Salvage surgery for local recurrences after stereotactic ablative radiotherapy of colorectal pulmonary metastases.

INTRODUCTION: Local control following stereotactic ablative radiotherapy (SABR) for patients with colorectal pulmonary metastases is reportedly lower than for metastases from other tumors. Such recurrences may still be amenable to salvage therapy. We describe our experience with salvage surgery in 17 patients. METHODS: Patients who underwent salvage metastasectomy for a local recurrence following SABR for colorectal pulmonary metastases were identified from the surgical institutional databases of three Dutch major referral hospitals. Kaplan-Meier survival analysis was performed to determine survival. RESULTS: Seventeen patients underwent 20 salvage resections for local recurrence of colorectal pulmonary metastases. All patients had a progressive lesion on consecutive CT scans, with local uptake on 18 fluorodeoxyglucose-positron emission tomography computed tomography (FDG-PET CT), and were discussed in a thoracic oncology tumor board. Median time to local recurrence following SABR was 20 months (interquartile range [IQR]: 13-29). Fourteen procedures were performed minimally invasively. Extensive adhesions were observed during three procedures. A Clavien-Dindo grade III-IV complication occurred after four resections (20%). The 90-day mortality was 0%. The estimated median overall survival and progression-free survival following salvage resection were 71 months (confidence intervals [CI]: 50-92) and 39 months (CI: 19-58), respectively. Salvage resections were significantly more extensive, compared to the potential resection assessed on pre-SABR imaging. CONCLUSIONS: Our experience with 20 salvage pulmonary metastasectomy procedures for local recurrences following SABR in colorectal cancer patients demonstrates that salvage resection is a feasible option with acceptable morbidity and good oncological outcome in a highly selected cohort.

Investigating the potential of deep learning for patient-specific quality assurance of salivary gland contours using EORTC-1219-DAHANCA-29 clinical trial data.

INTRODUCTION: Manual quality assurance (QA) of radiotherapy contours for clinical trials is time and labor intensive and subject to inter-observer variability. Therefore, we investigated whether deep-learning (DL) can provide an automated solution to salivary gland contour QA. MATERIAL AND METHODS: DL-models were trained to generate contours for parotid (PG) and submandibular glands (SMG). Sørensen-Dice coefficient (SDC) and Hausdorff distance (HD) were used to assess agreement between DL and clinical contours and thresholds were defined to highlight cases as potentially sub-optimal. 3 types of deliberate errors (expansion, contraction and displacement) were gradually applied to a test set, to confirm that SDC and HD were suitable QA metrics. DL-based QA was performed on 62 patients from the EORTC-1219-DAHANCA-29 trial. All highlighted contours were visually inspected. RESULTS: Increasing the magnitude of all 3 types of errors resulted in progressively severe deterioration/increase in average SDC/HD. 19/124 clinical PG contours were highlighted as potentially sub-optimal, of which 5 (26%) were actually deemed clinically sub-optimal. 2/19 non-highlighted contours were false negatives (11%). 15/69 clinical SMG contours were highlighted, with 7 (47%) deemed clinically sub-optimal and 2/15 non-highlighted contours were false negatives (13%). For most incorrectly highlighted contours causes for low agreement could be identified. CONCLUSION: Automated DL-based contour QA is feasible but some visual inspection remains essential. The substantial number of false positives were caused by sub-optimal performance of the DL-model. Improvements to the model will increase the extent of automation and reliability, facilitating the adoption of DL-based contour QA in clinical trials and routine practice.

An integrated multidisciplinary algorithm for the management of spinal metastases: an International Spine Oncology Consortium report.

Spinal metastases are becoming increasingly common because patients with metastatic disease are living longer. The close proximity of the spinal cord to the vertebral column limits many conventional therapeutic options that can otherwise be used to treat cancer. In response to this problem, an innovative multidisciplinary approach has been developed for the management of spinal metastases, leveraging the capabilities of image-guided stereotactic radiosurgery, separation surgery, vertebroplasty, and minimally invasive local ablative approaches. In this Review, we discuss the variables that should be considered during the management of these patients and review the role of each discipline and their respective management options to provide optimal care. This work is synthesised into a practical algorithm to aid clinicians in the management of patients with spinal metastasis.

Optimizing SABR delivery for synchronous multiple lung tumors using volumetric-modulated arc therapy.

BACKGROUND: Volumetric-modulated arc therapy (VMAT) delivery for stereotactic ablative radiotherapy (SABR) of multiple lung tumors allows for faster treatments. We report on clinical outcomes and describe a general approach for treatment planning. MATERIAL AND METHODS: Patients undergoing multi iso-center VMAT-based SABR for ≥2 lung lesions between 2009 and 2014 were identified from the VU University Medical Center and London Health Sciences Centre. Patients were eligible if the start date of the SABR treatment for the different lesions was within a time range of 30 days. SABR was delivered using separate iso-centers for lesions at a substantial distance from each other. Tumors were either treated with a single fraction of 34 Gy, or using three risk-adapted dose-fractionation schemes, namely three fractions of 18 Gy, five fractions of 11 Gy, or eight fractions of 7.5 Gy, depending on the tumor size and the location. Multivariable analysis was performed to assess factors predictive of clinical outcomes. RESULTS: Of 84 patients (188 lesions) identified, 46% were treated for multiple metastases and 54% for multiple primary NSCLC. About 97% were treated for two or three lesions, and 56% had bilateral disease. After a median follow-up of 28 months, median overall survival (OS) for primary tumors was 27.6 months, and not reached for metastatic lesions (p = .028). Grade ≥3 toxicity was observed in 2% of patients. Multivariable analysis showed that grade 2 or higher radiation pneumonitis (n = 9) was best predicted by a total lung V35Gy of ≥6.5% (in 2Gy/fraction equivalent) (p = .007). CONCLUSION: Severe toxicity was uncommon following SABR using VMAT for up to three lung tumors. Further investigations of planning parameters are needed in patients presenting with more lesions.

Roll and pitch set-up errors during volumetric modulated arc delivery: can adapting gantry and collimator angles compensate?

PURPOSE: The purpose of this work was to investigate whether adapting gantry and collimator angles can compensate for roll and pitch setup errors during volumetric modulated arc therapy (VMAT) delivery. METHODS: Previously delivered clinical plans for locally advanced head-and-neck (H&N) cancer (n = 5), localized prostate cancer (n = 2), and whole brain with simultaneous integrated boost to 5 metastases (WB + 5M, n = 1) were used for this study. Known rigid rotations were introduced in the planning CT scans. To compensate for these, in-house software was used to adapt gantry and collimator angles in the plan. Doses to planning target volumes (PTV) and critical organs at risk (OAR) were calculated with and without compensation and compared with the original clinical plan. Measurements in the sagittal plane in a polystyrene phantom using radiochromic film were compared by gamma (γ) evaluation for 2 H&N cancer patients. RESULTS: For H&N plans, the introduction of 2°-roll and 3°-pitch rotations reduced mean PTV coverage from 98.7 to 96.3%. This improved to 98.1% with gantry and collimator compensation. For prostate plans respective figures were 98.4, 97.5, and 98.4%. For WB + 5M, compensation worked less well, especially for smaller volumes and volumes farther from the isocenter. Mean comparative γ evaluation (3%, 1 mm) between original and pitched plans resulted in 86% γ < 1. The corrected plan restored the mean comparison to 96% γ < 1. CONCLUSION: Preliminary data suggest that adapting gantry and collimator angles is a promising way to correct roll and pitch set-up errors of < 3° during VMAT for H&N and prostate cancer.

Is there a preferred IMRT technique for left-breast irradiation?

Not all clinics have breath-hold radiotherapy available for left-breast irradiation. However intensity-modulated radiotherapy (IMRT) has also been advocated as a means of lowering heart doses. There is currently no large-scale, long-term follow-up data after breast IMRT and, since dose distributions may differ from classic tangent-based radiotherapy, caution is needed to avoid unexpected worsening of the late toxicity profile. We compared four IMRT techniques for free-breathing left-breast irradiation. Consistent with the aforementioned concerns, our goal in planning was to prioritize organ at risk (OAR) sparing in a way that mimicked tangent-based radiotherapy. Ten simultaneous integrated boost treatment plans (PTVelective = 15 × 2.67 Gy; PTVboost = 15 × 3.35 Gy) were created using 1) hybrid-IMRT (H-IMRT), 2) full IMRT (F-IMRT), and 3) volumetric-modulated arc therapy with two partial arcs (2ARC) and 4) six partial arcs (6ARC). Reduction in OAR mean and low dose was prioritized. End-points included OAR sparing (e.g., heart, left anterior descending artery [LAD+3 mm], lungs, and contralateral breast) and PTV coverage/dose homogeneity. Under these conditions we found the following: 1) H-IMRT provided the best mean and low dose OAR sparing, PTVelective coverage (mean V95% = 98%), PTVboost coverage (V95% = 98%), and PTV homogeneity. However, it delivered most intermediate-high dose to the heart, LAD+3 mm and ipsilateral lung; 2) 6ARC had the best intermediate-high dose sparing, followed by F-IMRT, but this was at the expense of more dose in the contralateral lung and breast and worse PTV coverage (PTVelective mean V95% = 96%/97% and PTVboost mean V95% = 91%/96% for 6ARC/F-IMRT). When trying to spare mean and low dose to OARs, the preferred IMRT technique for left-breast irradiation without breath-hold was H-IMRT. This is currently the standard solution in our institution for left-breast radiotherapy under free-breathing and breath-hold conditions.

Investigating strategies to reduce toxicity in stereotactic ablative radiotherapy for central lung tumors.

BACKGROUND: [corrected] Stereotactic radiotherapy for central lung tumors has a narrower therapeutic index than that for peripheral tumors. Tumor tracking strategies have been proposed to reduce treatment volumes and toxicity, however they need to consider uncertainties in tumor size and shape change throughout respiration to ensure optimal local control. We quantified these uncertainties and explored strategies to account for them. MATERIAL AND METHODS: Ten patients with central tumors, PTV > 100 cm(3), motion > 5 mm and a 10-phase 4DCT without significant artifact in the tumor region were evaluated. Uncertainties were quantified using GTV size in different phases, and the Hausdorff distance (HD) between the phase 50% GTV and other phases after soft-tissue rigid registration. An individualized internal target volume for tracking (ITV(T)) was generated from the union of the GTVs in all phases after rigid registration. This was compared to ITVs generated for tracking based on the phase 50% GTV alone or with isotropic margins of 3 or 5 mm for size and volume overlap. RESULTS: Median free-breathing PTV size and motion were 162.1 cm(3) (110-210) and 8.9 mm (6.1-14.1). Overall, median GTV size variation and HD were 4.7% (0.2-22.3) and 6.3 mm (3.9-17.6). Tracking using GTV 50% alone resulted in median volume overlap with ITV(T) of 71.7% (range 56.8-85.1). Isotropic margins of 3 or 5mm always resulted in a volume overlap less than 95% or a volume larger than the ITV(T). CONCLUSIONS: Changes in size and shape of central lung tumors are substantial during respiration. These limit the ability to reduce treatment volumes with tracking, especially if isotropic margins are used. An individualized ITV for tracking, such as the ITV(T) is preferred.

Changes in non-surgical management of stage III non-small cell lung cancer at a single institution between 2003 and 2010.

BACKGROUND: Concurrent chemo-radiotherapy (CON-CRT) is recommended for selected patients with stage III non-small cell lung cancer (NSCLC), but utilization varies. We assessed the response to national guidelines introduced in 2004 and the impact on outcomes. MATERIAL AND METHODS: Retrospective study of stage III NSCLC patients treated with radical intent non-surgical treatment during 2003-2010 in a university medical center characterized by multidisciplinary assessment, routine use of four-dimensional computed tomography for radiotherapy planning, and rapid implementation of radiotherapy advances. RESULTS: Between 2003 and 2010, 319/435 (73%) patients with stage III NSCLC received (chemo) radiotherapy. The number receiving CON-CRT in successive two-year periods increased from 13/48 (27%) - 40/80 (50%) - 63/90 (70%), to 74/101 (73%). Median overall survival (OS) from start of radiotherapy was 18.6 months for CON-CRT (190/319) and 17.4 months for sequential (SEQ), typically hypofractionated, CRT (90/319) (p = 0.78). Eleven months OS with radiotherapy alone (39/319) was significantly shorter (p = 0.006). OS did not differ between the four periods (p = 0.87). CON-CRT was not over-represented in the 16% of patients dying within five months of starting radiotherapy. CONCLUSIONS: Between 2003 and 2010, CON-CRT for stage III NSCLC was rapidly and safely increased. However, OS did not increase and, as practiced, did not differ between CON- or SEQ-CRT.

Spine Stereotactic Body Radiation Therapy Without Immobilization: Detailed Analysis of Intrafraction Motion Using High-Frequency kV Imaging During Irradiation.

PURPOSE: Spine stereotactic body radiation therapy (SBRT) requires high positioning accuracy and a stable patient to maximize target coverage and reduce excessive irradiation to organs at risk. Positional verification during spine SBRT delivery helps to ensure accurate positioning for all patients. We report our experience with noninvasive 3-dimensional target position monitoring during volumetric modulated arc therapy of spine metastases in nonimmobilized patients positioned using only a thin mattress and simple arm and knee supports. METHODS AND MATERIALS: Fluoroscopic planar kV images were acquired at 7 frames/s using the on-board imaging system during volumetric modulated arc therapy spine SBRT. Template matching and triangulation were used to track the target in vertical, longitudinal, and lateral directions. If the tracking trace deviated >1 mm from the planned position in ≥1 direction, treatment was manually interrupted and 6-dimensional cone beam computed tomography (CBCT)-based couch correction was performed. Tracking data were used to retrospectively analyze the target position. Positional data, agreement with CBCT, correlation between position of the couch and direction of any positional correction, and treatment times were analyzed. RESULTS: In total, 175 fractions were analyzed. Delivery was interrupted 83 times in 66 fractions for a deviation >1 mm. In 97% of cases the difference between tracking data and subsequent clinical shift performed after the CBCT match was ≤0.5 mm. Lateral/longitudinal shift performed after intervention correlated with the couch roll/pitch at the start of treatment (correlation coefficient, -0.63/0.53). Mean (SD; range) time between start of first imaging and end of the last arc was 15.2 minutes (5.1; 7.6-36.3). CONCLUSIONS: Spine tracking during irradiation can be used to prompt an intervention CBCT scan and repositioning so that a spine SBRT target deviates by ≤1 mm from the planned position, even in nonimmobilized patients. kV tracking and CBCT are in good agreement. The data support verification CBCT after all 6 degrees-of-freedom positional corrections in nonimmobilized spine SBRT patients.

Chest wall resections for sulcus superior tumors.

Chemoradiotherapy followed by surgical resection (trimodality therapy) is a guideline recommended treatment for sulcus superior tumors (SST). By definition, SSTs invade the chest wall and therefore require en-bloc chest wall resection with the upper lung lobe or segments. The addition of a chest wall resection, potentially results in higher morbidity and mortality rates when compared to standard anatomical pulmonary resection. This, together with their anatomical location in the thoracic outlet, and varying grades of fibrosis and adhesions resulting from induction chemoradiotherapy in the operation field, make surgery challenging. Depending on the exact location of the tumor and extent to which it invades the surrounding structures, the preferred surgical approach may vary, e.g., anterior, posterolateral, hemi-clamshell, or combined approach; all with their own potential advantages and morbidities. Careful patient selection, adequate staging and discussion in a multidisciplinary tumor board in a center experienced in complex thoracic oncology leads to the best long-term survival outcomes with the least morbidity and mortality. Enhanced recovery guidelines are now available for thoracic surgery, promoting faster recovery and helping to minimize complications and morbidity, including infections and thoracotomy pain. Although minimally invasive surgery can enhance recovery and reduce chest wall morbidity, and is in widespread use in thoracic oncology, its use for SST has been limited. However, this is an evolving area and hybrid surgical approaches (including use of the robot) are being reported. Chest wall reconstruction is rarely necessary, but if so, the prosthetic materials are preferably radiolucent/non-scattering, rigid enough while still being somewhat flexible, and inert, providing structural support, allowing chest wall movement, and closing defects, while inciting a limited inflammatory response. New techniques such as 3D image reconstructions/volume rendering, 3D-printing, and virtual reality modules may help pre-operative planning and informed patient consent.

Technical note: Dosimetry and FLASH potential of UHDR proton PBS for small lung tumors: Bragg-peak-based delivery versus transmission beam and IMPT.

BACKGROUND: High-energy transmission beams (TBs) are currently the main delivery method for proton pencil beam scanning ultrahigh dose-rate (UHDR) FLASH radiotherapy. TBs place the Bragg-peaks behind the target, outside the patient, making delivery practical and achievement of high dose-rates more likely. However, they lead to higher integral dose compared to conventional intensity-modulated proton therapy (IMPT), in which Bragg-peaks are placed within the tumor. It is hypothesized that, when energy changes are not required and high beam currents are possible, Bragg-peak-based beams can not only achieve more conformal dose distributions than TBs, but also have more FLASH-potential. PURPOSE: This works aims to verify this hypothesis by taking three different Bragg-peak-based delivery techniques and comparing them with TB and IMPT-plans in terms of dosimetry and FLASH-potential for single-fraction lung stereotactic body radiotherapy (SBRT). METHODS: For a peripherally located lung target of various sizes, five different proton plans were made using "matRad" and inhouse-developed algorithms for spot/energy-layer/beam reduction and minimum monitor unit maximization: (1) IMPT-plan, reference for dosimetry, (2) TB-plan, reference for FLASH-amount, (3) pristine Bragg-peak plan (non-depth-modulated Bragg-peaks), (4) Bragg-peak plan using generic ridge filter, and (5) Bragg-peak plan using 3D range-modulated ridge filter. RESULTS: Bragg-peak-based plans are able to achieve sufficient plan quality and high dose-rates. IMPT-plans resulted in lowest OAR-dose and integral dose (also after a FLASH sparing-effect of 30%) compared to both TB-plans and Bragg-peak-based plans. Bragg-peak-based plans vary only slightly between themselves and generally achieve lower integral dose than TB-plans. However, TB-plans nearly always resulted in lower mean lung dose than Bragg-peak-based plans and due to a higher amount of FLASH-dose for TB-plans, this difference increased after including a FLASH sparing-effect. CONCLUSION: This work indicates that there is no benefit in using Bragg-peak-based beams instead of TBs for peripherally located, UHDR stereotactic lung radiotherapy, if lung dose is the priority.

Impact of EDP-M on survival of patients with metastatic adrenocortical carcinoma: A population-based study.

INTRODUCTION: Historically, stage IV adrenocortical carcinoma (mACC) has a poor prognosis with a median overall survival (OS) of only 5 months. Based on the FIRM-ACT trial published in 2012, guidelines now advise first line systemic treatment with etoposide, cisplatin, doxorubicin and mitotane (EDP-M). The effect of EDP-M on patient survival in clinical practice in the Netherlands is unknown. METHODS: The data of all patients with mACC (2005-2020) were obtained from the Netherlands comprehensive cancer organization (IKNL). The effect of EDP-M on patient survival was assessed using Kaplan-Meier analysis and multivariate Cox regression analysis including clinical, therapy and tumor characteristics. RESULTS: In total 167 patients with mACC were included. For patients diagnosed from 2014 onwards, EDP-M (in 22 patients (22%)) lead to a numerically but not statistically significant improved OS compared to those not receiving EDP-M (11.8 vs 5.6 months, p = 0.525). For systemic treatments, patients treated with mitotane only had the best 5-year OS (11.4%, p = 0.006) regardless of year of diagnosis. In multivariate Cox regression analysis EPD-M was not associated with OS; palliative adrenalectomy (HR: 0.26, p = <.001) and local treatment of metastases (HR: 0.35, p = 0.001) were associated with a better OS and a primary tumor Ki-67 index > 20% (HR: 2.67, p = 0.003) with a worse OS from 2014 onwards. Patients diagnosed before 2014 had a significantly poorer OS compared to from 2014 onwards (5-yr: 4.5 vs 8.4%, OS: 6.8 vs 8.3 months, p = 0.032). CONCLUSION: OS for mACC in the Netherlands has improved in the last decade. Receiving EDP-M did not significantly improve OS for patients with mACC. The use of multimodality treatment including palliative adrenalectomy, mitotane and local treatment of (oligo-)metastases in appropriately selected patients has improved the OS for mACC patients since 2014.

Stereotactic Body Radiation Therapy for Spinal Metastases: Benefits and Limitations.

Progress in biological cancer characterization, targeted systemic therapies and multimodality treatment strategies have shifted the goals of radiotherapy for spinal metastases from short-term palliation to long-term symptom control and prevention of compilations. This article gives an overview of the spine stereotactic body radiotherapy (SBRT) methodology and clinical results of SBRT in cancer patients with painful vertebral metastases, metastatic spinal cord compression, oligometastatic disease and in a reirradiation situation. Outcomes after dose-intensified SBRT are compared with results of conventional radiotherapy and patient selection criteria will be discussed. Though rates of severe toxicity after spinal SBRT are low, strategies to minimize the risk of vertebral compression fracture, radiation induced myelopathy, plexopathy and myositis are summarized, to optimize the use of SBRT in multidisciplinary management of vertebral metastases.

Impact of imperfection in medical imaging data on deep learning-based segmentation performance: An experimental study using synthesized data.

BACKGROUND: Clinical data used to train deep learning models are often not clean data. They can contain imperfections in both the imaging data and the corresponding segmentations. PURPOSE: This study investigates the influence of data imperfections on the performance of deep learning models for parotid gland segmentation. This was done in a controlled manner by using synthesized data. The insights this study provides may be used to make deep learning models better and more reliable. METHODS: The data were synthesized by using the clinical segmentations, creating a pseudo ground-truth in the process. Three kinds of imperfections were simulated: incorrect segmentations, low image contrast, and artifacts in the imaging data. The severity of each imperfection was varied in five levels. Models resulting from training sets from each of the five levels were cross-evaluated with test sets from each of the five levels. RESULTS: Using synthesized data led to almost perfect parotid gland segmentation when no error was added. Lowering the quality of the parotid gland segmentations used for training substantially lowered the model performance. Additionally, lowering the image quality of the training data by decreasing the contrast or introducing artifacts made the resulting models more robust to data containing those respective kinds of data imperfection. CONCLUSION: This study demonstrated the importance of good-quality segmentations for deep learning training and it shows that using low-quality imaging data for training can enhance the robustness of the resulting models.

Deep learning-based markerless lung tumor tracking in stereotactic radiotherapy using Siamese networks.

BACKGROUND: Radiotherapy (RT) is involved in about 50% of all cancer patients, making it a very important treatment modality. The most common type of RT is external beam RT, which consists of delivering the radiation to the tumor from outside the body. One novel treatment delivery method is volumetric modulated arc therapy (VMAT), where the gantry continuously rotates around the patient during the radiation delivery. PURPOSE: Accurate tumor position monitoring during stereotactic body radiotherapy (SBRT) for lung tumors can help to ensure that the tumor is only irradiated when it is inside the planning target volume. This can maximize tumor control and reduce uncertainty margins, lowering organ-at-risk dose. Conventional tracking methods are prone to errors, or have a low tracking rate, especially for small tumors that are in close vicinity to bony structures. METHODS: We investigated patient-specific deep Siamese networks for real-time tumor tracking, during VMAT. Due to lack of ground truth tumor locations in the kilovoltage (kV) images, each patient-specific model was trained on synthetic data (DRRs), generated from the 4D planning CT scans, and evaluated on clinical data (x-rays). Since there are no annotated datasets with kV images, we evaluated the model on a 3D printed anthropomorphic phantom but also on six patients by computing the correlation coefficient with the breathing-related vertical displacement of the surface-mounted marker (RPM). For each patient/phantom, we used 80% of DRRs for training and 20% for validation. RESULTS: The proposed Siamese model outperformed the conventional benchmark template matching-based method (RTR): (1) when evaluating both methods on the 3D phantom, the Siamese model obtained a 0.57-0.79-mm mean absolute distance to the ground truth tumor locations, compared to 1.04-1.56 mm obtained by RTR; (2) on patient data, the Siamese-determined longitudinal tumor position had a correlation coefficient of 0.71-0.98 with the RPM, compared to 0.07-0.85 for RTR; (3) the Siamese model had a 100% tracking rate, compared to 62%-82% for RTR. CONCLUSIONS: Based on these results, we argue that Siamese-based real-time 2D markerless tumor tracking during radiation delivery is possible. Further investigation and development of 3D tracking is warranted.

Dose distribution prediction for head-and-neck cancer radiotherapy using a generative adversarial network: influence of input data.

Purpose: A three-dimensional deep generative adversarial network (GAN) was used to predict dose distributions for locally advanced head and neck cancer radiotherapy. Given the labor- and time-intensive nature of manual planning target volume (PTV) and organ-at-risk (OAR) segmentation, we investigated whether dose distributions could be predicted without the need for fully segmented datasets. Materials and methods: GANs were trained/validated/tested using 320/30/35 previously segmented CT datasets and treatment plans. The following input combinations were used to train and test the models: CT-scan only (C); CT+PTVboost/elective (CP); CT+PTVs+OARs+body structure (CPOB); PTVs+OARs+body structure (POB); PTVs+body structure (PB). Mean absolute errors (MAEs) for the predicted dose distribution and mean doses to individual OARs (individual salivary glands, individual swallowing structures) were analyzed. Results: For the five models listed, MAEs were 7.3 Gy, 3.5 Gy, 3.4 Gy, 3.4 Gy, and 3.5 Gy, respectively, without significant differences among CP-CPOB, CP-POB, CP-PB, among CPOB-POB. Dose volume histograms showed that all four models that included PTV contours predicted dose distributions that had a high level of agreement with clinical treatment plans. The best model CPOB and the worst model PB (except model C) predicted mean dose to within ±3 Gy of the clinical dose, for 82.6%/88.6%/82.9% and 71.4%/67.1%/72.2% of all OARs, parotid glands (PG), and submandibular glands (SMG), respectively. The R2 values (0.17/0.96/0.97/0.95/0.95) of OAR mean doses for each model also indicated that except for model C, the predictions correlated highly with the clinical dose distributions. Interestingly model C could reasonably predict the dose in eight patients, but on average, it performed inadequately. Conclusion: We demonstrated the influence of the CT scan, and PTV and OAR contours on dose prediction. Model CP was not statistically different from model CPOB and represents the minimum data statistically required to adequately predict the clinical dose distribution in a group of patients.

Single Ultra-High Dose Rate Proton Transmission Beam for Whole Breast FLASH-Irradiation: Quantification of FLASH-Dose and Relation with Beam Parameters.

Healthy tissue-sparing effects of FLASH (≥40 Gy/s, ≥4-8 Gy/fraction) radiotherapy (RT) make it potentially useful for whole breast irradiation (WBI), since there is often a lot of normal tissue within the planning target volume (PTV). We investigated WBI plan quality and determined FLASH-dose for various machine settings using ultra-high dose rate (UHDR) proton transmission beams (TBs). While five-fraction WBI is commonplace, a potential FLASH-effect might facilitate shorter treatments, so hypothetical 2- and 1-fraction schedules were also analyzed. Using one tangential 250 MeV TB delivering 5 × 5.7 Gy, 2 × 9.74 Gy or 1 × 14.32 Gy, we evaluated: (1) spots with equal monitor units (MUs) in a uniform square grid with variable spacing; (2) spot MUs optimized with a minimum MU-threshold; and (3) splitting the optimized TB into two sub-beams: one delivering spots above an MU-threshold, i.e., at UHDRs; the other delivering the remaining spots necessary to improve plan quality. Scenarios 1-3 were planned for a test case, and scenario 3 was also planned for three other patients. Dose rates were calculated using the pencil beam scanning dose rate and the sliding-window dose rate. Various machine parameters were considered: minimum spot irradiation time (minST): 2 ms/1 ms/0.5 ms; maximum nozzle current (maxN): 200 nA/400 nA/800 nA; two gantry-current (GC) techniques: energy-layer and spot-based. For the test case (PTV = 819 cc) we found: (1) a 7 mm grid achieved the best balance between plan quality and FLASH-dose for equal-MU spots; (2) near the target boundary, lower-MU spots are necessary for homogeneity but decrease FLASH-dose; (3) the non-split beam achieved >95% FLASH for favorable (not clinically available) machine parameters (SB GC, low minST, high maxN), but <5% for clinically available settings (EB GC, minST = 2 ms, maxN = 200 nA); and (4) splitting gave better plan quality and higher FLASH-dose (~50%) for available settings. The clinical cases achieved ~50% (PTV = 1047 cc) or >95% (PTV = 477/677 cc) FLASH after splitting. A single UHDR-TB for WBI can achieve acceptable plan quality. Current machine parameters limit FLASH-dose, which can be partially overcome using beam-splitting. WBI FLASH-RT is technically feasible.

Focal 18 F-FDG uptake predicts progression of pre-invasive squamous bronchial lesions to invasive cancers.

INTRODUCTION: Pre-invasive squamous lesions of the central airways can progress into invasive lung cancers. Identifying these high-risk patients could enable detection of invasive lung cancers at an early stage. In this study, we investigated the value of 18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography (PET) scans in predicting progression in patients with pre-invasive squamous endobronchial lesions. METHODS: In this retrospective study, patients with pre-invasive endobronchial lesions, who underwent an 18 F-FDG PET scan at the VU University Medical Center Amsterdam, between January 2000 and December 2016, were included. Autofluorescence bronchoscopy (AFB) was used for tissue sampling and was repeated every 3 months. The minimum and median follow-up was 3 and 46.5 months. Study endpoints were the occurrence of biopsy proven invasive carcinoma, time-to-progression and overall survival (OS). RESULTS: A total number of 40 of 225 patients met the inclusion criteria of which 17 (42.5%) patients had a positive baseline 18 F-FDG PET scan. A total of 13 of 17 (76.5%) developed invasive lung carcinoma during follow-up, with a median time to progression of 5.0 months (range, 3.0-25.0). In 23 (57.5%) patients with a negative 18 F-FDG PET scan at baseline, 6 (26%) developed lung cancer, with a median time to progression of 34.0 months (range, 14.0-42.0 months, p < 0.002). With a median OS of 56.0 months (range, 9.0-60.0 months) versus 49.0 months (range, 6.0-60.0 months) (p = 0.876) for the 18 F-FDG PET positive and negative groups, respectively. CONCLUSIONS: Patients with pre-invasive endobronchial squamous lesions and a positive baseline 18 F-FDG PET scan were at high-risk for developing lung carcinoma, highlighting that this patient group requires early radical treatment.