Esophageal Dose Research Articles

Potential Morbidity Reduction for Lung Stereotactic Body Radiation Therapy Using Respiratory Gating.

Simple SummaryLung stereotactic body radiotherapy (SBRT) is the standard of care for early-stage lung cancer and oligometastases. For SBRT, motion has to be considered to avoid misdosage. Respiratory phase gating, meaning to irradiate the target volume only in a predefined gating motion phase window, can be applied to mitigate motion-induced effects. The aim of this study was to exploit the clinical benefit of gating for lung SBRT. For the majority of 14 lung tumor patients and various gating windows, we could prove a reduced dose to normal tissue by gating simulation. A normal tissue complication probability (NTCP) model analysis revealed a major reduction of normal tissue toxicity for moderate gating window sizes. The most beneficial effect of gating was found for those patients with the highest prior toxicity risk. The presented results are useful for personalized risk assessment prior to treatment and may help to select patients and optimal gating windows.We investigated the potential of respiratory gating to mitigate the motion-caused misdosage in lung stereotactic body radiotherapy (SBRT). For fourteen patients with lung tumors, we investigated treatment plans for a gating window (GW) including three breathing phases around the maximum exhalation phase, GW40–60. For a subset of six patients, we also assessed a preceding three-phase GW20–40 and six-phase GW20–70. We analyzed the target volume, lung, esophagus, and heart doses. Using normal tissue complication probability (NTCP) models, we estimated radiation pneumonitis and esophagitis risks. Compared to plans without gating, GW40–60 significantly reduced doses to organs at risk without impairing the tumor doses. On average, the mean lung dose decreased by 0.6 Gy (p < 0.001), treated lung V20Gy by 2.4% (p = 0.003), esophageal dose to 5cc by 2.0 Gy (p = 0.003), and maximum heart dose by 3.2 Gy (p = 0.009). The model-estimated mean risks of 11% for pneumonitis and 12% for esophagitis without gating decreased upon GW40–60 to 7% and 9%, respectively. For the highest-risk patient, gating reduced the pneumonitis risk from 43% to 32%. Gating is most beneficial for patients with high-toxicity risks. Pre-treatment toxicity risk assessment may help optimize patient selection for gating, as well as GW selection for individual patients.

MA06.01 Death From Intercurrent Disease After Proton- Versus Photon-Based Chemoradiotherapy for Non-Small Cell Lung Cancer

Patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with chemoradiotherapy (CRT) often have cardiopulmonary comorbidities and receive significant radiation dose to normal structures. One way to reduce normal tissue exposure is with proton beam therapy (PBT). We sought to determine if PBT was associated with a reduced risk of death from intercurrent disease in this patient population. We retrospectively reviewed the records of 187 patients with LA-NSCLC who received definitive CRT with either PBT (n=98) or photon therapy (n=89) between December 2008 and November 2016 at a single academic center. No patient received consolidation immunotherapy as this cohort predated the results of the PACIFIC trial. Baseline patient-, tumor-, and treatment-related parameters were collected. Primary endpoint was death from intercurrent disease (DID), defined as death in the absence of disease progression. DID was compared between PBT and photon therapy groups using the cumulative incidence function and Gray’s test and modelled using the Fine-Gray method. Disease progression was considered a competing event. Secondary endpoint was overall survival (OS), assessed using the Kaplan-Meier method and Cox regression. The PBT group was older (median 69 years vs 62 years, p<0.001), had a more extensive smoking history (median 40 pack-years vs 30 pack-years, p=0.043), and had a greater burden of pre-CRT cardiovascular events (54.1% vs 34.8%, p=0.008). Median radiotherapy dose in both groups was 66.6Gy (range, 52.2-74Gy). The PBT group experienced lower mean heart dose (MHD) (median 6.7Gy vs 15Gy, p<0.001), total lung V5Gy (median 35.9% vs 48.2%, p<0.001), contralateral mean lung dose (median 0.97Gy vs 5.9Gy, p<0.001), and mean esophageal dose (MED) (median 22.1Gy vs 26.5Gy, p=0.003). Median follow-up was 28.8 months (range, 3.6-131.6 months). Following CRT, 25 patients (13.4%) experienced DID. Presumed causes of DID included: respiratory failure due to congestive heart failure, COPD, pneumonia, or aspiration (n=10), out-of-hospital cardiopulmonary arrest of unclear etiology (n=4), undifferentiated sepsis (n=2), probable radiation pneumonitis (n=1), esophagopleural fistula (n=1), and unknown (n=7). 3-year cumulative incidence of DID was 7.1% in the PBT group versus 14.6% in the photon therapy group (p=0.098). PBT (subdistribution hazard ratio [sHR] 0.25, p=0.0042), MHD (sHR 1.06/Gy, p=0.0018), and MED (sHR 1.05/Gy, p=0.019) were associated with a reduced, increased, and increased risk of DID, respectively, after controlling for age and ECOG performance status in three separate 3-variable regression models. OS was similar between the PBT and photon therapy groups (median 29 months vs 28.8 months, p=0.6; HR 1.09, p=0.6). MHD (HR 1.02/Gy, p=0.013) was associated with worse OS after controlling for age, ECOG performance status, baseline pulmonary comorbidity, and internal gross tumor volume. Patients receiving MHD >10Gy vs ≤10Gy experienced higher 3-year cumulative incidence of DID (15.6% vs 6.7%, p=0.049) and inferior OS (median 22.9 months vs 34.1 months, p<0.001). In this cohort of patients treated with definitive CRT for LA-NSCLC, PBT was associated with reduced cardiac, pulmonary, and esophageal dose and reduced risk of DID on multivariable analysis. These results suggest PBT may have a clinically meaningful benefit in this population.

Comparison of dose volumetric parameters of oesophagus in the radiation treatment of carcinoma breast with and without oesophagus delineation

Abstract Aim: There are only limited studies available in literature that discuss methods to reduce the oesophageal dose and acute oesophagitis during breast cancer radiotherapy. The aim of this study is to compare dose volumetric parameters of oesophagus in radiation treatment of breast with and without oesophagus delineation. Methods: Treatment plans of 44 patients, who underwent chest wall and supraclavicular fossa irradiation, were selected for the study. Oesophagus was later delineated and treatment replanned using three-dimensional conformal radiotherapy (3DCRT) considering oesophagus as an organ at risk (OAR). The dose prescribed was 40 Gy/15 fractions to the planning target volume (PTV). Dose volumetric parameters of oesophagus such as maximum dose (Dmax), mean dose (Dmean), the percentage of oesophagus volume receiving ≥15Gy (V15), ≥25Gy(V25), ≥33Gy(V33) and ipsilateral lung volume parameters V4, V8 and V16 were compared with already executed plans in which oesophagus was not delineated. Results: Contouring the oesophagus as an OAR as a part of the radiotherapy treatment for Carcinoma Breast resulted in statistically significant reduction in dose to the oesophagus. No statistically significant change was found in the ipsilateral lung volume parameters. No compromise in plan quality was required as evident from the statistically non-significant differences in Homogeneity index and Conformity index. Findings: 3DCRT planning with oesophagus delineation can be considered as a method to reduce oesophageal dose and the acute oesophageal toxicity during radiotherapy for carcinoma breast.

PO-1174 3-weekly paclitaxel-carboplatin with radiation for stage III NSCLC – option during COVID-19 pandemic

Purpose or Objective: The optimal choice and schedule of chemotherapy (CT) given concurrently with radiation (RT) for primary treatment of stage III unresectable non-small cell lung cancer (NSCLC) remain debatable. 3-weekly paclitaxelcarboplatin (PC) is a convenient schedule but not well studied. This study aims to review the efficacy, toxicities and prognostic factors for treatment outcomes of this regime. Materials and Methods: Patients with unresectable stage III (AJCC TNM 7th edition) NSCLC treated with radical chemoradiotherapy using 3-weekly PC (P 175mg/m2, C AUC=5 on day 1 of 21-day cycle) from January 2007 to April 2017 were retrospectively reviewed. RT was given 5 days per week in 2 Gy daily fractions to the planning target volume using 3D-conformal technique. Total of 4 to 6 cycles of CT were allowed at clinicians’ discretion. Patients who had >2 CT cycles before RT, <1 cycle of CT concurrently with RT and total RT dose < 60 Gy were excluded. Results: A total of 65 patients with median age 63 years (range 45-74 years) were included. Stage distribution was similar between IIIA (53.8%) and IIIB (46.2%). Majority (41.5%) of patients had adenocarcinoma, followed by squamous histology (38.5%). Most patients received 60 Gy of RT (96.9%) and 4 cycles of CT (83.1%). At a median follow up of 29.5 months (mo) (Interquartile range 13.4-53.6 mo), the median overall survival (OS) was 35.0 mo (95% CI 17.5-52.4 mo) and the median progressive free survival (PFS) was 12.2 mo (95% CI 8.7-15.8 mo). The 1, 3 and 5-year OS rates were 76.9%, 48.3% and 29.7% respectively. Multivariate analyses showed that gross tumour volume (HR 1.005 [95% CI 1.002-1.008];p<0.01), mean heart dose ≥ 5 Gy (HR 2.507 [95% CI 1.293-5.108];p< 0.01) and more than 4 cycles of CT given (HR 3.830 [95% CI 1.479-9.921];p <0.01) were independent prognostic factors for worse OS, while ≥ grade 2 esophagitis was an independent prognostic factor for worse PFS (HR 2.563 [95% CI 1.031-6.370];p=0.04). The maximum grade toxicity was grade 2 in 20 patients (41.5%), grade 3 in 27 patients (20.0%) and grade 4 in 5 patients (7.7%). No grade 5 events were observed. The most common grade 3 or 4 toxicity was neutropenia, which occurred in 9 (13.8%) and 5 (7.7%) patients respectively. Neutropenic fever was seen in 3 patients (4.6%). Grade 2 or above pneumonitis and esophagitis occurred in 5 (7.7%) and 9 (13.8%) patients respectively. (Figure Presented) Conclusion: Radical chemoradiotherapy using 3-weekly PC for unresectable stage III NSCLC is well tolerated, with comparable outcomes to historical data and less hospital visits which is preferred during the COVID-19 pandemic. Prospective studies evaluating whether this regime in combination with more sophisticated RT techniques to lower the cardiac and esophageal doses could improve the survival outcomes and further enhance the therapeutic ratio in the era of consolidative durvalumab are warranted.

Introducing a probabilistic definition of the target in a robust treatment planning framework

The ‘clinical target distribution’ (CTD) has recently been introduced as a promising alternative to the binary clinical target volume (CTV). However, a comprehensive study that considers the CTD, together with geometric treatment uncertainties, was lacking. Because the CTD is inherently a probabilistic concept, this study proposes a fully probabilistic approach that integrates the CTD directly in a robust treatment planning framework. First, the CTD is derived from a reported microscopic tumor infiltration model such that it explicitly features the probability of tumor cell presence in its target definition. Second, two probabilistic robust optimization methods are proposed that evaluate CTD coverage under uncertainty. The first method minimizes the expected-value (EV) over the uncertainty scenarios and the second method minimizes the sum of the expected value and standard deviation (EV-SD), thereby penalizing the spread of the objectives from the mean. Both EV and EV-SD methods introduce the CTD in the objective function by using weighting factors that represent the probability of tumor presence. The probabilistic methods are compared to a conventional worst-case approach that uses the CTV in a worst-case optimization algorithm. To evaluate the treatment plans, a scenario-based evaluation strategy is implemented that combines the effects of microscopic tumor infiltrations with the other geometric uncertainties. The methods are tested for five lung tumor patients, treated with intensity-modulated proton therapy. The results indicate that for the studied patient cases, the probabilistic methods favor the reduction of the esophagus dose but compensate by increasing the high-dose region in a low conflicting organ such as the lung. These results show that a fully probabilistic approach has the potential to obtain clinical benefits when tumor infiltration uncertainties are taken into account directly in the treatment planning process.

Functional and patient-reported changes in swallowing and voice after combined chemotherapy and radiotherapy for limited-stage small-cell lung cancer.

The purpose of this study was to describe the nature and impact of dysphagia and dysphonia in patients with limited-stage small-cell lung cancer (SCLC) before and after chemoradiation. A prospective cohort study was conducted on patients receiving chemoradiotherapy for limited-stage SCLC. Patients received either 40, 45 or 50Gy, commencing the second cycle of chemotherapy. Outcomes included: videofluoroscopy (VFSS) to investigate aspiration, swallowing function and oesophageal motility; oral intake limitations; patient-reported dysphagia; and patient-reported dysphonia. Data were collected before treatment and one, three and six months post-treatment. Twelve patients were enrolled. Oropharyngeal swallowing was safe and functional at all times. Three patients exhibited oesophageal motility disorders before treatment, and a further three post-treatment. Oral intake was most compromised one month post-treatment with five patients either tube dependent or eating very limited diets. At all other times patients were eating normal or near-normal diets. Despite normal oropharyngeal swallowing on VFSS, three patients reported moderate or severe dysphagia one month post-treatment. Three additional patients reported moderate or severe difficulties three and six months post-treatment. Patients who reported dysphagia one month post-treatment all received a mean and maximum oesophageal dose of ≥15.7Gy and ≥42Gy, respectively. Dose-response relationships were not apparent three and six months post-treatment. Voice problems varied, with worst scores reported one month post-treatment. This study identified discordance between observed swallowing function and patient-reported problems, which has clinical implications for patient management, and highlights future research needs. Ongoing efforts to reduce mucosal toxicity in patients with lung cancer are essential.

Esophageal Cancer Radiotherapy Dose Escalation Meta Regression Commentary: “High vs. Low Radiation Dose of Concurrent Chemoradiotherapy for Esophageal Carcinoma With Modern Radiotherapy Techniques: A Meta-Analysis”

Esophageal Cancer Radiotherapy Dose Escalation Meta Regression Commentary: “High vs. Low Radiation Dose of Concurrent Chemoradiotherapy for Esophageal Carcinoma With Modern Radiotherapy Techniques: A Meta-Analysis”

Regression models for predicting physical and EQD2 plan parameters of two methods of hybrid planning for stage III NSCLC

Background/purposeTo establish regression models of physical and equivalent dose in 2 Gy per fraction (EQD2) plan parameters of two kinds of hybrid planning for stage III NSCLC.MethodsTwo kinds of hybrid plans named conventional fraction radiotherapy & stereotactic body radiotherapy (C&S) and conventional fraction radiotherapy & simultaneous integrated boost (C&SIB) were retrospectively made for 20 patients with stage III NSCLC. Prescription dose of C&S plans was 2 Gy × 30f for planning target volume of lymph node (PTVLN) and 12.5 Gy × 4f for planning target volume of primary tumor (PTVPT), while prescription dose of C&SIB plans was 2 Gy × 26f for PTVLN and sequential 2 Gy × 4f for PTVLN combined with 12.5 Gy × 4f for PTVPT. Regression models of physical and EQD2 plan parameters were established based on anatomical geometry features for two kinds of hybrid plans. The features were mainly characterized by volume ratio, min distance and overlapping slices thickness of two structures. The possibilities of regression models of EQD2 plan parameters were verified by spearman’s correlation coefficients between physical and EQD2 plan parameters, and the influence on the consistence of fitting goodness between physical and EQD2 models was investigated by the correlations between physical and EQD2 plan parameters. Finally, physical and EQD2 models predictions were compared with plan parameters for two new patients.ResultsPhysical and EQD2 plan parameters of PTVLN CI60Gy have shown strong positive correlations with PTVLN volume and min distance(PT to LN), and strong negative correlations with PTVPT volume for two kinds of hybrid plans. PTV(PT+LN) CI60Gy is not only correlated with above three geometry features, but also negatively correlated with overlapping slices thickness(PT and LN). When neck lymph node metastasis was excluded from PTVLN volume, physical and EQD2 total lung V20 showed a high linear correlation with corrected volume ratio(LN to total lung). Meanwhile, physical total lung mean dose (MLD) had a high linear correlation with corrected volume ratio(LN to total lung), while EQD2 total lung MLD was not only affected by corrected volume ratio(LN to total lung) but also volume ratio(PT to total lung). Heart D5, D30 and mean dose (MHD) would be more susceptible to overlapping structure(heart and LN). Min distance(PT to ESO) may be an important feature for predicting EQD2 esophageal max dose for hybrid plans. It’s feasible for regression models of EQD2 plan parameters, and the consistence of the fitting goodness of physical and EQD2 models had a positive correlation with spearman’s correlation coefficients between physical and EQD2 plan parameters. For total lung V20, ipsilateral lung V20, and ipsilateral lung MLD, the models could predict that C&SIB plans were higher than C&S plans for two new patients.ConclusionThe regression models of physical and EQD2 plan parameters were established with at least moderate fitting goodness in this work, and the models have a potential to predict physical and EQD2 plan parameters for two kinds of hybrid planning.

A novel nomogram containing acute radiation esophagitis predicting radiation pneumonitis in thoracic cancer receiving radiotherapy

BackgroundRadiation-induced pneumonitis (RP) is a non-negligible and sometimes life-threatening complication among patients with thoracic radiation. We initially aimed to ascertain the predictive value of acute radiation-induced esophagitis (SARE, grade ≥ 2) to symptomatic RP (SRP, grade ≥ 2) among thoracic cancer patients receiving radiotherapy. Based on that, we established a novel nomogram model to provide individualized risk assessment for SRP.MethodsThoracic cancer patients who were treated with thoracic radiation from Jan 2018 to Jan 2019 in Shandong Cancer Hospital and Institute were enrolled prospectively. All patients were followed up during and after radiotherapy (RT) to observe the development of esophagitis as well as pneumonitis. Variables were analyzed by univariate and multivariate analysis using the logistic regression model, and a nomogram model was established to predict SRP by “R” version 3.6.0.ResultsA total of 123 patients were enrolled (64 esophageal cancer, 57 lung cancer and 2 mediastinal cancer) in this study prospectively. RP grades of 0, 1, 2, 3, 4 and 5 occurred in 29, 57, 31, 0, 3 and 3 patients, respectively. SRP appeared in 37 patients (30.1%). In univariate analysis, SARE was shown to be a significant predictive factor for SRP (P < 0.001), with the sensitivity 91.9% and the negative predictive value 93.5%. The incidence of SRP in different grades of ARE were as follows: Grade 0–1: 6.5%; Grade 2: 36.9%; Grade 3: 80.0%; Grade 4: 100%. Besides that, the dosimetric factors considering total lung mean dose, total lung V5, V20, ipsilateral lung mean dose, ipsilateral lung V5, and mean esophagus dose were correlated with SRP (all P < 0.05) by univariate analysis. The incidence of SRP was significantly higher in patients whose symptoms of RP appeared early. SARE, mean esophagus dose and ipsilateral mean lung dose were still significant in multivariate analysis, and they were included to build a predictive nomogram model for SRP.ConclusionsAs an early index that can reflect the tissue’s radiosensitivity visually, SARE can be used as a predictor for SRP in patients receiving thoracic radiation. And the nomogram containing SARE may be fully applied in future’s clinical work.

Patient individual phase gating for stereotactic radiation therapy of early stage non-small cell lung cancer (NSCLC)

Stereotactic body radiotherapy (SBRT) applies high doses and requires advanced techniques to spare surrounding tissue in the presence of organ motion. In this work patient individual phase gating is investigated. We studied peripheral and central primary lung tumors. The internal target volume (ITV) was defined including different numbers of phases picked from a 4D Computed tomography (CT) defining the gating window (gw). Planning target volume (PTV) reductions depending on the gw were analyzed. A treatment plan was calculated on a reference phase CT (rCT) and the dose for each breathing phase was calculated and accumulated on the rCT. We compared the dosimetric results with the dose calculated when all breathing phases were included for ITV definition. GWs including 1 to 10 breathing phases were analyzed. We found PTV reductions up to 38.4%. The mean reduction of the lung volume receiving 20 Gy due to gating was found to be 25.7% for peripheral tumors and 16.7% for central tumors. Gating considerably reduced esophageal doses. However, we found that simple reduction of the gw does not necessarily influence the dose in a clinically relevant range. Thus, we suggest a patient individual definition of the breathing phases included within the gw.

Generalizable cone beam CT esophagus segmentation using physics-based data augmentation

Automated segmentation of the esophagus is critical in image-guided/adaptive radiotherapy of lung cancer to minimize radiation-induced toxicities such as acute esophagitis. We have developed a semantic physics-based data augmentation method for segmenting the esophagus in both planning CT (pCT) and cone beam CT (CBCT) using 3D convolutional neural networks. One hundred and ninety-one cases with their pCTs and CBCTs from four independent datasets were used to train a modified 3D U-Net architecture and a multi-objective loss function specifically designed for soft-tissue organs such as the esophagus. Scatter artifacts and noises were extracted from week-1 CBCTs using a power-law adaptive histogram equalization method and induced to the corresponding pCT were reconstructed using CBCT reconstruction parameters. Moreover, we leveraged physics-based artifact induction in pCTs to drive the esophagus segmentation in real weekly CBCTs. Segmentations were evaluated using the geometric Dice coefficient and Hausdorff distance as well as dosimetrically using mean esophagus dose and D 5cc. Due to the physics-based data augmentation, our model trained just on the synthetic CBCTs was robust and generalizable enough to also produce state-of-the-art results on the pCTs and CBCTs, achieving Dice overlaps of 0.81 and 0.74, respectively. It is concluded that our physics-based data augmentation spans the realistic noise/artifact spectrum across patient CBCT/pCT data and can generalize well across modalities, eventually improving the accuracy of treatment setup and response analysis.

P20.05 Oesophageal Dose Predicts on Treatment Toxicity in Patients Receiving Concurrent Chemo-Radiotherapy for Non-Small Cell Lung Cancer

P20.05 Oesophageal Dose Predicts on Treatment Toxicity in Patients Receiving Concurrent Chemo-Radiotherapy for Non-Small Cell Lung Cancer

Adaptive intensity-modulated radiotherapy with simultaneous integrated boost for stage III non-small cell lung cancer: Is a routine adaptation beneficial?

PurposeTumor and anatomical changes during radiotherapy have been observed in stage III non-small cell lung cancer (NSCLC) from many previous studies. We hypothesized that a routinely scheduled adaptive radiotherapy would have clinical important dose benefits to lower the risk of toxicities, without increasing the tumor recurrences. MethodsWe retrospectively reviewed 92 consecutive patients with inoperable stage III NSCLC between November 2017 and March 2019. All eligible patients should received simultaneously integrated boost (SIB) using intensity-modulated radiation therapy (IMRT). A mid-treatment CT simulation and a new adapted plan were routinely given after the first 20 fractions. The organs at risk (OARs) were delineated per RTOG 1106 atlas. Dose-volume histograms were quantitatively compared between the initial and composite adaptive plans. Logistic regression was applied to analyze the dose–response relationship. Clinical endpoints included acute symptomatic radiation pneumonitis (RP2) and esophagitis (RE2), local and regional tumor control, and progression-free survival (PFS). ResultsSixty-four eligible patients received adaptive SIB-IMRT were consecutively included. The GTVs reduced by a median of −38.2% after 42 to 44 Gy in 20 fractions of radiotherapy. By adapting to tumor and anatomical changes, dosimetric parameters of OARs decreased significantly. The mean lung dose decreased by an average of −74.8 cGy, and mean esophagus dose was lower by 183.1 cGy. We found grade 2 or higher acute RP in 11 patients (17.2%), and RE2 in 28 patients (43.8%). Commonly used lung and esophagus dose metrics were significantly associated with RP2 and RE2. The adaptation could reduce RP2 probability by 3%, and RE2 risk by 5%. Subgroups with higher OARs dose or larger tumor shrinkage may get more dose and toxicities benefits. The estimated median PFS was 12.5 months from the start of radiotherapy. ConclusionsWe demonstrated that the routinely adaptive SIB-IMRT strategy could significantly reduce the dose to surrounding normal tissues, potentially lower the associated acute RP and RE, without increasing the risk of tumor recurrences.

Treatment planning and outcomes effects of reducing the preferred mean esophagus dose for conventionally fractionated non-small cell lung cancer radiotherapy.

Based on an analysis of published literature, our department recently lowered the preferred mean esophagus dose (MED) constraint for conventionally fractionated (2 Gy/fraction in approximately 30 fractions) treatment of locally advanced non‐small cell lung cancer (LA‐NSCLC) with the goal of reducing the incidence of symptomatic acute esophagitis (AE). The goal of the change was to encourage treatment planners to achieve a MED close to 21 Gy while still permitting MED to go up to the previous guideline of 34 Gy in difficult cases. We compared all our suitable LA‐NSCLC patients treated with plans from one year before through one year after the constraint change. The primary endpoint for this study was achievability of the new constraint by the planners; the secondary endpoint was reduction in symptomatic AE. Planners were able to achieve the new constraint in statistically significantly more cases during the year following its explicit implementation than in the year before (P = 0.0025). Furthermore, 38% of patients treated after the new constraint developed symptomatic AE during their treatment as opposed to 48% of the patients treated before. This is a clinically desirable endpoint although the observed difference was not statistically significant. A subsequent power calculation suggests that this is due to the relatively small number of patients in the study.

Early Prediction of Acute Esophagitis for Adaptive Radiation Therapy

Acute esophagitis (AE) is a common dose-limiting toxicity in radiation therapy of locally advanced non-small cell lung cancer (LA-NSCLC). We developed an early AE prediction model from weekly accumulated esophagus dose and its associated local volumetric change. Fifty-one patients with LA-NSCLC underwent treatment with intensity modulated radiation therapy to 60 Gy in 2-Gy fractions with concurrent chemotherapy and weekly cone beam computed tomography (CBCT). Twenty-eight patients (55%) developed grade ≥2 AE (≥AE2) at a median of 4 weeks after the start of radiation therapy. For early ≥AE2 prediction, the esophagus on CBCT of the first 2 weeks was deformably registered to the planning computed tomography images, and weekly esophagus dose was accumulated. Week 1-to-week 2 (w1→w2) esophagus volume changes including maximum esophagus expansion (MEex%) and volumes with ≥x% local expansions (VEx%; x = 5, 10, 15) were calculated from the Jacobian map of deformation vector field gradients. Logistic regression model with 5-fold cross-validation was built using combinations of the accumulated mean esophagus doses (MED) and the esophagus change parameters with the lowest P value in univariate analysis. The model was validated on an additional 18 and 11 patients with weekly CBCT and magnetic resonance imaging (MRI), respectively, and compared with models using only planned mean dose (MEDPlan). Performance was assessed using area under the curve (AUC) and Hosmer-Lemeshow test (PHL). Univariately, w1→w2 VE10% (P = .004), VE5% (P = .01) and MEex% (P = .02) significantly predicted ≥AE2. A model combining MEDW2 and w1→w2 VE10% had the best performance (AUC = 0.80; PHL = 0.43), whereas the MEDPlan model had a lower accuracy (AUC = 0.67; PHL = 0.26). The combined model also showed high accuracy in the CBCT (AUC = 0.78) and MRI validations (AUC = 0.75). A CBCT-based, cross-validated, and internally validated model on MRI with a combination of accumulated esophagus dose and local volume change from the first 2 weeks of chemotherapy significantly improved AE prediction compared with conventional models using only the planned dose. This model could inform plan adaptation early to lower the risk of esophagitis.

Early High-Grade Thoracic Toxicity After Palliative Radiotherapy for Non-Small Cell Lung Cancer.

Introduction: Palliative radiotherapy or chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) may cause thoracic toxicities due to the radiation dose delivered to the lungs, heart, and esophagus. We studied severe thoracic toxicities resulting in hospitalization or death during the acute and sub-acute phase, i.e., three months from commencing radiotherapy. In addition, risk factors were identified. Methods: A retrospective review of 165 patients treated with three-dimensional conformal palliative radiotherapy or CRT was performed. The prescribed total dose was equivalent to at least 30 Gy in 10 fractions. Uni- and multivariate analyses were employed.Results: Twelve patients (7%) were hospitalized within three months from the start of radiotherapy or CRT. Six patients were hospitalized for esophagitis, three for dyspnea most likely caused by pneumonitis, and three for cardiac arrhythmia. Fatal toxicity was not observed. However, 19% of the 165 patients died from tumor-related causes during the time period of interest. In multivariate analysis, the only esophageal dose was significantly associated with the risk of hospitalization. Conclusion: The safety profile of palliative radiotherapy or CRT in the acute and subacute phases was satisfactory. The hospitalization rate can be reduced by lowering the esophageal dose, as long as safe lung and heart doses can be maintained.

Dosimetric parameters associated with radiation-induced esophagitis in breast cancer patients undergoing regional nodal irradiation

Background/PurposeRates of acute esophagitis in breast cancer patients undergoing regional nodal irradiation (RNI) are under-reported. We set to identify esophageal dose–volume constraints associated with grade 2 esophagitis (G2E). We hypothesized that the G2E rate was higher with intensity modulated radiation therapy (IMRT) vs. 3D conformal radiation therapy (3DCRT). Materials/MethodsWe identified patients that received RNI (50 Gy/25 fractions) from 1/2013 to 6/2019. We retrospectively contoured the esophagus in a consistent manner and recorded esophageal mean dose, max dose, and V10–V50. Our primary endpoint was the G2E rate. Receiver operating characteristics curves analysis (e.g., Youden’s J statistic) were used to determine the cutpoints for the dosimetric parameters which were then tested in logistic regression models. ResultsWe identified 531 patients (50% left-sided; 41% IMRT; 16.2% G2E). G2E was significantly higher in IMRT vs. 3DCRT patients (23.6% vs. 10.9%, p < 0.0001). All esophageal dosimetric parameters were significantly associated with G2E after adjusting for age and laterality. The cutpoints for esophageal mean dose, V10 and V20 were 11 Gy, 30%, and 15%, respectively. The associations between the dichotomized dose–volume parameters and G2E were OR = 3.82 (95% CI 2.28–6.40, p < 0.0001) for esophageal mean dose, OR = 5.37 (95% CI 3.01–9.58, p < 0.0001) for esophageal V10, and OR = 3.23 (95% CI 1.93–5.41, p < 0.0001) for esophageal V20. ConclusionIn patients receiving RNI with modern techniques, we found that G2E occurs in >15%, and more frequently with IMRT. These data strongly support the routine contouring of the esophagus in RNI planning, and our constraints should be incorporated in future prospective protocols of RNI.

Early Prediction of Acute Esophagitis Using Accumulated Dose and Local Volume Change of Esophagus

Acute esophagitis (AE) is a common dose-limiting toxicity with significant impact on quality of life in patients with locally advanced non-small cell lung cancer (LA-NSCLC). In this study, we performed early AE prediction using weekly accumulated esophagus dose and its associated local volumetric change. The study included 60 LA-NSCLC patients consecutively treated (2017 to 2019) via IMRT to 50-72Gy in 2 Gy-fractions with concurrent chemotherapy and had weekly cone beam CTs (CBCTs). In addition, nine of the patients also had weekly respiratory triggered T2-weighted MRIs (3T) during the RT course. A total of 35 patients (58%) developed grade 2 AE (AE2; requiring medication cf. CTCAE) at a median of 4 weeks post-RT start. The weekly esophagus dose was accumulated on the contours delineated by a radiation oncologist on CBCTs and MRIs. Week to week esophagus changes were calculated using determinant of the gradient of the deformation vector field as Jacobian map obtained via a regularized diffeomorphic registration. The Jacobian at each voxel measures the percentage of local esophagus volume expansion/shrinkage. Parameters quantifying esophagus volume changes were the net volume change, maximum percentage of expansion (ExMax%) and volumes with ≥5%,10% and 15% local expansions (VE5%, VE10%, VE15%) at the current week with respect to the previous week. For the 51 patients with CBCTs only, a multivariate logistic regression model was built with 5-fold cross-validation to perform early prediction of AE2 using a combination of the accumulated Mean Esophagus Dose at week two (MEDW2) and VE10% from week one to two (w1→2). The model was externally validated on the nine patients who had MRI; and compared to a previously published model using only planned mean dose (MEDPlan). Performance was assessed using AUC and the Hosmer-Lemeshow test (PHL). Univariate analysis showed VE10% (p = 0.003), VE5% (p = 0.006) and ExMax% (p = 0.02) significantly predicted AE2 (p<0.05 after Bonferroni correction). A model combining MEDW2 and w1→2 VE10% from CBCT data had the highest accuracy (AUC = 0.74) with good calibration (PHL = 0.27) and was considerably better than the MEDPlan model (AUC = 0.64; PHL = 0.09). When externally validated on the MRI data, the combined model showed high accuracy (AUC = 0.79). The population average w1→2 VE10% and MEDW2 for AE2 vs. non-AE2 patients were 2.5cm3 vs. 0.6cm3 and 5.4Gy vs. 4Gy, respectively. According to the model, w1→2 VE10% >2.8cm3 and MEDW2 >8.1Gy correspond to a 50% complication probability of AE2. A cross-validated model with a combination of local volume change and accumulated dose of esophagus from the first two weeks of RT significantly improved the prediction of AE compared to previously published model using only the planned dose. This model could inform plan adaptation early during the treatment to lower the risk of esophagitis.

Acute Radiation-induced Esophagitis as a Novel and Early Predictor for Radiation-Induced Pneumonitis: A Real-World Study

Radiation-induced pneumonitis (RP) is a non-negligible and life-threatening complication in patients undergoing thoracic radiation. We have observed that many patients with severe RP (SRP, grade≥2) were accompanied with severe acute radiation-induced esophagitis (SARE, grade≥2) in clinic. The aim of this study was to ascertain the application value of SARE to SRP and establish a novel and visible nomogram model for it. Patients with thoracic cancer who were treated with thoracic radiation from Jan.2018 to Jan.2019 in Shandong Cancer Hospital and Institute were enrolled prospectively. All patients were followed up during and after radiotherapy (RT) to observe the appearance of esophagitis and pneumonitis. Variables were analyzed by univariate and multivariate analysis using the logistic regression model, and a nomogram model was established to predict SRP by "R” version 3.6.0. A total of 123 patients were enrolled (64 esophageal cancer, 57 lung cancer and 2 mediastinal cancer) in this study prospectively. With a median follow-up of 3.3 months (range 1–14.2 months), RP grades of 0, 1, 2, 3, 4 and 5 occurred in 29, 57, 31, 0, 3 and 3 patients, respectively. SRP appeared in 37 patients (30.1%). In univariate analysis, SARE was shown to be a significant predictive factor for SRP (P < 0.001). The incidence of SRP in different grades of ARE were as follows: Grade 0-1:6.52%; Grade 2: 36.92%; Grade 3: 80.00%; Grade 4: 100%. Besides that, the dosimetric factors considered total lung mean dose, total lung V5, V20; ipsilateral lung mean dose, ipsilateral lung V5, and mean esophagus dose to be correlated with SRP (all P < 0.005) in univariate analysis. The incidence of SRP was significantly higher in patients whose symptoms of RP appeared early. SARE (HR 34.408, P = 0.001), mean esophagus dose and ipsilateral mean lung dose were still significant in multivariate analysis, and they were included to build a predictive nomogram model for SRP. SARE was the first intuitive index that can reflect the radiation sensitivity of normal tissue visually. It could be a significant predictor to SRP for patients receiving thoracic radiation, which can be earlier and easier than previously reported laboratory or clinical indicators. And the nomogram model could assist in doctor’s decision and guide to make personalized radiation dose prescription.

The esophageal dose-volume parameters for predicting Grade I-II acute esophagitis correlated with weight loss and serum albumin decrease in lung cancer radiotherapy.

Acute esophagitis (AE) is a commonly encountered side effect of curative thoracic radiotherapy (CTRT) for lung cancer patients. Nevertheless, its identification for widely used scoring systems depends on patients' statements. It is aimed to evaluate the correlation between the esophagus doses during CTRT and Grade 1-2 AE, weight change, and change in serum albumin (Alb) levels. The data collected from 124 lung cancer patients treated with ≥60 Gy CTRT were evaluated retrospectively. Weight and serum Alb level difference of each patient, throughout CTRT, were calculated. The percentage of the esophagus volume receiving ≥5 Gy (V5), V10, V35, V50, and V60; the absolute esophagus volume receiving ≥60 Gy (V60(cc)); the length of esophagus receiving ≥60 Gy (L60); the average esophagus dose (Dmean); and the maximum esophagus dose (Dmax) were the dose parameters calculated. The correlations were performed by Spearman's rank correlation coefficient. Grade 1 and Grade 2 AE were reported in 62 and 25 patients, respectively. All of the dose parameters were correlated with Grade 1-2 AE (P < 0.001) and weight loss (P < 0.001 for all, except Dmax P = 0.018). Decrease in serum Alb level was significantly correlated with all the parameters, but V5 and V10. Receiver operating characteristic curve analysis was performed for five parameters with the highest correlation coefficient (V35, V50, V60(%), V60(cc), and Dmean), and the cutoff values were 39.5%, 28.17%, 2.21%, 0.5cc, and 26.04 Gy, respectively. The correlation of the dose parameters that might be effective on Grade 1-2 AE with the weight loss and Alb loss was investigated, and the cutoff values corresponding to the best sensitivity and specificity were identified.