MAD, MGD, MSD, and maxSD as a function of each morphological feature with only upto 0.5 mGy RSE. CONCLUSION: We presented the typical morphological features and standard dose values according to the breast size acquired from a large patient cohort. We established radiation dose estimation models allowing accurate estimation of dose values including MGD with an acceptable RSE based on each of the easily measured morphological features of the breast. Clinicians could use the breast length to operate as a dosimetric alert of the scanner prior to a BCT scan. Radiation exposure for BCT was lower than diagnostic mammography (MG) and cone-beam breast CT (BCT).

Volumetric memory network for interactive medical image segmentation.

Despite recent progress of automatic medical image segmentation techniques, fully automatic results usually fail to meet clinically acceptable accuracy, thus typically require further refinement. To this end, we propose a novel Volumetric Memory Network, dubbed as VMN, to enable segmentation of 3D medical images in an interactive manner. Provided by user hints on an arbitrary slice, a 2D interaction network is firstly employed to produce an initial 2D segmentation for the chosen slice. Then, the VMN propagates the initial segmentation mask bidirectionally to all slices of the entire volume. Subsequent refinement based on additional user guidance on other slices can be incorporated in the same manner. To facilitate smooth human-in-the-loop segmentation, a quality assessment module is introduced to suggest the next slice for interaction based on the segmentation quality of each slice produced in the previous round. Our VMN demonstrates two distinctive features: First, the memory-augmented network design offers our model the ability to quickly encode past segmentation information, which will be retrieved later for the segmentation of other slices; Second, the quality assessment module enables the model to directly estimate the quality of each segmentation prediction, which allows for an active learning paradigm where users preferentially label the lowest-quality slice for multi-round refinement. The proposed network leads to a robust interactive segmentation engine, which can generalize well to various types of user annotations (e.g., scribble, bounding box, extreme clicking). Extensive experiments have been conducted on three public medical image segmentation datasets (i.e., MSD, KiTS19, CVC-ClinicDB), and the results clearly confirm the superiority of our approach in comparison with state-of-the-art segmentation models. The code is made publicly available at https://github.com/0liliulei/Mem3D.

Fully automated breast segmentation on spiral breast computed tomography images.

INTRODUCTION: The quantification of the amount of the glandular tissue and breast density is important to assess breast cancer risk. Novel photon-counting breast computed tomography (CT) technology has the potential to quantify them. For accurate analysis, a dedicated method to segment the breast components-the adipose and glandular tissue, skin, pectoralis muscle, skinfold section, rib, and implant-is required. We propose a fully automated breast segmentation method for breast CT images. METHODS: The framework consists of four parts: (1) investigate, (2) segment the components excluding adipose and glandular tissue, (3) assess the breast density, and (4) iteratively segment the glandular tissue according to the estimated density. For the method, adapted seeded watershed and region growing algorithm were dedicatedly developed for the breast CT images and optimized on 68 breast images. The segmentation performance was qualitatively (five-point Likert scale) and quantitatively (Dice similarity coefficient [DSC] and difference coefficient [DC]) demonstrated according to human reading by experienced radiologists. RESULTS: The performance evaluation on each component and overall segmentation for 17 breast CT images resulted in DSCs ranging 0.90-0.97 and in DCs 0.01-0.08. The readers rated 4.5-4.8 (5 highest score) with an excellent inter-reader agreement. The breast density varied by 3.7%-7.1% when including mis-segmented muscle or skin. CONCLUSION: The automatic segmentation results coincided with the human expert's reading. The accurate segmentation is important to avoid the significant bias in breast density analysis. Our method enables accurate quantification of the breast density and amount of the glandular tissue that is directly related to breast cancer risk.

A novel stochastic optimization method for handling misalignments of proton and photon doses in combined treatments.

Objective.Combined proton-photon treatments, where most fractions are delivered with photons and only a few are delivered with protons, may represent a practical approach to optimally use limited proton resources. It has been shown that, when organs at risk (OARs) are located within or near the tumor, the optimal multi-modality treatment uses protons to hypofractionate parts of the target volume and photons to achieve near-uniform fractionation in dose-limiting healthy tissues, thus exploiting the fractionation effect. These plans may be sensitive to range and setup errors, especially misalignments between proton and photon doses. Thus, we developed a novel stochastic optimization method to directly incorporate these uncertainties into the biologically effective dose (BED)-based simultaneous optimization of proton and photon plans.Approach.The method considers the expected valueEband standard deviationσbof the cumulative BEDbin every voxel of a structure. For the target, a piecewise quadratic penalty function of the formbmin-Eb-2σb+2is minimized, aiming for plans in which the expected BED minus two times the standard deviation exceeds the prescribed BEDbmin.Analogously,Eb+2σb-bmax+2is considered for OARs.Main results.Using a spinal metastasis case and a liver cancer patient, it is demonstrated that the novel stochastic optimization method yields robust combined treatment plans. Tumor coverage and a good sparing of the main OARs are maintained despite range and setup errors, and especially misalignments between proton and photon doses. This is achieved without explicitly considering all combinations of proton and photon error scenarios.Significance.Concerns about range and setup errors for safe clinical implementation of optimized proton-photon radiotherapy can be addressed through an appropriate stochastic planning method.

A dataset on patient-individual lymph node involvement in oropharyngeal squamous cell carcinoma.

Dataset: We provide a dataset on lymph node level (LNL) involvement in 287 patients with newly diagnosed oropharyngeal squamous cell carcinoma (OPSCC). For each patient, ipsilateral and contralateral LNL involvement for levels I to VII is reported together with clinicopathological factors including TNM-stage, primary tumor subsite, tumor lateralization, HPV status, sex, age, smoking status, and primary treatment. LNL involvement was assessed individually based on available diagnostic modalities (PET, MRI, CT, fine needle aspiration) by reviewing pathology and radiology reports together with the radiological images. The data is shared as a CSV-table with rows of patients and columns of patient/tumor-specific information and the involvement of individual LNL based on the respective diagnostic modalities. Reuse potential: Patterns of lymphatic progression have never been reported on a patient-individual basis in as much detail as provided in this dataset. The data can be used to build quantitative models for lymphatic tumor progression to estimate the probability of occult metastases in LNLs. This may in turn allow for further personalization of the elective clinical target volume definition in radiotherapy and the extent of neck dissection for surgically treated patients. The data can be pooled with other data to build large multi-institutional datasets on lymphatic metastatic progression in the future. Co-submission: This paper supports the original scientific article by Roman Ludwig, Jean-Marc Hoffmann, Bertrand Pouymayou, Grégoire Morand, Martina Broglie Däppen, Matthias Guckenberger, Vincent Grégoire, Panagiotis Balermpas, Jan Unkelbach, "Detailed patient-individual reporting of lymph node involvement in oropharyngeal squamous cell carcinoma with an online interface", Radiotherapy & Oncology [1].

Technical note: Optimal allocation of limited proton therapy resources using model-based patient selection.

PURPOSE: We consider the following scenario: A radiotherapy clinic has a limited number of proton therapy slots available each day to treat cancer patients of a given tumor site. The clinic's goal is to minimize the expected number of complications in the cohort of all patients of that tumor site treated at the clinic, and thereby maximize the benefit of its limited proton resources. METHODS: To address this problem, we extend the normal tissue complication probability (NTCP) model-based approach to proton therapy patient selection to the situation of limited resources at a given institution. We assume that, on each day, a newly diagnosed patient is scheduled for treatment at the clinic with some probability and with some benefit Δ N T C P $\Delta NTCP$ from protons over photons, which is drawn from a probability distribution. When a new patient is scheduled for treatment, a decision for protons or photons must be made, and a patient may wait only for a limited amount of time for a proton slot becoming available. The goal is to determine the Δ N T C P $\Delta NTCP$ thresholds for selecting a patient for proton therapy, which optimally balance the competing goals of making use of all available slots while not blocking slots with patients with low benefit. This problem can be formulated as a Markov decision process (MDP) and the optimal thresholds can be determined via a value-policy iteration method. RESULTS: The optimal Δ N T C P $\Delta NTCP$ thresholds depend on the number of available proton slots, the average number of patients under treatment, and the distribution of Δ N T C P $\Delta NTCP$ values. In addition, the optimal thresholds depend on the current utilization of the facility. For example, if one proton slot is available and a second frees up shortly, the optimal Δ N T C P $\Delta NTCP$ threshold is lower compared to a situation where all but one slot remain blocked for longer. CONCLUSIONS: MDP methodology can be used to augment current NTCP model-based patient selection methods to the situation that, on any given day, the number of proton slots is limited. The optimal Δ N T C P $\Delta NTCP$ threshold then depends on the current utilization of the proton facility. Although, the optimal policy yields only a small nominal benefit over a constant threshold, it is more robust against variations in patient load.

Radiation-induced lymphopenia does not impact treatment efficacy in a mouse tumor model.

Radiation-induced lymphopenia is a common occurrence in radiation oncology and an established negative prognostic factor, however the mechanisms underlying the relationship between lymphopenia and inferior survival remain elusive. The relevance of lymphocyte co-irradiation as critical normal tissue component at risk is an emerging topic of high clinical relevance, even more so in the context of potentially synergistic radiotherapy-immunotherapy combinations. The impact of the radiotherapy treatment volume on the lymphocytes of healthy and tumor-bearing mice was investigated in a novel mouse model of radiation-induced lymphopenia. Using an image-guided small-animal radiotherapy treatment platform, translationally relevant tumor-oriented volumes of irradiation with an anatomically defined increasing amount of normal tissue were irradiated, with a focus on the circulating blood and lymph nodes. In healthy mice, the influence of irradiation with increasing radiotherapy treatment volumes was quantified on the level of circulating blood cells and in the spleen. A significant decrease in the lymphocytes was observed in response to irradiation, including the minimally irradiated putative tumor area. The extent of lymphopenia correlated with the increasing volumes of irradiation. In tumor-bearing mice, differential radiotherapy treatment volumes did not influence the overall therapeutic response to radiotherapy alone. Intriguingly, an improved treatment efficacy in mice treated with draining-lymph node co-irradiation was observed in combination with an immune checkpoint inhibitor. Taken together, our study reveals compelling data on the importance of radiotherapy treatment volume in the context of lymphocytes as critical components of normal tissue co-irradiation and highlights emerging challenges at the interface of radiotherapy and immunotherapy.

Combined proton-photon therapy for non-small cell lung cancer.

PURPOSE: Advanced non-small cell lung cancer (NSCLC) is still a challenging indication for conventional photon radiotherapy. Proton therapy has the potential to improve outcomes, but proton treatment slots remain a limited resource despite an increasing number of proton therapy facilities. This work investigates the potential benefits of optimally combined proton-photon therapy delivered using a fixed horizontal proton beam line in combination with a photon Linac, which could increase accessibility to proton therapy for such a patient cohort. MATERIALS AND METHODS: A treatment planning study has been conducted on a patient cohort of seven advanced NSCLC patients. Each patient had a planning computed tomography scan (CT) and multiple repeated CTs from three different days and for different breath-holds on each day. Treatment plans for combined proton-photon therapy (CPPT) were calculated for individual patients by optimizing the combined cumulative dose on the initial planning CT only (non-adapted) as well as on each daily CT respectively (adapted). The impact of inter-fractional changes and/or breath-hold variability was then assessed on the repeat breath-hold CTs. Results were compared to plans for IMRT or IMPT alone, as well as against combined treatments assuming a proton gantry. Plan quality was assessed in terms of dosimetric, robustness and NTCP metrics. RESULTS: Combined treatment plans improved plan quality compared to IMRT treatments, especially in regard to reductions of low and medium doses to organs at risk (OARs), which translated into lower NTCP estimates for three side effects. For most patients, combined treatments achieved results close to IMPT-only plans. Inter-fractional changes impact mainly the target coverage of combined and IMPT treatments, while OARs doses were less affected by these changes. With plan adaptation however, target coverage of combined treatments remained high even when taking variability between breath-holds into account. CONCLUSIONS: Optimally combined proton-photon plans improve treatment plan quality compared to IMRT only, potentially reducing the risk of toxicity while also allowing to potentially increase accessibility to proton therapy for NSCLC patients.

Fully automatic classification of automated breast ultrasound (ABUS) imaging according to BI-RADS using a deep convolutional neural network.

PURPOSE: The aim of this study was to develop and test a post-processing technique for detection and classification of lesions according to the BI-RADS atlas in automated breast ultrasound (ABUS) based on deep convolutional neural networks (dCNNs). METHODS AND MATERIALS: In this retrospective study, 645 ABUS datasets from 113 patients were included; 55 patients had lesions classified as high malignancy probability. Lesions were categorized in BI-RADS 2 (no suspicion of malignancy), BI-RADS 3 (probability of malignancy < 3%), and BI-RADS 4/5 (probability of malignancy > 3%). A deep convolutional neural network was trained after data augmentation with images of lesions and normal breast tissue, and a sliding-window approach for lesion detection was implemented. The algorithm was applied to a test dataset containing 128 images and performance was compared with readings of 2 experienced radiologists. RESULTS: Results of calculations performed on single images showed accuracy of 79.7% and AUC of 0.91 [95% CI: 0.85-0.96] in categorization according to BI-RADS. Moderate agreement between dCNN and ground truth has been achieved (κ: 0.57 [95% CI: 0.50-0.64]) what is comparable with human readers. Analysis of whole dataset improved categorization accuracy to 90.9% and AUC of 0.91 [95% CI: 0.77-1.00], while achieving almost perfect agreement with ground truth (κ: 0.82 [95% CI: 0.69-0.95]), performing on par with human readers. Furthermore, the object localization technique allowed the detection of lesion position slice-wise. CONCLUSIONS: Our results show that a dCNN can be trained to detect and distinguish lesions in ABUS according to the BI-RADS classification with similar accuracy as experienced radiologists. KEY POINTS: • A deep convolutional neural network (dCNN) was trained for classification of ABUS lesions according to the BI-RADS atlas. • A sliding-window approach allows accurate automatic detection and classification of lesions in ABUS examinations.

Detailed patient-individual reporting of lymph node involvement in oropharyngeal squamous cell carcinoma with an online interface.

PURPOSE/OBJECTIVE: Whereas the prevalence of lymph node level (LNL) involvement in head & neck squamous cell carcinomas (HNSCC) has been reported, the details of lymphatic progression patterns are insufficiently quantified. In this study, we investigate how the risk of metastases in each LNL depends on the involvement of upstream LNLs, T-category, HPV status and other risk factors. MATERIALS/METHODS: We retrospectively analyzed patients with newly diagnosed oropharyngeal squamous cell carcinoma (OPSCC) treated at a single institution, resulting in a dataset of 287 patients. For all patients, involvement of LNLs I-VII was recorded individually based on available diagnostic modalities (PET, MRI, CT, FNA) together with clinicopathological factors. To analyze the dataset, a web-based graphical user interface (GUI) was developed, which allows querying the number of patients with a certain combination of co-involved LNLs and tumor characteristics. RESULTS: The full dataset and GUI is part of the publication. Selected findings are: Ipsilateral level IV was involved in 27% of patients with level II and III involvement, but only in 2% of patients with level II but not III involvement. Prevalence of involvement of ipsilateral levels II, III, IV, V was 79%, 34%, 7%, 3% for early T-category patients (T1/T2) and 85%, 50%, 17%, 9% for late T-category (T3/T4), quantifying increasing involvement with T-category. Contralateral levels II, III, IV were involved in 41%, 19%, 4% and 12%, 3%, 2% for tumors with and without midline extension, respectively. T-stage dependence of LNL involvement was more pronounced in HPV negative than positive tumors, but overall involvement was similar. Ipsilateral level VII was involved in 14% and 6% of patients with primary tumors in the tonsil and the base of tongue, respectively. CONCLUSIONS: Detailed quantification of LNL involvement in HNSCC depending on involvement of upstream LNLs and clinicopathological factors may allow for further personalization of CTV-N definition in the future.

Combined proton-photon treatment for breast cancer.

Objective.Proton therapy remains a limited resource due to gantry size and its cost. Recently, a new design without a gantry has been suggested. It may enable combined proton-photon therapy (CPPT) in conventional bunkers and allow the widespread use of protons. In this work, we explore this concept for breast cancer.Methods.The treatment room consists of a LINAC for intensity modulated radiation therapy (IMRT), a fixed proton beamline (FBL) with beam scanning and a motorized couch for treatments in lying positions with accurate patient setup. Thereby, proton and photon beams are delivered in the same fraction. Treatment planning is performed by simultaneously optimizing IMRT and IMPT plans based on the cumulative dose. The concept is investigated for three breast cancers where the goal is to minimize mean dose to the heart and lung while delivering 40.05 Gy in 15 fractions to the PTV with a SIB of 48 Gy to the tumor bed. The probabilistic approach is applied to mitigate the sensitivity to range uncertainties.Results. CPPT is particularly advantageous for irradiating concave target volumes that wrap around a curved chest wall. There, protons may deliver dose to the peripheral and medial parts of the target volume including lymph nodes. Thereby, the mean dose in normal tissues is reduced compared to single-modality IMRT. However, tangential photon beams may treat parts of the target volume near the interface to the lung. To ensure target coverage for range undershoot in an IMPT plan, proton beams have to deliberately overshoot into the lung tissue-a problem that can be mitigated via the photon component which ensures plan conformity and robustness.Conclusion.CPPT using an FBL may represent a realistic approach to make protons available to more patients. In addition, CPPT may generally improve treatment quality compared to both single-modality proton and photon treatments.

Quantification of the spatial distribution of primary tumors in the lung to develop new prognostic biomarkers for locally advanced NSCLC.

The anatomical location and extent of primary lung tumors have shown prognostic value for overall survival (OS). However, its manual assessment is prone to interobserver variability. This study aims to use data driven identification of image characteristics for OS in locally advanced non-small cell lung cancer (NSCLC) patients. Five stage IIIA/IIIB NSCLC patient cohorts were retrospectively collected. Patients were treated either with radiochemotherapy (RCT): RCT1* (n = 107), RCT2 (n = 95), RCT3 (n = 37) or with surgery combined with radiotherapy or chemotherapy: S1* (n = 135), S2 (n = 55). Based on a deformable image registration (MIM Vista, 6.9.2.), an in-house developed software transferred each primary tumor to the CT scan of a reference patient while maintaining the original tumor shape. A frequency-weighted cumulative status map was created for both exploratory cohorts (indicated with an asterisk), where the spatial extent of the tumor was uni-labeled with 2 years OS. For the exploratory cohorts, a permutation test with random assignment of patient status was performed to identify regions with statistically significant worse OS, referred to as decreased survival areas (DSA). The minimal Euclidean distance between primary tumor to DSA was extracted from the independent cohorts (negative distance in case of overlap). To account for the tumor volume, the distance was scaled with the radius of the volume-equivalent sphere. For the S1 cohort, DSA were located at the right main bronchus whereas for the RCT1 cohort they further extended in cranio-caudal direction. In the independent cohorts, the model based on distance to DSA achieved performance: AUCRCT2 [95% CI] = 0.67 [0.55-0.78] and AUCRCT3 = 0.59 [0.39-0.79] for RCT patients, but showed bad performance for surgery cohort (AUCS2 = 0.52 [0.30-0.74]). Shorter distance to DSA was associated with worse outcome (p = 0.0074). In conclusion, this explanatory analysis quantifies the value of primary tumor location for OS prediction based on cumulative status maps. Shorter distance of primary tumor to a high-risk region was associated with worse prognosis in the RCT cohort.