Radiation-induced Esophagitis Research Articles

Amomum subulatum fruits protect against radiation-induced esophagitis by regulating antioxidant status and inflammatory responses

Radiation esophagitis (RE) is an inimical event that requires proper management while carrying out radiotherapy for thoracic cancers. The present study investigates the protective effect of dry fruits of the culinary and folkloric spice Amomum subulatum against experimental thoracic radiation-induced esophagitis. C57BL/6 mice were subjected to 25 Gy whole thorax irradiation and administered with 250 mg/kg body weight of methanolic extract of A. subulatum dry fruits (MEAS) orally for four consecutive weeks. Changes in tissue antioxidant activities, oxidative stress parameters, expression of antioxidant, inflammation, and fibrosis-related genes were observed. Administration of MEAS boosted antioxidant status, thereby reducing radiation-induced oxidative stress in the esophagus. PCR (polymerase chain reaction) results showed decreased expression of apoptosis, inflammation, and fibrosis-associated genes as well as increased expression of vital cytoprotective and antioxidant genes in MEAS-treated mice, manifesting its protective effect against radiation-induced oxidative stress, inflammatory responses, and fibrosis in the esophagus. Further, histopathology, immunohistochemistry (Cyclooxygenase-2), and Masson’s Trichrome staining ascertained the protective effect of MEAS in alleviating radiation-induced esophageal injury. The synergistic effect of bioactive phytochemicals in MEAS with potent antioxidant and anti-inflammatory efficacies might have contributed to its mitigating effect against RE. Taken together, our results ascertained the radioprotective potential of MEAS, suggesting its possible nutraceutical application as a radiation countermeasure.

A systematic review of the normal tissue complication probability models and parameters: Head and neck cancers treated with conformal radiotherapy.

This systematic review study aims to provide comprehensive data on different radiobiological models, parameters, and endpoints used for calculating the normal tissue complication probability (NTCP) based on clinical data from head and neck cancer patients treated with conformal radiotherapy. A systematic literature search was carried out according to the PRISMA guideline for the identification of relevant publications in six electronic databases of Embase, PubMed, Scopus, and Google Scholar to July 2022 using specific keywords in the paper's title and abstract. The initial search resulted in 1368 articles for all organs for the review article about the NTCP parameters. One hundred and seventy-eight articles were accepted for all organs with complete parameters for the mentioned models and finally, 20 head and neck cancer articles were accepted for review. Analysis of the studies shows that the Lyman-Kutcher-Burman (LKB) model properly links the NTCP curve parameters to the postradiotherapy endpoints. In the LKB model for esophagus, the minimum, and maximum corresponding parameters were reported as TD50 = 2.61 Gy with grade ≥3 radiation-induced esophagitis endpoints as the minimum TD50 and TD50 = 68 Gy as the maximum ones. nmin = 0.06, nmax = 1.04, mmin = 0.1, and mmax = 0.65, respectively. Unfortunately, there was not a wide range of published articles on other organs at risk like ear or cauda equina except Burman et al. (Fitting of normal tissue tolerance data to an analytic function. Int J Radiat Oncol Biol Phys Ther. 1991;21:123-135). Findings suggest that the validation of different radiobiological models and their corresponding parameters need to be investigated in vivo and in vitro for developing a more accurate NTCP model to be used for radiotherapy treatment planning optimization.

A retrospective study of adjuvant proton radiotherapy for breast cancer after lumpectomy: a comparison of conventional-dose and hypofractionated dose

PurposeThis study aimed to compare the adverse reactions of conventional-dose and hypofractionated dose of proton therapy for breast cancer.Materials and methodsBreast cancer patients treated with proton radiotherapy in conventional-dose or hypofractionated dose were studied retrospectively.ResultFrom January 2017 to December 2019, our center treated 50 patients following lumpectomy with proton radiotherapy. According to the AJCC 8th Edition standard, there were stage I in 26 patients, stage II in 22 patients, and stage III in 2 patients. A total of 14 patients received intensity-modulated proton therapy at a dose of 50 Gy in 25 fractions, followed by a 10 Gy 4 fractionated boost to the lumpectomy cavity, while 36 received 40.05 Gy in 15 fractions, simultaneous integrated boost (SIB) 48 Gy to the lumpectomy cavity. Median follow-up time for 40.05 Gy group was 35.6 months (15–43 months). Median follow-up time for 50 Gy group was 46.8 months (36–68 months). For acute toxicity, the grade 1 and 2 radiodermatitis in conventional-dose group were 35.7% and 57.1%, respectively. In hypofractionated dose group, the grade 1 and 2 radiodermatitis were 91.7% and 8.3%, respectively. The radiodermatitis is hypofractionneted dose better than conventional-dose significantly. Grade 1 radiation-induced esophagitis in conventional-dose group and hypofractionated dose group were 85.71% and 60%, respectively. For late toxicity, no patients developed radiation-induced pneumonitis and rib fracture in conventional-dose group. Three patients presented grade 1 pneumonitis; one patient presented graded 2 pneumonitides and two patients presented rib fracture in hypofractionated dose group. One presented hypothyroidism in hypofractionated dose group. All patients were satisfied with breast shape. The one- and two-year OS and DFS for conventional-dose group were 100 and 100; 100 and 92.9%, respectively. The one- and two-year OS and DFS for hypofractionated dose group were 100 and 100; 100 and 100%, respectively.ConclusionProton radiation therapy can significantly reduce the normal tissue dose in breast cancer patients' hearts, lungs, and other organs. Hypofractionated proton therapy shortens the treatment course with mild radiation-related adverse effects, and has a better effect on addressing the acute adverse reactions than conventional proton radiotherapy.

Moderately hypo-fractionated radiotherapy combined with S-1 in inoperable locally advanced esophageal squamous cell carcinoma: A prospective, single-arm phase II study (GASTO-1045).

We launched this prospective phase II single-arm trial on the combination of moderately hypo-fractionated radiotherapy and S-1, to explore the safety and efficacy of the new potent regimen in inoperable locally advanced esophageal squamous carcinoma (LA-ESCC) patients. Patients with unresectable stage II-IVB LA-ESCC (UICC 2002, IVB only with metastatic celiac or supraclavicular lymph nodes) were included. Moderately hypofractionated radiotherapy (60Gy in 24 fractions) concurrent with S-1 was delivered. Meanwhile, gastrostomy tube placement by percutaneous endoscopic gastrostomy (PEG) was performed to provide nutritional support. Nutritional supplements were prescribed to meet requirements. The study outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), failure pattern, toxicities, nutritional status and treatment compliance. Endoscopy was routinely performed during post-treatment follow-up. Fifty-eight patients were included with a median follow-up of 24.4 months. The median age was 63 years (range 49-83 years) and 42 patients (72.4%) had stage III or IV diseases. The ORR was 91.3% and the CR rate was 60.3%. The estimated 2-year PFS rate and 2-year OS rate was 44.2% (95% confidence interval (CI), 31.3-57.1%) and 71.4% (95% CI, 59.4-83.4%), respectively. Radiation-induced esophagitis was the most common non-hematologic toxicity and 5 patients (8.6%) developed grade≥3 esophagitis. While, with PEG nutrition support, the nutrition-related indicators presented a clear trend toward a gradual improvement. Treatment-related death was not observed. The moderately hypo-fractionated radiotherapy combined with S-1 showed promising loco-regional disease control and survival benefit in inoperable LA-ESCC patients. Meanwhile, favorable nutritional status and low incidence of severe radiation-induced esophagitis were observed with PEG nutritional support. Moreover, endoscopy examination contributed to the early detection of recurrent esophageal lesions and timely salvage treatment. The efficacy and toxicity of the combined regimen deserved further evaluation. Clinicaltrials.gov, identifier NCT03660449.

Radiation-induced esophagitis in patients with breast cancer receiving supraclavicular nodal irradiation: A retrospective observational study

ABSTRACT JOURNAL/crsat/04.03/02201859-202306020-00006/figure1/v/2023-08-03T140821Z/r/image-tiff Background: Radiotherapy is an important treatment modality for locally advanced breast cancer and includes irradiation of the chest wall and supraclavicular nodes, with or without the axilla. Since the esophagus is close to the supraclavicular nodes, patients may experience acute radiation esophagitis during treatment which decreases their quality of life. Objective: To identify the dosimetric parameters of the esophagus which may affect the occurrence of esophagitis in patients with breast cancer who received supraclavicular nodal irradiation. Materials and Methods: This was a single-center retrospective observational study carried out from January 2021 to June 2022 at Father Muller Medical College Hospital, Mangalore, India. We enrolled patients with histologically proven breast cancer, who had received post-mastectomy radiation to the chest wall and supraclavicular nodes to a dose of 50 Gy in 25 fractions, 2 Gy per fraction, 5 fractions per week with 6 MV photon linear accelerator by intensity modulated radiation therapy. Toxicities were recorded every week. The parameters documented included the mean esophageal dose, maximum dose to the esophagus, and length of the esophagus within the treatment area. Results: We enrolled 25 patients with infiltrating ductal carcinoma of the breast who had undergone mastectomy and received neoadjuvant or adjuvant chemotherapy. The median age was 53 years (IQR, 44.5-63.5). Esophagitis (any grade) was noted in 18 of the 25 patients (72%). Grade 2 esophagitis developed in all 6 patients (100%) who had received a mean esophageal dose >20 Gy, and in none of the 19 (0%) who received a dose <20 Gy; P < 0.001. The development of esophagitis was not significantly associated with the esophageal length included in the treating area (P = 0.62), the maximum dose to the esophagus (P = 0.09), V10 (P = 0.49), or V20 (P = 1). The esophageal mean dose (Dmean) was the sole predictive factor for the development of esophagitis; P = 0.04. Conclusion: In patients with breast cancer receiving post-mastectomy radiation to the chest wall and supraclavicular area, the mean esophageal radiation dose is the only factor that correlates with the development of esophageal toxicity. Thus, esophageal toxicity can be reduced by prescribing dose constraints to the esophagus, thereby potentially improving the quality of life of patients.

AESOP: Phase 2 Open-Label Trial of Avasopasem Manganese (GC4419) for Reduction of Esophagitis in Patients Receiving Chemoradiotherapy for Nonmetastatic Lung Cancer

<h3>Purpose/Objective(s)</h3> National Cancer Institute (NCI) grade 3+ esophagitis has been reported in up to 20% of advanced lung cancer patients receiving standard fractionation radiotherapy with concurrent chemotherapy (Provencio 2011, Curran 2011). Avasopasem (GC4419) is an investigational selective dismutase mimetic that rapidly and selectively converts superoxide to hydrogen peroxide, interrupting the initiation of radiation-induced mucosal injury (Thompson 2010, Sonis 2021). Avasopasem demonstrated the potential to reduce severe oral mucositis due to chemoradiotherapy for head and neck cancer in a randomized phase 2 clinical trial (Anderson 2019), supporting the hypothesis that avasopasem might reduce severe radiation-induced esophagitis in patients with lung cancer. <h3>Materials/Methods</h3> In a single-arm open-label trial, patients with stage 3 or post-operative stage 2B non-small cell lung cancer (NSCLC) or limited stage small-cell lung cancer (LS-SCLC) received 90 mg avasopasem by 60-minute infusion prior to radiation therapy (1.8–2.0 Gy 5 days/week up to 60 Gy total), in combination with investigator's choice of chemotherapy other than gemcitabine. Primary objective to assess the incidence of acute (NCI ≥gr 2) radiation esophagitis, with observed incidence of grade 3–4 radiation esophagitis as a secondary endpoint. <h3>Results</h3> A total of 39 patients were enrolled and received at least 1 dose of avasopasem: median age 64 (range 38–85); 22 (56.4%) were male; 95% performance status (PS) 0 or 1. Thirty-two (82.1%) had NSCLC and 7 (17.9%) had LS-SCLC. Median duration of exposure to avasopasem was 43.0 days (range 2–54). Preliminary results with data analysis ongoing showed 14 of 29 evaluable patients (48.3%) experienced acute esophagitis at week 6 (95% confidence interval [CI], 29.5–67.5). Of these, 13 (44.8%) were grade 2 and 1 (3.4%) was grade 3; there were no grade 4 events. Adverse events (AEs, all grades) considered possibly related to avasopasem occurring in at least 15% of patients were nausea (36%), paresthesia (26%), dizziness, fatigue (21% each), and hypotension (15%). Three patients had grade 3 AEs (7 events) possible related to avasopasem (nausea, vomiting, dehydration, hypokalemia, dysphagia, muscular weakness, hypoxia). <h3>Conclusion</h3> In this phase 2 open-label study, grade 3 esophagitis was infrequent with avasopasem at an unscheduled interim analysis. The AE profile appeared consistent with expectations for standard therapy and avasopasem appeared well tolerated. Final data will be presented at the conference. This study (NCT04529850) is funded by Galera Therapeutics, Inc.

Clinical Outcome-Related Cancer Pathways and Mutational Signatures in Patients With Unresectable Esophageal Squamous Cell Carcinoma Treated With Chemoradiotherapy

Definitive chemoradiotherapy (dCRT) is a standard-of-care for locally advanced unresectable esophageal squamous cell carcinoma (ESCC). However, even in individuals treated with the same dCRT regimen, differences in the local control rate and radiation-induced thoracic toxicity exist (radiation-induced esophagitis [RIE]). Here, we describe a comprehensive genomic evaluation of pretreatment tumor tissue samples from 183 patients with ESCC using targeted sequencing of 474 cancer-related genes. The association between endpoints (progression-free survival [PFS], overall survival, locoregional relapse-free survival, distant metastasis-free survival), toxicity (RIE) and genomic features, including altered pathways and the mutational signature, was analyzed. An independent cohort of 84 stage II-III patients with ESCC was used for validation. Gene alterations in the cell cycle pathway were identified in 87% of cases. Other frequently altered pathways included PI3K-AKT (45.9%), NOTCH (38.3%), NRF2 (36.6%), RKT-RAS (28.4%), and homologous recombination repair (HRR; 20.2%). HRR pathway alterations correlated with shortened PFS (mutation vs wild-type: 9.00 vs 14.40 months, hazard ratio, 2.10; 95% confidence interval, 1.29-3.44), while altered RTK-RAS pathways were correlated with worse overall survival in patients with ESCC treated with chemoradiotherapy (mutation vs wild-type: 23.70 vs 33.50 months; hazard ratio, 1.65; 95% confidence interval, 1.01-2.69). Furthermore, enrichment of apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) signatures (signatures 2 and 13) was identified in ESCC tumors with altered HRR pathways. High APOBEC signatures and an altered HRR pathway were correlated with poor prognoses in dCRT-treated ESCC. Moreover, the APOBEC signature and/or the presence of HRR pathway alterations were associated with poor PFS and overall survival, which was validated in an independent whole exome sequence cohort. Notably, the altered HRR pathway was also associated with high-grade RIE toxicity in patients with ESCC. Collectively, our results support the use of comprehensive genomic profiling to guide treatment and minimize RIE in patients with ESCC.

Gut Microbiota Characteristics Are Associated With Severity of Acute Radiation-Induced Esophagitis.

BackgroundAcute radiation-induced esophagitis (ARIE) is one of the most debilitating complications in patients who receive thoracic radiotherapy, especially those with esophageal cancer (EC). There is little known about the impact of the characteristics of gut microbiota on the initiation and severity of ARIE.Materials and MethodsGut microbiota samples of EC patients undergoing radiotherapy (n = 7) or concurrent chemoradiotherapy (n = 42) were collected at the start, middle, and end of the radiotherapy regimen. Assessment of patient-reported ARIE was also performed. Based on 16S rRNA gene sequencing, changes of the gut microbial community during the treatment regimen and correlations of the gut microbiota characteristics with the severity of ARIE were investigated.ResultsThere were significant associations of several properties of the gut microbiota with the severity of ARIE. The relative abundance of several genera in the phylum Proteobacteria increased significantly as mucositis severity increased. The predominant genera had characteristic changes during the treatment regimen, such as an increase of opportunistic pathogenic bacteria including Streptococcus. Patients with severe ARIE had significantly lower alpha diversity and a higher abundance of Fusobacterium before radiotherapy, but patients with mild ARIE were enriched in Klebsiella, Roseburia, Veillonella, Prevotella_9, Megasphaera, and Ruminococcus_2. A model combining these genera had the best performance in prediction of severe ARIE (area under the curve: 0.907).ConclusionThe characteristics of gut microbiota before radiotherapy were associated with subsequent ARIE severity. Microbiota-based strategies have potential use for the early prediction of subsequent ARIE and for the selection of interventions that may prevent severe ARIE.

Predictive performance of different NTCP techniques for radiation-induced esophagitis in NSCLC patients receiving proton radiotherapy

This study aimed to compare the predictive performance of different modeling methods in developing normal tissue complication probability (NTCP) models for predicting radiation-induced esophagitis (RE) in non–small cell lung cancer (NSCLC) patients receiving proton radiotherapy. The dataset was composed of 328 NSCLC patients receiving passive-scattering proton therapy and 41.6% of the patients experienced ≥ grade 2 RE. Five modeling methods were used to build NTCP models: standard Lyman–Kutcher–Burman (sLKB), generalized LKB (gLKB), multivariable logistic regression using two variable selection procedures-stepwise forward selection (Stepwise-MLR), and least absolute shrinkage and selection operator (LASSO-MLR), and support vector machines (SVM). Predictive performance was internally validated by a bootstrap approach for each modeling method. The overall performance, discriminative ability, and calibration were assessed using the Negelkerke R2, area under the receiver operator curve (AUC), and Hosmer–Lemeshow test, respectively. The LASSO-MLR model showed the best discriminative ability with an AUC value of 0.799 (95% confidence interval (CI): 0.763–0.854), and the best overall performance with a Negelkerke R2 value of 0.332 (95% CI: 0.266–0.486). Both of the optimism-corrected Negelkerke R2 values of the SVM and sLKB models were 0.301. The optimism-corrected AUC of the gLKB model (0.796) was higher than that of the SVM model (0.784). The sLKB model had the smallest optimism in the model variation and discriminative ability. In the context of classification and probability estimation for predicting the NTCP for radiation-induced esophagitis, the MLR model developed with LASSO provided the best predictive results. The simplest LKB modeling had similar or even better predictive performance than the most complex SVM modeling, and it was least likely to overfit the training data. The advanced machine learning approach might have limited applicability in clinical settings with a relatively small amount of data.

Radiation-Induced Esophagitis in Non-Small-Cell Lung Cancer Patients: Voxel-Based Analysis and NTCP Modeling.

The aim of our study is to characterize the risk of radiation-induced esophagitis (RE) in a cohort of Non-Small-Cell Lung Cancer (NSCLC) patients treated with concurrent chemotherapy and photon/proton therapy. For each patient, the RE was graded according to the CTCAE v.3. The esophageal dose-volume histograms (DVHs) were extracted. Voxel-based analyses (VBAs) were performed to assess the spatial patterns of the dose differences between patients with and without RE of grade ≥ 2. Two hierarchical NTCP models were developed by multivariable stepwise logistic regression based on non-dosimetric factors and on the DVH metrics for the whole esophagus and its anatomical subsites identified by the VBA. In the 173 analyzed patients, 76 (44%) developed RE of grade ≥ 2 at a median follow-up time of 31 days. The VBA identified regions of significant association between dose and RE in a region encompassing the thoracic esophagus. We developed two NTCP models, including the RT modality and a dosimetric factor: V55Gy for the model related to the whole esophagus, and the mean dose for the model designed on the thoracic esophagus. The cross-validated performance showed good predictions for both models (ROC-AUC of 0.70 and 0.73, respectively). The only slight improvement provided by the analysis of the thoracic esophageal subsites might be due to the relevant sparing of cervical and lower thoracic esophagus in the analyzed cohort. Further studies on larger cohorts and a more heterogeneous set of dose distributions are needed to validate these preliminary findings and shed further light on the spatial patterns of RE development.

Interferon-α exerts proinflammatory properties in experimental radiation-induced esophagitis: Possible involvement of plasmacytoid dendritic cells

AimsRadiation-induced esophagitis, experienced during radiation therapy for lung cancer and head and neck cancer, is a major dose-limiting side effect of the treatment. This study aimed to elucidate the role of interferon-α (IFN-α) in radiation-induced esophagitis. Main methodsC57BL/6 mice were exposed to 10 and 25Gy of single thoracic irradiation. Esophageal mucosal damage and inflammatory reactions were assessed for 5 days after irradiation. Key findingsIrradiation induced esophagitis, characterized by reduction in the thickness of epithelial layer, upregulation of proinflammatory cytokines and chemokines, infiltration of inflammatory cells into the esophageal mucosa, and apoptosis of epithelial cells. Irradiation upregulated the level of gene expression for IFN-α in the esophageal tissue, and the neutralizing antibody against IFN-α ameliorated radiation-induced esophageal mucosal damage, while administration of IFN-α receptor agonist (RO8191) had an inverse effect. Depletion of plasmacytoid dendritic cells (pDCs) by anti-CD317 antibody or pharmacological inactivation with bortezomib suppressed radiation-induced mucosal inflammation and damage, accompanied by decrease in IFN-α expression level. SignificanceThese findings suggest that IFN-α and pDCs exert proinflammatory properties in the pathophysiology of radiation-induced esophagitis.

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.

A randomized trial of sodium alginate prevention of esophagitis in LA-NSCLC receiving chemoradiotherapy: OLCSG1401.

Radiation esophagitis is a critical adverse event that needs to be appropriately managed while administering thoracic irradiation. This trial aimed to investigate whether sodium alginate has preventative effects on esophagitis in patients with non-small-cell lung cancer (NSCLC) receiving concurrent chemoradiotherapy (CRT). Patients with untreated stage III NSCLC who were eligible for concurrent CRT were randomly assigned at a 1:1:1 ratio to receive one of the following treatments: initial or late use of oral sodium alginate (arms A and B) or water as control (arm C). The primary endpoint was the proportion of patients developing G3 or worse esophagitis. Overall, 94 patients were randomly assigned between February 2014 and September 2018. The study was prematurely terminated because of slow accrual. The proportions of patients with G3 or worse esophagitis were 12.5%, 9.8%, and 19.4% in arms A, B, and C, respectively. Patients receiving sodium alginate had fewer onsets of G3 esophagitis; however, differences compared with arm C were not significant (A vs. C: p = 0.46; B vs. C: p = 0.28). The rates of grade 3 or worse non-hematologic toxicities besides esophagitis were 29%, 26%, and 43% in arms A, B, and C, respectively. Interestingly, compared with arm C, a low rate of febrile neutropenia was observed in arm A (3.1% vs. 19.4%: p = 0.04). Sodium alginate did not show significant preventative effects on radiation-induced esophagitis in patients with NSCLC. The frequency of CRT-induced febrile neutropenia was lower in the early use sodium alginate arm. ClinicalTrials.gov Identifier Registry number: UMIN000013133.

Radiation-induced Esophagitis in Lung Cancer—A Common Problem with Limited Therapeutic Options

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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.

Have We Underestimated the Risk of Radiation-induced Esophagitis in Non-Small Cell Lung Cancer Patients Receiving Proton Therapy Using Constant RBE?

Have We Underestimated the Risk of Radiation-induced Esophagitis in Non-Small Cell Lung Cancer Patients Receiving Proton Therapy Using Constant RBE?

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.

Surveillance of Clinically Complete Responders Using Serial 18F-FDG PET/CT Scans in Patients with Esophageal Cancer After Neoadjuvant Chemoradiotherapy

Active surveillance for patients with esophageal cancer and a clinically complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT) is being studied. Active surveillance requires accurate clinical response evaluations. 18F-FDG PET/CT might be able to detect local tumor recurrence after nCRT as soon as the esophagus recovers from radiation-induced esophagitis. The aims of this study were to assess the value of serial 18F-FDG PET/CT scans for detecting local recurrence in patients beyond 3 mo after nCRT and to determine when radiation-induced esophagitis has resolved. Methods: This retrospective multicenter study included patients who had cCR after nCRT, who initially declined surgery, and who subsequently underwent active surveillance. Clinical response evaluations included 18F-FDG PET/CT, endoscopic biopsies, and endoscopic ultrasound with fine-needle aspiration at regular intervals. SUVmax normalized for lean body mass (SULmax) was measured at the primary tumor site. The percentage change in SULmax (Δ%SULmax) between the last follow-up scan and the scan at 3 mo after nCRT was calculated. Tumor recurrence was defined as biopsy-proven vital tumor at the initial tumor site. Results: Of 41 eligible patients, 24 patients had recurrent disease at a median of 6.5 mo after nCRT and 17 patients remained cancer free during a median follow-up of 24 mo after nCRT. Five of 24 patients with tumor recurrence had sudden intense SULmax increases of greater than 180%. In 19 of 24 patients with tumor recurrence, SULmax gradually increased (median Δ%SULmax, +18%), whereas SULmax decreased (median Δ%SULmax, -12%) in patients with ongoing cCR (P < 0.001, independent-samples t test). In patients with ongoing cCR, SULmax was lowest at 11 mo after nCRT. Conclusion: Serial 18F-FDG PET/CT might be a useful tool for detecting tumor recurrence during active surveillance. In patients with ongoing cCR, the lowest SULmax was reached at 11 mo after nCRT, suggesting that radiation-induced esophagitis had mostly resolved by that time. These findings warrant further evaluation in a larger cohort.

Efficacy of oral epigallocatechin-3-gallate solution administration during radiotherapy for non-small-cell lung cancer patients: A long-term observational study

ObjectiveSeveral studies have found that epigallocatechin-3-gallate (EGCG) can alleviate acute radiation-induced esophagitis, inhibit pulmonary inflammation and fibrosis, and reduce the severity of cardiovascular disease. Therefore, this study was aimed at exploring the influence of EGCG on late radiation toxicity in the heart, esophagus, and lungs among patients with locally advanced lung cancer. MethodsThe patients were divided into an EGCG group and a control group, the groups received EGCG and symptomatic treatment, respectively. The Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme was used to determine the late toxicity scores. Tumor responses were evaluated by chest computed tomography (CT), based on the Response Evaluation Criteria in Solid Tumors version 1.1. ResultsWe retrospectively analyzed 74 patients treated at our hospital from September 2012 to September 2016 (37 patients received EGCG and 37 received supportive treatment). The late toxicity scores of the EGCG group decreased compared to those of the control group. An obvious clinical significance was observed for the oral EGCG solution in the treatment and prevention of late cardiac, esophageal, and pulmonary toxicity. However, no significant difference was found (P ​> ​0.05). The tumor response rates were similar in the two groups. Moreover, there was no difference in progression-free survival (PFS) between the groups (P ​> ​0.05). ConclusionOral EGCG solution might alleviate radiation-induced late cardiac, esophageal, and pulmonary toxicity but has no significant effect on the tumor response rate and PFS following radiotherapy.

Lyman–Kutcher–Burman normal tissue complication probability modeling for radiation-induced esophagitis in non-small cell lung cancer patients receiving proton radiotherapy

PurposeTo develop and test an Lyman–Kutcher–Burman (LKB) normal tissue complication probability (NTCP) model to predict radiation-induced esophagitis (RE) in non-small cell lung cancer (NSCLC) patients receiving passive-scattering proton therapy (PSPT). Material and methodsWe retrospectively reviewed 328 NSCLC patients receiving PSPT at our institution. Esophagitis severity was graded by physicians according to the Common Toxicity Criteria for Adverse Events version 3.0, and the primary endpoint was grade ≥2 RE within 6 months from the first treatment. LKB model parameters (n, m, and TD50) were determined using maximum likelihood estimation. Overall performance of the model was quantified by Nagelkerke’s R2 and the scaled Brier score. Discriminative ability was evaluated using the area under the receiver operating curve (AUC), and calibration was assessed with the Hosmer–Lemeshow goodness-of-fit test. Bootstrap internal validation was performed to assess the model uncertainty and generalizability. ResultsGrade 2–3 RE was observed in 136 (41.5%) patients, and no grade 4–5 RE was reported. The optimal LKB parameters were: n = 0.24, m = 0.51, and TD50 = 44.83 Gy (relative biological effectiveness). The optimism-corrected AUC was 0.783, and the Hosmer–Lemeshow test showed significant agreement between predicted and observed morbidity. Bootstrap validation verified that the model was robust to similar future populations. ConclusionOur LKB NTCP model to predict grade ≥2 RE in NSCLC patients who received PSPT showed good predictive performance and robustness to similar future populations, and a smaller volume effect than the previously observed in photon-treated populations. External validation of the model is warranted.