Clinical implications of dose to functional lung volumes in the trimodality treatment of esophageal cancer.

BACKGROUND: Trimodality treatment, i.e., neoadjuvant chemoradiotherapy (nCRT) followed by surgery, for locally advanced esophageal cancer (EC) improves overall survival but also increases the risk of postoperative pulmonary complications. Here, we tried to identify a relation between dose to functional lung volumes (FLV) as determined by 4D-CT scans in EC patients and treatment-related lung toxicity. MATERIALS AND METHODS: All patients with EC undergoing trimodality treatment between 2017 and 2022 in UZ Leuven and scanned with 4D-CT-simulation were selected. FLVs were determined based on Jacobian determinants of deformable image registration between maximum inspiration and expiration phases. Dose/volume parameters of the anatomical lung volume (ALV) and FLV were compared between patients with versus without postoperative pulmonary complications. Results of pre- and post-nCRT pulmonary function tests (PFTs) were collected and compared in relation to radiation dose. RESULTS: Twelve out of 51 EC patients developed postoperative pulmonary complications. ALV was smaller while FLV10Gy and FLV20Gy were larger in patients with complications (respectively 3141 ± 858mL vs 3601 ± 635mL, p = 0.025; 360 ± 216mL vs 264 ± 139mL, p = 0.038; 166 ± 106mL vs 118 ± 63mL, p = 0.030). No differences in ALV dose-volume parameters were detected. Baseline FEV1 and TLC were significantly lower in patients with complications (respectively 90 ± 17%pred vs 102 ± 20%pred, p = 0.033 and 93 ± 17%pred vs 110 ± 13%pred, p = 0.001), though no other PFTs were significantly different between both groups. DLCO was the only PFT that had a meaningful decrease after nCRT (85 ± 17%pred vs 68 ± 15%pred, p < 0.001) but was not related to dose to ALV/FLV. CONCLUSION: Small ALV and increasing FLV exposed to intermediate (10 to 20 Gy) dose are associated to postoperative pulmonary complications. Changes of DLCO occur during nCRT but do not seem to be related to radiation dose to ALV or FLV. This information could attribute towards toxicity risk prediction and reduction strategies for EC.

Stroke rate after external fractionated radiotherapy for benign meningioma.

PURPOSE: Patients with a benign meningioma often have a long survival following the treatment of their meningioma. Since radiotherapy is frequently part of the treatment, long-term side effects are of considerable concern. A controversial long-term side effect of radiotherapy is stroke. Due to its severity, it is important to know the frequency of this side effect. The aim of this study was to assess the stroke incidence and risk factors among patients receiving radiotherapy for their benign meningioma. METHODS: We performed a retrospective database study of patients who underwent primary or adjuvant radiotherapy for their benign meningioma at University Hospitals Leuven from January 2003 to December 2017. RESULTS: We included 169 patients with a median age of 51 years (range 22-84). Every patient received fractionated radiotherapy using photons with a median dose of 56 Gy (range 54-56) in fractions of 2 Gy (range 1.8-2). The median follow-up was 5.3 years (range 0.1-14). The cumulative stroke incidence function showed an incidence of 11.6% after 9 years of follow-up, translating to a stroke incidence per year of 1.29%. We found two significant risk factors for stroke: medically treated arterial hypertension (p = 0.005) and history of previous stroke or transient ischemic attack (p < 0.001). 5-year local control and overall survival rates were respectively 97.4% and 91.2%. Other late grade III/IV toxicities occurred in 16.0% (27/169) of patients. CONCLUSION: Our study shows a higher incidence of stroke in patients who received radiotherapy for their benign meningioma compared to the general population.

Development and External Validation of a Multiparametric Magnetic Resonance Imaging and International Society of Urological Pathology Based Add-On Prediction Tool to Identify Prostate Cancer Candidates for Pelvic Lymph Node Dissection.

PURPOSE: We sought to expand current prediction tools for lymph node invasion in patients with prostate cancer using current state-of-the-art available tumor information, including multiparametric magnetic resonance imaging based tumor stage and detailed biopsy information. MATERIALS AND METHODS: We selected patients with prostate cancer for study who had available registered information on ISUP (International Society of Urological Pathology) based biopsy grading and multiparametric magnetic resonance imaging, and who had undergone radical prostatectomy with extended pelvic lymph node dissection. We developed a lymph node invasion prediction tool in 420 patients and externally validated it in 187. A concordance index was estimated to quantify the discriminative performance of the model. RESULTS: In the development cohort a median of 21 lymph nodes were removed per patient and 71 patients (16.9%) were diagnosed with lymph node invasion. Statistically significant predictors of lymph node invasion were the initial prostate specific antigen value, multiparametric magnetic resonance imaging based T stage, maximum tumor length in 1 core in mm and ISUP grade group corresponding to the maximum tumor involvement in 1 core. The predictive accuracy of this lymph node invasion prediction tool was 79.7% after fivefold internal cross validation and 72.5% after external validation. CONCLUSIONS: We report a contemporary, externally validated prediction tool for lymph node invasion in patients with prostate cancer. This prediction tool is a response to the paradigm shift from systematic to targeted biopsies by incorporating additional core specific biopsy information instead of the percent of positive cores. This new tool will also overcome stage migration, which is a potential risk when multiparametric magnetic resonance imaging information is used in digital rectal examination based nomograms.

Stereotactic robotic body radiotherapy for patients with oligorecurrent pulmonary metastases.

BACKGROUND: Our aim is to report treatment efficacy and toxicity of patients treated by robotic (Cyberknife®) stereotactic body radiotherapy (SBRT) for oligorecurrent lung metastases (ORLM). Additionally we wanted to evaluate influence of tumor, patient and treatment related parameters on local control (LC), lung and distant progression free- (lung PFS/Di-PFS) and overall survival (OS). METHODS: Consecutive patients with up to 5 ORLM (confirmed by FDG PET/CT) were included in this study. Intended dose was 60Gy in 3 fractions (prescribed to the 80% isodose volume). Patients were followed at regular intervals and tumor control and toxicity was prospectively scored. Tumor, patient and treatment data were analysed using competing risk- and Cox regression. RESULTS: Between May 2010 and March 2016, 104 patients with 132 lesions were irradiated from primary lung carcinoma (47%), gastro-intestinal (34%) and mixed primary histologies (19%). The mean tumor volume was 7.9 cc. After a median follow up of 22 months, the 1, 2 and 3 year LC rate (per lesion) was 89.3, 80.0 and 77.8% respectively. The corresponding (per patient) 1, 2 and 3 years lung PFS were 66.3, 50.0, 42.6%, Di-PFS were 80.5, 64.4, 60.6% and OS rates were 92.2, 80.9 and 72.0% respectively. On univariable analysis, gastro-intestinal (GI) as primary tumor site showed a significant superior local control versus the other primary tumor sites. For OS, significant variables were primary histology and primary tumor site with a superior OS for patients with metastases of primary GI origin. LC was significantly affected by the tumor volume, physical and biologically effective dose coverage. Significant variables in multivariable analysis were BED prescription dose for LC and GI as primary site for OS. The vast majority of patients developed no toxicity or grade 1 acute and late toxicity. Acute and late grade 3 radiation pneumonitis (RP) was observed in 1 and 2 patients respectively. One patient with a centrally located lesion developed grade 4 RP and died due to possible RT-induced pulmonary hemorrhage. CONCLUSIONS: SBRT is a highly effective local therapy for oligorecurrent lung metastases and could achieve long term survival in patients with favourable prognostic features.

Regional lung avoidance by CT numbers to reduce radiation-induced lung damage risk in non-small-cell lung cancer: a simulation study.

Background: Selective avoidance aims at sparing functional lung regions. Here, we preferentially direct radiation to irreversibly nonfunctional lung areas based on planning CT imaging to reduce functional lung damage.Materials and methods: For 12 stage I-IV NSCLC patients, 5 lung substructures were segmented on the planning CT, combining voxels <-900HU, -900HU to -801HU, -800HU to -701HU, -700HU to -601HU and ≥-600HU (Level 1 to 5). Two VMAT plans were optimized: a reference plan blinded from substructures and a selective avoidance plan (AV) imposing gradually stricter constraints on Level 1-5, based on previously validated associations between lung subvolume baseline density and density increase (ΔHU) after treatment. Characteristics of treatment plans were evaluated, including subvolumes, dose, and predicted ΔHU (with reported 95% CI reflecting prediction model uncertainty).Results: Segmented substructures were on average 477 cc, 1157 cc, 484 cc, 69 cc, and 123 cc (Level 1-5). AV plans could spare Level 3-5, e.g., mean dose decrease of 3.5 Gy (range 0.6 Gy; 6.0 Gy) for Level 5, p<.001. This significantly reduced the average lung mass with predicted ΔHU>20HU by 12.5 g (95% CI: 5.4-16.9) and 27.1 g (95% CI: 10.2-32.9) for a median and upper 10th percentile patient susceptibility for damage simulation, respectively.Conclusions: Lung damage avoidance based on CT density is feasible and easy to implement. A biomarker providing a reliable selection of patients with high susceptibility for lung damage will be crucial to show the clinical relevance of this avoidance planning strategy.

Validation of a normal tissue complication probability model for late unfavourable aesthetic outcome after breast-conserving therapy.

PURPOSE: To validate a normal tissue complication probability (NTCP) model for late unfavourable aesthetic outcome (AO) after breast-conserving therapy. MATERIALS/METHODS: The BCCT.core software evaluated the AO using standardized photographs of patients treated at the University Hospitals Leuven between April 2015 and April 2016. Dose maps in 2 Gy equivalents were calculated assuming α/ß = 3.6 Gy. The discriminating ability of the model was described by the AUC of the receiver operating characteristic curve. A 95% confidence interval (CI) of AUC was calculated using 10,000 bootstrap replications. Calibration was evaluated with the calibration plot and Nagelkerke R2. Patients with unfavourable AO at baseline were excluded. Patient, tumour and treatment characteristics were compared between the development and the validation cohort. The prognostic value of the characteristics in the validation cohort was further evaluated in univariable and multivariable analysis. RESULTS: Out of 175 included patients, 166 were evaluated two years after RT and 44 (26.51%) had unfavourable AO. AUC was 0.66 (95% CI 0.56; 0.76). Calibration was moderate with small overestimations at higher risk. When applying all of the univariable significant clinicopathological and dosimetrical variables from the validation cohort in a multivariable model, the presence of a seroma and V45 were selected as significant risk factors for unfavourable AO (Odds Ratio 4.40 (95% CI 1.96; 9.86) and 1.14 (95% CI 1.03; 1.27), p-value <.001 and .01, respectively). CONCLUSIONS: The NTCP model for unfavourable AO shows a moderate discrimination and calibration in the present prospective validation cohort with a small overestimation in the high risk patients.

Development of a normal tissue complication probability model for late unfavourable aesthetic outcome after breast-conserving therapy.

PURPOSE/OBJECTIVES: To develop a normal tissue complication probability (NTCP) model for late unfavourable aesthetic outcome (AO) after breast-conserving therapy. MATERIAL AND METHODS: The BCCT.core software evaluated the AO using standardized photographs of patients treated between 2009 and 2014. Dose maps in 2 Gy equivalents were calculated assuming α/ß = 3.6 Gy. Uni- and multivariable logistic regression analysis was performed to study the predictive value of clinicopathological and dosimetric variables for unfavourable AO. The Lyman Kutcher Burman (LKB) model was fit to the data with dose modifying factors (dmf). Model performance was assessed with the area under the curve (AUC) of the receiver operating characteristic curve and bootstrap sampling. RESULTS: Forty-four of the 121 analysed patients (36%) developed unfavourable AO. In the optimal multivariable logistic regression model, a larger breast volume receiving ≥55 Gy (V55), a seroma and an axillary lymph node dissection (ALND) were independently associated with an unfavourable AO, AUC = 0.75 (95%CI 0.64;0.85). Beta-estimates were -2.68 for ß0, 0.057 for V55, 1.55 for seroma and 1.20 for ALND. The optimal LKB model parameters were EUD3.6(50) = 63.3 Gy, n = 1.00, m = 0.23, dmf(seroma) = 0.83 and dmf(ALND) = 0.84, AUC = 0.74 (95%CI 0.61;0.83). CONCLUSIONS: An NTCP model for late unfavourable AO after breast-conserving therapy was developed including seroma, axillary lymphadenectomy and V55.

Is there a different dose-effect relation between the primary tumor and involved lymph nodes in locally advanced non-small-cell lung cancer? A hypothesis-generating study.

PURPOSE: It is unknown whether the dose-response relation of the primary tumor in NSCLC is different from that of the involved lymph nodes (LN). As the recurrence rate is much lower in LN, we hypothesized that LN need a lower radiation dose. MATERIAL AND METHODS: A retrospective analysis of prospective data was performed on patients with locally advanced NSCLC treated with (chemo)radiotherapy. The impact of EQD2,T prescription dose on relapse was analyzed using Cox regression modeling correcting for baseline diameter. RESULTS: From 2006 to 2010, 75 consecutive patients were included, resulting in 142 lymph nodes in the analysis. Any relapse (locoregional/distant) occurred in 58 patients (77%), while involved nodal relapse (INR) was observed in 13% of patients. No dose-response relationship was observed for INR (p = .22). Primary tumor progression was seen in 40% of patients together with a significant dose-response relationship (p = .033). Baseline nodal diameter was not associated with INR (p = .76), while primary tumor diameter was a highly significant predictor for relapse (p = .0031). CONCLUSIONS: These results suggest that LN control may be achieved at lower radiation doses than needed for the primary tumor. Prospective dose de-escalation studies on LN are warranted to decrease the incidence of severe esophagitis without compromising local tumor control.

Optimal gross tumor volume definition in lung-sparing intensity modulated radiotherapy for pleural mesothelioma: an in silico study.

BACKGROUND: The gross tumor volume (GTV) definition for malignant pleural mesothelioma (MPM) is ill-defined. We therefore investigated which imaging modality is optimal: computed tomography (CT) with intravenous contrast (IVC), positron emission tomography-CT (PET/CT) or magnetic resonance imaging (MRI). MATERIAL AND METHODS: Sixteen consecutive patients with untreated stage I-IV MPM were included. Patients with prior pleurodesis were excluded. CT with IVC, 18FDG-PET/CT and MRI (T2 and contrast-enhanced T1) were obtained. CT was rigidly co-registered with PET/CT and with MRI. Three sets of pleural GTVs were defined: GTVCT, GTVCT+PET/CT and GTVCT+MRI. Quantitative and qualitative evaluations of the contoured GTVs were performed. RESULTS: Compared to CT-based GTV definition, PET/CT identified additional tumor sites (defined as either separate nodules or greater extent of a known tumor) in 12/16 patients. Compared to either CT or PET/CT, MRI identified additional tumor sites in 15/16 patients (p = .7). The mean GTVCT, GTVCT+PET/CT and GTVCT+MRI [±standard deviation (SD)] were 630.1 cm3 (±302.81), 640.23 cm3 (±302.83) and 660.8 cm3 (±290.8), respectively. Differences in mean volumes were not significant. The mean Jaccard Index was significantly lower in MRI-based contours versus all the others. CONCLUSION: As MRI identified additional pleural disease sites in the majority of patients, it may play a role in optimal target volume definition.

The photon dose calculation algorithm used in breast radiotherapy has significant impact on the parameters of radiobiological models.

The comparison of the pencil beam dose calculation algorithm with modified Batho heterogeneity correction (PBC-MB) and the analytical anisotropic algorithm (AAA) and the mutual comparison of advanced dose calculation algorithms used in breast radiotherapy have focused on the differences between the physical dose distributions. Studies on the radiobiological impact of the algorithm (both on the tumor control and the moderate breast fibrosis prediction) are lacking. We, therefore, investigated the radiobiological impact of the dose calculation algorithm in whole breast radiotherapy. The clinical dose distributions of 30 breast cancer patients, calculated with PBC-MB, were recalculated with fixed monitor units using more advanced algorithms: AAA and Acuros XB. For the latter, both dose reporting modes were used (i.e., dose-to-medium and dose-to-water). Next, the tumor control probability (TCP) and the normal tissue complication probability (NTCP) of each dose distribution were calculated with the Poisson model and with the relative seriality model, respectively. The endpoint for the NTCP calculation was moderate breast fibrosis five years post treatment. The differences were checked for significance with the paired t-test. The more advanced algorithms predicted a significantly lower TCP and NTCP of moderate breast fibrosis then found during the corresponding clinical follow-up study based on PBC calculations. The differences varied between 1% and 2.1% for the TCP and between 2.9% and 5.5% for the NTCP of moderate breast fibrosis. The significant differences were eliminated by determination of algorithm-specific model parameters using least square fitting. Application of the new parameters on a second group of 30 breast cancer patients proved their appropriateness. In this study, we assessed the impact of the dose calculation algorithms used in whole breast radiotherapy on the parameters of the radiobiological models. The radiobiological impact was eliminated by determination of algorithm specific model parameters.

Balancing robustness and adaptation rate for proton therapy of lung cancer patients.

INTRODUCTION: An increase in plan robustness leads to a higher dose to organs-at-risk (OARs), and an increased chance of post-treatment toxicities. In contrast, more conformal plans lead to sparing of healthy surrounding tissue at the expense of a higher sensitivity to anatomical changes, requiring costly adaptations. In this study, we assess the trade-off and impact of treatment plan robustness on the adaptation rate. METHOD: Treatment planning was performed for 40 lung cancer patients, each having a planning 4DCT and up to eight weekly repeated 4DCTs (reCTs). For each patient, plans were made with three different levels of robustness based on setup uncertainty of 3, 6 and 9 mm. These plans were robustly re-evaluated on all reCTs to assess whether the clinical constraints were met. RESULTS: For the 3, 6 and 9 mm robustness levels, adaptation rates of 87.5 %, 70.0 % and 57.5 %, respectively, were observed. A mean absolute normal tissue complication probability (NTCP) gain of 2.9 percentage points (pp) was calculated for pneumonitis grade ≥ 2 when transitioning from 9 mm plans to 3 mm plans, 7.6 pp for esophagitis grade ≥ 2, and 2.5 pp for mortality risk 2 years post-treatment. CONCLUSION: The lowered risk of post treatment toxicities at lower robustness levels is clinically relevant but comes at the expense of more treatment adaptations, particularly in cases where meeting our clinical goals is not compromised by having a dose that is more conformal to the target. The trade-off between workload and reduced NTCP needs to be individually assessed.

Quantification of radiation-induced lung damage with CT scans: the possible benefit for radiogenomics.

BACKGROUND: Radiation-induced lung damage (RILD) is an important problem. Although physical parameters such as the mean lung dose are used in clinical practice, they are not suited for individualised radiotherapy. Objective, quantitative measurements of RILD on a continuous instead of on an ordinal, semi-quantitative, semi-subjective scale, are needed. METHODS: Hounsfield unit (HU) changes before versus three months post-radiotherapy were correlated per voxel with the radiotherapy dose in 95 lung cancer patients. Deformable registration was used to register pre- and post-CT scans and the density increase was quantified for various dose bins. The dose-response curve for increased HU was quantified using the slope of a linear regression (HU/Gy). The end-point for the toxicity analysis was dyspnoea ≥ grade 2. RESULTS: Radiation dose was linearly correlated with the change in HU (mean R(2) = 0.74 ± 0.28). No differences in HU/Gy between groups treated with stereotactic radiotherapy, conventional radiotherapy alone, sequential or concurrent chemo- radiotherapy were observed. In the whole patient group, 33/95 (34.7%) had dyspnoea ≥ G2. Of the 48 patients with a HU/Gy below the median, 16 (33.3%) developed dyspnoea ≥ G2, while in the 47 patients with a HU/Gy above the median, 17 (36.1%) had dyspnoea ≥ G2 (not significant). Individual patients showed a nearly 21-fold difference in radiosensitivity, with HU/Gy ranging from 0 to 10 HU/Gy. CONCLUSIONS: HU changes identify objectively the whole range of individual radiosensitivity on a continuous, quantitative scale. CT density changes may allow more robust and accurate radiogenomics studies.

Low-dose CT allows for accurate proton therapy dose calculation and plan optimization.

Objective.Protons offer a more conformal dose delivery compared to photons, yet they are sensitive to anatomical changes over the course of treatment. To minimize range uncertainties due to anatomical variations, a new CT acquisition at every treatment session would be paramount to enable daily dose calculation and subsequent plan adaptation. However, the series of CT scans results in an additional accumulated patient dose. Reducing CT radiation dose and thereby decreasing the potential risk of radiation exposure to patients is desirable, however, lowering the CT dose results in a lower signal-to-noise ratio and therefore in a reduced quality image. We hypothesized that the signal-to-noise ratio provided by conventional CT protocols is higher than needed for proton dose distribution estimation. In this study, we aim to investigate the effect of CT imaging dose reduction on proton therapy dose calculations and plan optimization.Approach.To verify our hypothesis, a CT dose reduction simulation tool has been developed and validated to simulate lower-dose CT scans from an existing standard-dose scan. The simulated lower-dose CTs were then used for proton dose calculation and plan optimization and the results were compared with those of the standard-dose scan. The same strategy was adopted to investigate the effect of CT dose reduction on water equivalent thickness (WET) calculation to quantify CT noise accumulation during integration along the beam.Main results.The similarity between the dose distributions acquired from the low-dose and standard-dose CTs was evaluated by the dose-volume histogram and the 3D Gamma analysis. The results on an anthropomorphic head phantom and three patient cases indicate that CT imaging dose reduction up to 90% does not have a significant effect on proton dose calculation and plan optimization. The relative error was employed to evaluate the similarity between WET maps and was found to be less than 1% after reducing the CT imaging dose by 90%.Significance.The results suggest the possibility of using low-dose CT for proton therapy dose estimation, since the dose distributions acquired from the standard-dose and low-dose CTs are clinically equivalent.

Automated clinical decision support system with deep learning dose prediction and NTCP models to evaluate treatment complications in patients with esophageal cancer.

BACKGROUND AND PURPOSE: This study aims to investigate how accurate our deep learning (DL) dose prediction models for intensity modulated radiotherapy (IMRT) and pencil beam scanning (PBS) treatments, when chained with normal tissue complication probability (NTCP) models, are at identifying esophageal cancer patients who are at high risk of toxicity and should be switched to proton therapy (PT). MATERIALS AND METHODS: Two U-Net were created, for photon (XT) and proton (PT) plans, respectively. To estimate the dose distribution for each patient, they were trained on a database of 40 uniformly planned patients using cross validation and a circulating test set. These models were combined with a NTCP model for postoperative pulmonary complications. The NTCP model used the mean lung dose, age, histology type, and body mass index as predicting variables. The treatment choice is then done by using a ΔNTCP threshold between XT and PT plans. Patients with ΔNTCP ≥ 10% were referred to PT. RESULTS: Our DL models succeed in predicting dose distributions with a mean error on the mean dose to the lungs (MLD) of 1.14 ± 0.93% for XT and 0.66 ± 0.48% for PT. The complete automated workflow (DL chained with NTCP) achieved 100% accuracy in patient referral. The average residual (ΔNTCP ground truth - ΔNTCP predicted) is 1.43 ± 1.49%. CONCLUSION: This study evaluates our DL dose prediction models in a broader patient referral context and demonstrates their ability to support clinical decisions.

Treatment planning comparison in the PROTECT-trial randomising proton versus photon beam therapy in oesophageal cancer: Results from eight European centres.

PURPOSE: To compare dose distributions and robustness in treatment plans from eight European centres in preparation for the European randomized phase-III PROTECT-trial investigating the effect of proton therapy (PT) versus photon therapy (XT) for oesophageal cancer. MATERIALS AND METHODS: All centres optimized one PT and one XT nominal plan using delineated 4DCT scans for four patients receiving 50.4 Gy (RBE) in 28 fractions. Target volume receiving 95% of prescribed dose (V95%iCTVtotal) should be >99%. Robustness towards setup, range, and respiration was evaluated. The plans were recalculated on a surveillance 4DCT (sCT) acquired at fraction ten and robustness evaluation was performed to evaluate the effect of respiration and inter-fractional anatomical changes. RESULTS: All PT and XT plans complied with V95%iCTVtotal >99% for the nominal plan and V95%iCTVtotal >97% for all respiratory and robustness scenarios. Lung and heart dose varied considerably between centres for both modalities. The difference in mean lung dose and mean heart dose between each pair of XT and PT plans was in median [range] 4.8 Gy [1.1;7.6] and 8.4 Gy [1.9;24.5], respectively. Patients B and C showed large inter-fractional anatomical changes on sCT. For patient B, the minimum V95%iCTVtotal in the worst-case robustness scenario was 45% and 94% for XT and PT, respectively. For patient C, the minimum V95%iCTVtotal was 57% and 72% for XT and PT, respectively. Patient A and D showed minor inter-fractional changes and the minimum V95%iCTVtotal was >85%. CONCLUSION: Large variability in dose to the lungs and heart was observed for both modalities. Inter-fractional anatomical changes led to larger target dose deterioration for XT than PT plans.

Overview of health-related quality of life and toxicity of non-small cell lung cancer patients receiving curative-intent radiotherapy in a real-life setting (the REQUITE study).

OBJECTIVES: Radiotherapy-induced toxicity may negatively impact health-related quality of life (HRQoL). This report investigates the impact of curative-intent radiotherapy on HRQoL and toxicity in early stage and locally-advanced non-small cell lung cancer patients treated with radiotherapy or chemo-radiotherapy enrolled in the observational prospective REQUITE study. MATERIALS AND METHODS: HRQoL was assessed using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire up to 2 years post radiotherapy. Eleven toxicities were scored by clinicians using the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Toxicity scores were calculated by subtracting baseline values. Mixed model analyses were applied to determine statistical significance (p ≤ 0.01). Meaningful clinical important differences (MCID) were determined for changes in HRQoL. Analysis was performed on the overall data, different radiotherapy techniques, multimodality treatments and disease stages. RESULTS: Data of 510 patients were analysed. There was no significant change in HRQoL or its domains, except for deterioration in cognitive functioning (p = 0.01). Radiotherapy technique had no significant impact on HRQoL. The addition of chemotherapy was significantly associated with HRQoL over time (p <.001). Overall toxicity did not significantly change over time. Acute toxicities of radiation-dermatitis (p =.003), dysphagia (p =.002) and esophagitis (p <.001) peaked at 3 months and decreased thereafter. Pneumonitis initially deteriorated but improved significantly after 12 months (p =.011). A proportion of patients experienced meaningful clinically important improvements and deteriorations in overall HRQoL and its domains. In some patients, pre-treatment symptoms improved gradually. CONCLUSIONS: While overall HRQoL and toxicity did not change over time, some patients improved, whereas others experienced acute radiotherapy-induced toxicities and deteriorated HRQoL, especially physical and cognitive functioning. Patient characteristics, more so than radiotherapy technique and treatment modality, impact post-radiotherapy toxicity and HRQoL outcomes. This stresses the importance of considering the potential impact of radiotherapy on individuals' HRQoL, symptoms and toxicity in treatment decision-making.

The correlation between pre-treatment symptoms, acute and late toxicity and patient-reported health-related quality of life in non-small cell lung cancer patients: Results of the REQUITE study.

BACKGROUND AND PURPOSE: To investigate the association between clinician-scored toxicities and patient-reported health-related quality of life (HRQoL), in early-stage (ES-) and locally-advanced (LA-) non-small cell lung cancer (NSCLC) patients receiving loco-regional radiotherapy, included in the international real-world REQUITE study. MATERIALS AND METHODS: Clinicians scored eleven radiotherapy-related toxicities (and baseline symptoms) with the Common Terminology Criteria for Adverse Events version 4. HRQoL was assessed with the European Organization for Research and Treatment of Cancer core HRQoL questionnaire (EORTC-QLQ-C30). Statistical analyses used the mixed-model method; statistical significance was set at p = 0.01. Analyses were performed for baseline and subsequent time points up to 2 years after radiotherapy and per treatment modality, radiotherapy technique and disease stage. RESULTS: Data of 435 patients were analysed. Pre-treatment, overall symptoms, dyspnea, chest wall pain, dysphagia and cough impacted overall HRQoL and specific domains. At subsequent time points, cough and dysphagia were overtaken by pericarditis in affecting HRQoL. Toxicities during concurrent chemo-radiotherapy and 3-dimensional radiotherapy had the most impact on HRQoL. Conversely, toxicities in sequential chemo-radiotherapy and SBRT had limited impact on patients' HRQoL. Stage impacts the correlations: LA-NSCLC patients are more adversely affected by toxicity than ES-NSCLC patients, mimicking the results of radiotherapy technique and treatment modality. CONCLUSION: Pre-treatment symptoms and acute/late toxicities variously impact HRQoL of ES- and LA-NSCLC patients undergoing different treatment approaches and radiotherapy techniques. Throughout the disease, dyspnea seems crucial in this association, highlighting the additional effect of co-existing comorbidities. Our data call for optimized radiotherapy limiting toxicities that may affect patients' HRQoL.

Companding technique for high dynamic range measurements using Gafchromic films.

PURPOSE: To introduce a methodology to perform dose measurements using Gafchromic films which can span several decades of dose levels. METHODS: The technique is based on a rescaling approach using different films irradiated at different dose levels. This is combined with a registration protocol correcting positioning and scaling factors for each film. The methodology is validated using TLD's for out-of-field doses. Furthermore, two examples are provided using the technique to characterize small sized radiosurgery cones and compared with measurements made with a pinpoint chamber. RESULTS: Excellent agreement with TLD, planning systems and measurement was found. The superior resolution of the film technique was apparent. CONCLUSIONS: The authors have introduced a new technique allowing users to quantify very low doses in conjunction with commissioning measurements. The use of film also provides 2D information on beam characteristics in high resolution measurements.

The use of tumour markers in oesophageal cancer to quantify setup errors and baseline shifts during treatment.

PURPOSE: To prospectively evaluate the feasibility of solid gold marker placement in oesophageal cancer patients and to quantify inter-fractional and intra-fractional (baseline shift) marker motion during radiation treatment. Radiotherapy target margins and matching strategies were investigated. MATERIALS/METHODS: Thirty-four markers were implanted by echo-endoscopy in 10 patients. Patients received a planning 4D CT, daily pre-treatment cone-beam CT (CBCT) and a post-treatment CBCT for at least five fractions. For fractions with both pre- and post-treatment CBCT, marker displacement between planning CT and pre-treatment CBCT (inter-fractional) and between pre-treatment and post-treatment CBCT (intra-fractional; only for fractions without rotational treatment couch correction) were calculated in left-right (LR), cranio-caudal (CC) and anterior-posterior (AP) direction after bony-anatomy and soft-tissue matching. Systematic/random setup errors were estimated; treatment margins were calculated. RESULTS: No serious adverse events occurred. Twenty-three (67.6%) markers were visible during radiotherapy (n = 3 middle oesophagus, n = 16 distal oesophagus, n = 4 proximal stomach). Margins for inter-fractional displacement after bony-anatomy match depended on the localisation of the primary tumour and were 11.2 mm (LR), 16.4 mm (CC) and 8.2 mm (AP) for distal markers. Soft-tissue matching reduced the CC margin for these markers (16.4 mm to 10.5 mm). The mean intra-fractional shift of 12 distal markers was 0.4 mm (LR), 2.3 mm (CC) and 0.7 mm (AP). Inclusion of this shift resulted in treatment margins for distal markers of 12.8 mm (LR), 17.3 mm (CC) and 10.4 mm (AP) after bony-anatomy matching and 12.4 mm (LR), 11.4 mm (CC) and 9.7 mm (AP) after soft-tissue matching. CONCLUSION: This study demonstrated that the implantation of gold markers was safe, albeit less stable compared to other marker types. Inter-fractional motion was largest cranio-caudally for markers in the distal oesophagus, which was reduced after soft-tissue compared to bony-anatomy matching. The impact of intra-fractional baseline shifts on margin calculation was rather small.

Deep learning dose prediction for IMRT of esophageal cancer: The effect of data quality and quantity on model performance.

PURPOSE: To investigate the effect of data quality and quantity on the performance of deep learning (DL) models, for dose prediction of intensity-modulated radiotherapy (IMRT) of esophageal cancer. MATERIAL AND METHODS: Two databases were used: a variable database (VarDB) with 56 clinical cases extracted retrospectively, including user-dependent variability in delineation and planning, different machines and beam configurations; and a homogenized database (HomDB), created to reduce this variability by re-contouring and re-planning all patients with a fixed class-solution protocol. Experiment 1 analysed the user-dependent variability, using 26 patients planned with the same machine and beam setup (E26-VarDB versus E26-HomDB). Experiment 2 increased the training set by groups of 10 patients (E16, E26, E36, E46, and E56) for both databases. Model evaluation metrics were the mean absolute error (MAE) for selected dose-volume metrics and the global MAE for all body voxels. RESULTS: For Experiment 1, E26-HomDB reduced the MAE for the considered dose-volume metrics compared to E26-VarDB (e.g. reduction of 0.2 Gy for D95-PTV, 1.2 Gy for Dmean-heart or 3.3% for V5-lungs). For Experiment 2, increasing the database size slightly improved performance for HomDB models (e.g. decrease in global MAE of 0.13 Gy for E56-HomDB versus E26-HomDB), but increased the error for the VarDB models (e.g. increase in global MAE of 0.20 Gy for E56-VarDB versus E26-VarDB). CONCLUSION: A small database may suffice to obtain good DL prediction performance, provided that homogenous training data is used. Data variability reduces the performance of DL models, which is further pronounced when increasing the training set.