Oesophageal IGRT considerations for SBRT of LA-NSCLC: barium-enhanced CBCT and interfraction motion.

BACKGROUND: To determine the optimal volume of barium for oesophageal localisation on cone-beam CT (CBCT) for locally-advanced non-small cell lung cancers (NSCLC) and quantify the interfraction oesophageal movement relative to tumour. METHODS: Twenty NSCLC patients with mediastinal and/or hilar disease receiving radical radiotherapy were recruited. The first five patients received 25 ml of barium prior to their planning CT and alternate CBCTs during treatment. Subsequent five patient cohorts, received 15 ml, 10 ml and 5 ml. Six observers contoured the oesophagus on each of the 107 datasets and consensus contours were created. Overall 642 observer contours were generated and interobserver contouring reproducibility was assessed. The kappa statistic, dice coefficient and Hausdorff Distance (HD) were used to compare barium-enhanced CBCTs and non-enhanced CBCTs. Oesophageal displacement was assessed using the HD between consensus contours of barium-enhanced CBCTs and planning CTs. RESULTS: Interobserver contouring reproducibility was significantly improved in barium-enhanced CBCTs compared to non-contrast CBCTs with minimal difference between barium dose levels. Only 10 mL produced a significantly higher kappa (0.814, p = 0.008) and dice (0.895, p = 0.001). The poorer the reproducibility without barium, the greater the improvement barium provided. The median interfraction HD between consensus contours was 4 mm, with 95% of the oesophageal displacement within 15 mm. CONCLUSIONS: 10 mL of barium significantly improves oesophageal localisation on CBCT with minimal image artifact. The oesophagus moves substantially and unpredictably over a course of treatment, requiring close daily monitoring in the context of hypofractionation.

Duration of acute esophageal toxicity in concomitant radio-chemotherapy for non-small cell lung cancer with different fractionation schedules.

OBJECTIVES: In our previous prospective trial on accelerated hypofractionated concomitant radiochemotherapy (AHRT-CHT) for non-small-cell lung cancer (NSCLC), the incidence of grade ≥3 acute esophageal toxicity (AET) was similar to that reported for conventionally fractionated concomitant radiochemotherapy (CFRT-CHT), but its duration was prolonged. Thus, we aimed to compare the duration of grade ≥3 AET between AHRT-CHT and CFRT-CHT. METHODS: Clinical data of 76 NSCLC patients treated with CFRT-CHT (60-66 Gy/2 Gy) during 2015-2020 were retrospectively compared with the data of 92 patients treated with AHRT-CHT (58.8 Gy/2.8 Gy) in the prospective trial. The maximum grade of AET, incidence, and duration of grade ≥3 AET were the end points. Univariate and multivariate analyses were applied to correlate clinical and treatment variables with these end points. RESULTS: Neither the maximum grade of AET (p = 0.71), nor the incidence of grade ≥3 AET (p = 0.87) differed between the two groups. The number of CHT cycles delivered (2 vs 1, p = 0.005) and higher esophagus mean BED (p = 0.009) were significant predictors for a higher maximum grade of AET; older age was a significant predictor for higher incidence of grade ≥3 AET (p = 0.03). The median duration of grade ≥3 AET in AHRT-CHT and CFRT-CHT group was 30 days (range 5-150) vs 7 days (range 3-20), respectively, p = 0.0005. In multivariate analysis, only the AHRT-CHT schedule (p=0.003) was a significant predictor for a longer duration of grade ≥3 AET. CONCLUSION: Despite similar incidence of grade ≥3 AET, its duration is significantly prolonged in NSCLC patients treated with AHRT-CHT compared to CFRT-CHT. ADVANCES IN KNOWLEDGE: Reporting only the rate of grade ≥3 AET in clinical trials may underestimate the real extent of the esophageal toxicity; its duration should also be routinely reported.

Unrecognized digestive toxicities of radiation therapy.

The aim of this article is to review unrecognized toxicities resulting from radiation therapy of digestive neoplasms. Due to their precocious occurrence, acute toxicities are well-known by radiation oncologist, and their treatment well-established. Thus, acute toxicities will not be described in this review. We will focus on incidence, diagnosis, and management of late and uncommon toxicities occurring in the digestive tract and digestive organs. Prevention, by respecting healthy tissues constraints, is the main tool to reduce incidence of those rare complications. Nonetheless, once installed, late toxicities remain a major burden in terms of quality of life and can even be life threatening. Hence, information and education about their diagnosis and management is important.

[Dosimetric and toxicity comparison of IMRT and 3D-CRT of non-small cell lung cancer]. / Comparaison dosimétrique et de la toxicité de la radiothérapie conformationnelle avec modulation d'intensité et de la radiothérapie conformationnelle tridimensionnelle des carcinomes bronchiques non à petites cellules.

PURPOSE: Although three-dimensional conformal radiotherapy (3D-CRT) remains the gold standard as a curative treatment for NSCLC when surgery is not possible, intensity modulated radiotherapy (IMRT) is increasingly used routinely. The purpose of this study was to assess the clinical (immediate toxicities) and dosimetric impact of IMRT compared to 3D-CRT in the treatment of locally advanced (stages IIIA to IIIC) non-small cell lung cancer (NSCLC) treated with concomitant radiochemotherapy, while IMRT in lung cancer was implemented in the radiotherapy department of the Jean-Perrin Center. PATIENTS AND METHODS: Between March 2015 and October 2019, 64 patients treated with concomitant radiochemotherapy were retrospectively included. Thirty-two received 3D-CRT and 32 IMRT. The radiotherapy prescription was 66Gy in 33 fractions of 2Gy. RESULTS: IMRT has improved coverage of target volumes (V95 increased by 14.81% in IMRT; P<0.001) without increasing doses to OARs and reducing dysphagia (RR=0.67; P=0.027). Low doses to the lung were not significantly increased in IMRT (pulmonary V5 increased by 7.46% in IMRT). CONCLUSION: Intensity modulated radiotherapy, compared with the standard RC3D technique, improve the coverage of target volumes without increasing the dose to the OARs. It also improves the immediate tolerance of the treatment by reducing the number of dysphagia.

FBX4 mediates rapid cyclin D1 proteolysis upon DNA damage in immortalized esophageal epithelial cells.

It has been implied that deregulation of cyclin D1 turnover under stresses can facilitate genomic instability and trigger tumorigenesis. Much focus has been placed on identifying the E3 ligases responsible for mediating cyclin D1 degradation. However, the findings were quite controversial and cell type-dependent. Little is known about how cyclin D1 is regulated in precancerous cells upon DNA damage and which E3 ligases mediate the effects. Here we found cyclin D1 reduction is an early response to DNA damage in immortalized esophageal epithelial cells, with expression dropping to a low level within 1 h after γ-irradiation. Comparison of temporal expression of cyclin D1 upon DNA damage between immortalized NE083-hTERT and NE083-E6E7, the latter being p53/p21-defective, showed that DNA damage-induced rapid cyclin D1 reduction was p53-independent and occurred before p21 accumulation. Overexpression of cyclin D1 in NE083-E6E7 cells could attenuate G0/G1 cell cycle arrest at 1 h after irradiation. Furthermore, rapid reduction of cyclin D1 upon DNA damage was attributed to proteasomal degradation, as evidenced by data showing that proteasomal inhibition by MG132 blocked cyclin D1 reduction while cycloheximide facilitated it. Inhibition of ATM activation and knockdown of E3 ligase adaptor FBX4 reversed cyclin D1 turnover in immortalized NE083-hTERT cells. Further study showed that knockdown of FBX4 facilitated DNA breaks, as indicated by an increase in γ-H2AX foci in esophageal cancer cells. Taken together, the results substantiated a pivotal role of ATM and FBX4 in cyclin D1 proteolysis upon DNA damage in precancerous esophageal epithelial cells, implying that deregulation of the process may contribute to carcinogenesis of esophageal squamous cell carcinoma.

Interstitial single fraction brachytherapy for malignant pulmonary tumours.

PURPOSE: Interstitial brachytherapy for pulmonary tumours is an alternative to stereotactic radiotherapy, allowing high conformity despite it being an invasive technique. The aim of the study was the analysis of dose distribution, toxicity and tumour response rates. METHODS: In the years 2014-2019, 27 patients with pulmonary tumours received 36 interstitial brachytherapies with Ir-192: 11 patients with non-small cell lung cancer, 16 patients with pulmonary metastases of other entities. RESULTS: Patients were treated with a median (interquartile range) prescription dose of 20 (20-26) Gy in a single fraction. Mean lung dose to the ipsilateral lung was 2.8 (1.6-4.7) Gy. Maximum doses to the heart, oesophagus, thoracic wall and spinal cord were 2.4 (1.8-4.6) Gy, 2.0 (1.2-6.2) Gy, 12.6 (8.0-18.2) Gy and 1.5 (0.6-3.9) Gy. Median survival after treatment was 15 months, with a 1- and 2­year local control of 84% and 60%. Median overall survival after initial cancer diagnosis was 94 months; 2 years following brachytherapy, 75% of patients with colorectal cancer vs. 37% with other histologies were alive; p = 0.14. In 69% (n = 25), brachytherapy could be performed without acute complications. A self-limiting bleeding occurred in 8% (n = 3), fever in 3% (n = 1), pneumothorax in 17% (n = 6), and pulmonary failure in 3% (n = 1). Patients with > 20 Gy in 95% of planning target volume had higher pneumothorax rates needing intervention (31% vs. 5%, p = 0.04). CONCLUSIONS: Interstitial brachytherapy for pulmonary tumours is a highly conformal therapy with minimal doses to the organs at risk. For the majority of patients, treatment can be performed without relevant complications in a single fraction with a satisfactory local control.

Radio-induced esophageal motility disorders: An unrecognized diagnosis.

PURPOSE: Esophageal motility disorders (EMD) after cervical or thoracic radiation therapy (RT) may represent a late impairment and appear under-diagnosed. This study aimed to assess the prevalence of EMD, diagnosed by high-resolution esophageal manometry (HREM) after cervical or thoracic RT. In this retrospective, single-centre study, all patients whom received cervical or thoracic RT and underwent HREM were eligible. MATERIAL AND METHODS: Oncologic data were collected: site of neoplasia, type of cancer, oncologic management (surgery and chemotherapy). EMD were classified according to the new Chicago Classification. RESULTS: Twenty patients (14 females), of mean age 62.33±11.14 years were included. Breast cancer was the most represented indication for RT (40%). Other cancers were lung tumor, head and neck tumors and Hogdkin's lymphoma. Dysphagia was the most frequent symptom justifying HREM (70%). Patients received a mean of 51±19.27 Gy, 70% of them (14/20) had radiation therapy concomitantly with chemotherapy. The delay between last radiation therapy session and HERM was 10.68±12.42 years. Twelve (60%) patients had an abnormal pattern at on HERM. Among them, 3 patients (15%) presented with a major motility disorder. The most frequent motility disorder was ineffective esophageal motility in 8 (40%) patients, 1 (5%) patient presented with type II achalasia. CONCLUSION: EMD should be suspected in patients with a history of cervical or thoracic RT in case of upper GI symptoms with normal endoscopy. In these particular patients, a manometric diagnosis that can explain their symptoms is of particular importance to limit anxiety linked to unexplained troubles.

Dose coverage impacts local control in ultra-central lung oligometastases treated with stereotactic radiotherapy.

INTRODUCTION: The use of Stereotactic Body Radiotherapy (SBRT) is controversial in Ultra-Central lung tumors, a subset of central lung tumors characterized by proximity to critical mediastinal structures. This is of interest in oligometastatic (≤3 metastases) patients, who can yield survival benefit from local treatments. The aim of our study is to assess the determinants of efficacy and toxicity in this setting. MATERIALS AND METHODS: Clinical and dosimetric parameters were reviewed in a cohort of oligometastatic patients treated with SBRT for ultra-central tumors. Local control rate (LC) and toxicity were assessed. Statistical Analysis was carried out to assess the impact of those predictors on local recurrence and adverse events. RESULTS: One-hundred-nine consecutive patients were included. A median Biologic Effective Dose (BED) of 105 (75-132) Gy10 was prescribed. At a median follow-up of 17 (range 3-78) months, 2-year LC was 87%. Improved LC was correlated to Planning Treatment Volume (PTV) covered by 95% of the prescription dose (V95% PTV) > 85% (HR 0.15, 95%CI 0.05-0.49, p = 0.0017) and to Gross Tumor Volume (GTV) < 90 cm3 (HR 0.2, 95%CI 0.07-0.56, p = 0.0021). Overall and grade ≥ 3 toxicity incidence was 20% and 5%, respectively. Patients experiencing acute and late toxicities received significantly higher dose to 1 cm3 (D1cm3) of esophagus and lung volume receiving ≥5 Gy (V5Gy) (p = 0.016 and p = 0.013), and higher dose to 0.1 cm3 (D0.1cm3) of heart (p = 0.036), respectively. CONCLUSION: V95% PTV > 85% and GTV < 90 cm3 are independent predictors of LC. Dose to esophagus, lung and heart should be carefully assessed to minimize treatment-related toxicities.

Patterns of Recurrence in Locally Advanced Resectable Oesophageal Carcinoma: Retrospective Review from a Tertiary Cancer Centre in South India.

PURPOSE: The study aims to analyse patterns of recurrence following neoadjuvant treatment and surgery in carcinoma oesophagus with an intent to postulate optimal nodal radiation. METHODOLOGY: A retrospective review of patients who presented to our centre within a 5-year period (2014-2018), with recurrence following sequential neoadjuvant treatment and radical surgery, was conducted in this single-institution study. The patterns of recurrence and duration of disease-free survival were analysed. RESULTS: Twenty-one patients (14 men, 7 women) presented with recurrence, of which 13, 7, and 1 patient(s) had received NACT, NACTRT, or both, respectively. Six patients who did not receive neoadjuvant radiotherapy received adjuvant RT. Among the 10 patients who had nodal recurrence after RT (either neoadjuvant or adjuvant), 6 and 4 patients had in-field and out-of-field nodal recurrences, respectively-the latter were equally distributed within 5 cm and outside 5 cm of the PTV margin. CONCLUSION: Among the patients who presented with recurrence, more than half had not received neoadjuvant RT (treated in the 'pre-CROSS era' or due to long-segment disease), reasserting the therapeutic superiority of NACTRT. Increased regularity of recurrences in the draining nodal region was not noted in this study, but large-scale, prospective, randomised head-to-head comparative trials to determine optimal nodal irradiation in carcinoma oesophagus are required.

Clinical significance of radiation dose-volume parameters and functional status on the patient-reported quality of life changes after thoracic radiotherapy for lung cancer: a prospective study.

PURPOSE: To date, limited data exist about the relationship between radiation dose-volume parameters and patient-reported quality of life (QOL) after thoracic radiotherapy (RT) for lung cancer. We conducted this prospective study to investigate which clinico-dosimetric factors have an impact on functional declines and symptom developments after thoracic RT for lung cancer. MATERIALS AND METHODS: The study included 44 patients who had underwent thoracic three-dimensional conformal RT at our institution from 2016 to 2017. The health-related QOL was assessed using the EORTC QLQ-C30 and QLQ-LC13 questionnaires before RT (preRT), at the end of RT (endRT), and 3, 6, and 12 months after the completion of RT. RT dose-volume parameters of adjacent normal organs such as the lung, heart, and esophagus were retrieved and used for regression analysis. RESULTS: Thoracic RT induced a temporary deterioration of many of the functional statuses and symptoms, but most of those improved and recovered to baseline levels 3 months after RT. However, the role function (RF) decline persisted until 6 months after RT (p < 0.05). Dysphagia showed the most noticeable change at the endRT (p < 0.001). In the multiple regression analysis, the absolute volume of body received at least 50 Gy (p = 0.021) and a preRT RF score (p = 0.001) was significantly associated with the endRT RF scores. Dysphagia at the endRT was significantly associated with the V40 of the esophagus (p = 0.047), preRT emotional function (p = 0.029), and receipt of concurrent chemotherapy (p = 0.022). CONCLUSIONS: Both the dosimetric parameters and preRT functional status have an impact on the weak aspect of patient-reported QOL, which may cause poor treatment compliance during and after thoracic RT. For patients with a low preRT QOL score or those having large tumor which may result in higher dose volumes, careful RT planning could prevent the deterioration of QOL after RT.

PROSPECTS FOR CREATION OF RADIOPROTECTIVE MEANS BASED ON NATURAL POLYPHENOLS AND POLYSACCHARIDES. / PERSPEKTYVY STVORENNIa ZASOBIV RADIOZAKhYSNOÏ DIÏ NA OSNOVI KOMPOZYTsII PRYRODNYKh POLIFENOL'NYKh SPOLUK I POLISAKhARYDIV.

The high level of nuclear radiation threats in the modern world determines the need to find new means of pharmacological protection of the health of military personnel and civilians from the effects of ionizing radiation. Of particular scientific interest in this aspect are natural polyphenols as a promising basis for the development of newdrugs, radiomodifiers. OBJECTIVE: Justification of the prospects of creating radioprotective agents based on compositions of plantpolyphenolic substances (PPS) and polysaccharides. MATERIAL AND METHODS: The experiments were performed on 130 laboratory white rats-male of Wistar line sexually mature weighting 180-240 g. Animals once received a total X-ray dose equivalent to 4.25 Gy. The effects ofquercetin and patulaten to the processes of reparative regeneration under conditions of X-ray irradiation andagainst the background of butadione suppression were investigated. Indicators in the study groups were compared using the Student's t-test for independent samples; the differences were considered statistically significantat p < 0.05. RESULTS: The various biological properties of quercetin, in particular, the ability to bind hydroxyl radicals, is thepotential for developing radioprotective agents based on it. At the first stage of the study, the effect of PPS andtheir compositions with polysaccharides on reparative regeneration was studied against the background of its suppression in intact and irradiated animals. With the oral administration of PPS and their compositions with pectin towhite rats, 30 minutes before the administration of butadion, an increase in the processes of reparative regeneration in the cells of the covering epitheliumof the esophagus was observed. At the same time, quercetin granulescaused the most expressive effect, which increased the statistically significant value of the mitotic index by 78.5 %in relation to the group of animals injected with butadion. At the second stage of the study, the effect of polyphenolic substances and their compositions with pectin on the processes of reparative regeneration in intact and irradiated white rats was studied on a model of linear skin wounds. The prophylactic administration of quercetin granules and the treatment of wounds with 20 % sterile quercetin gel significantly accelerated the healing process.Experimental data indicate that quercetin granules have the ability to stimulate the processes of reparative regeneration, quercetin showed the greatest efficiency with simultaneous use inside and topically. CONCLUSIONS: The research results indicate the promise of developing radioprotective drugs that can stimulatereparative regeneration processes based on compositions of plant polyphenolic substances and polysaccharides invarious qualitative and quantitative ratios.

Modeling esophageal protection from radiofrequency ablation via a cooling device: an analysis of the effects of ablation power and heart wall dimensions.

BACKGROUND: Esophageal thermal injury can occur after radiofrequency (RF) ablation in the left atrium to treat atrial fibrillation. Existing methods to prevent esophageal injury have various limitations in deployment and uncertainty in efficacy. A new esophageal heat transfer device currently available for whole-body cooling or warming may offer an additional option to prevent esophageal injury. We sought to develop a mathematical model of this process to guide further studies and clinical investigations and compare results to real-world clinical data. RESULTS: The model predicts that the esophageal cooling device, even with body-temperature water flow (37 °C) provides a reduction in esophageal thermal injury compared to the case of the non-protected esophagus, with a non-linear direct relationship between lesion depth and the cooling water temperature. Ablation power and cooling water temperature have a significant influence on the peak temperature and the esophageal lesion depth, but even at high RF power up to 50 W, over durations up to 20 s, the cooling device can reduce thermal impact on the esophagus. The model concurs with recent clinical data showing an 83% reduction in transmural thermal injury when using typical operating parameters. CONCLUSIONS: An esophageal cooling device appears effective for esophageal protection during atrial fibrillation, with model output supporting clinical data. Analysis of the impact of ablation power and heart wall dimensions suggests that cooling water temperature can be adjusted for specific ablation parameters to assure the desired myocardial tissue ablation while keeping the esophagus protected.

Volumetric modulated arc therapy versus intensity-modulated proton therapy in the postoperative irradiation of thymoma.

BACKGROUND: To investigate the role of intensity-modulated proton therapy (IMPT) compared to volumetric modulated arc therapy (VMAT) for the radiation treatment of thymoma cancer. METHODS: Twenty patients were retrospectively planned for IMPT [with (IMPT_R1 or IMPT_R2 according to the approach adopted) and without robust optimization] and VMAT. The results were compared according to dose-volume metrics on the clinical and planning target volumes (CTV and PTV) and the main organs at risk (heart, breasts, lungs, spinal cord and oesophagus). Estimates of the excess absolute risk (EAR) of secondary cancer induction were determined for the oesophagus, the breasts and the composite lungs. For the heart, the relative risk (RR) of chronic heart failure (CHF) was assessed. RESULTS: IMPT and VMAT plans resulted equivalent in terms of target coverage for both the CTV and the PTV. The CTV homogeneity index resulted in 0.03 ± 0.01 and 0.04 ± 0.01 for VMAT and all IMPT plans, respectively. The conformality index resulted in 1.1 ± 0.1 and 1.2 ± 0.1 for VMAT and all IMPT plans. The mean dose to the breasts resulted in 10.5 ± 5.0, 4.5 ± 3.4, 4.7 ± 3.5 and 4.6 ± 3.4 Gy for VMAT, IMPT, IMPT_R1 and IMPT_R2. For the lungs, the mean dose was 9.6 ± 2.3, 3.5 ± 1.5, 3.6 ± 1.6 and 3.8 ± 1.4 Gy; for the heart: 8.7 ± 4.4, 4.3 ± 1.9, 4.5 ± 2.0 and 4.4 ± 2.4 Gy and for the oesophagus 8.2 ± 3.5, 2.2 ± 3.4, 2.4 ± 3.6 and 2.5 ± 3.5 Gy. The RR for CHF was 1.6 ± 0.3 for VMAT and 1.3 ± 0.2 for IMPT (R1 or R2). The EAR was 3.6 ± 0.v vs 1.0 ± 0.6 or 1.2 ± 0.6 (excess cases/10,000 patients year) for the oesophagus; 17.4 ± 6.5 vs 5.7 ± 3.2 or 6.1 ± 3.8 for the breasts and 24.8 ± 4.3 vs 8.1 ± 2.7 or 8.7 ± 2.3 for the composite lungs for VMAT and IMPT_R, respectively. CONCLUSION: The data from this in-silico study suggest that intensity-modulated proton therapy could be significantly advantageous in the treatment of thymoma patients with particular emphasis to a substantial reduction of the risk of cardiac failure and secondary cancer induction. Robust planning is a technical pre-requisite for the safety of the delivery.

Is There a Role for Hypofractionated Thoracic Radiation Therapy in Limited-Stage Small Cell Lung Cancer? A Propensity Score Matched Analysis.

PURPOSE: Various radiation schedules are used in concurrent chemoradiation therapy for limited-stage small cell lung cancer (LS-SCLC). Since there is currently no randomized evidence comparing hypofractionated radiation therapy (HFRT) and conventionally fractionated radiation therapy (CFRT), the aim of this study was to compare overall survival (OS), progression-free survival (PFS), and toxicity of HFRT and CFRT in LS-SCLC. METHODS AND MATERIALS: Patients with LS-SCLC treated between 2000 and 2013 with HFRT (40 Gy/15 fractions, 45 Gy/15 fractions, 45 Gy/20 fractions) or CFRT (60 Gy/30 or 66 Gy/33 fractions) were included. Propensity scores were generated using a multivariable logistic regression model. Patients were matched on a 1:1 ratio with a caliper distance of 0.20. OS and PFS were estimated by the Kaplan-Meier method and compared using log-rank tests. As a sensitivity analysis, univariable and multivariable Cox regression was performed including all patients without matching. Logistic regression was performed to identify predictors of pulmonary and esophageal adverse events. RESULTS: In the overall group of 117 patients, there were significant baseline differences between the HFRT and CFRT cohorts. Patients who received CFRT were older, more often smoked concurrently with treatment, had higher Eastern Cooperative Oncology Group performance status, different T and N stage patterns, and more commonly received concurrent chemoradiation therapy and prophylactic cranial irradiation. After propensity score matching for these differences, 72 patients were included, 36 in the HFRT and CFRT cohorts, respectively. There was no difference in OS (P = .724), PFS (P = .862), or any pulmonary (P = .350) or esophageal (P = .097) adverse events between cohorts. Skin adverse events were significantly higher for CFRT (41.7%) compared with HFRT (16.7%, P = .020). Multivariable Cox regression also revealed no differences in OS (P = .886) or PFS (P = .717) between all HFRT and CFRT patients, without matching. No grade 5 adverse events were observed. CONCLUSIONS: In LS-SCLC patients, HFRT was associated with comparable survival and toxicity outcomes and may be considered as an alternative to CFRT, should its efficacy be confirmed in prospective studies.

Risk factors for esophagitis after hypofractionated palliative (chemo) radiotherapy for non-small cell lung cancer.

INTRODUCTION: Esophagitis influences quality of life and might cause treatment interruption and hospitalization. Previous studies of risk factors focused on curative treatment for non-small cell lung cancer (NSCLC), which often involves concomitant chemoradiation (CRT). Given the uncertainty around extrapolation of dose constraints, we analyzed risk factors in patients treated with hypofractionated palliative regimens. PATIENTS AND METHODS: A retrospective review of 106 patients treated with palliative radiotherapy or CRT between 2009 and 2017 was performed. INCLUSION CRITERIA: prescribed total dose 30-54 Gy, dose per fraction 2.5-4 Gy, esophageal dose > 1 Gy. Uni- and multivariate analyses were performed in 97 eligible patients to identify predictive factors for acute esophagitis grade ≥ 1 (CTCAE 5.0). RESULTS: Forty percent of patients were treated with 15 fractions of 2.8 Gy (42 Gy) and 28% also received chemotherapy according to the CONRAD study regimen (induction and concomitant Carboplatin/Vinorelbine) published by the Norwegian Lung Cancer Group. Thirty-four percent were treated with 10 fractions of 3 Gy. Stage IV NSCLC was present in 47%. Esophagus Dmax was 39 Gy (population median) and Dmean 15 Gy. Overall 31% of patients developed esophagitis (26% grade 2-3, no grade 4-5). Several dosimetric parameters correlated with the risk of esophagitis (Dmax, Dmean, D5cc, V20, V30, V35, V40). Dmax outperformed other dosimetric variables in multivariate analysis. Furthermore, concomitant chemotherapy significantly increased the risk of esophagitis, while oral steroid medication reduced it. In patients with Dmax ≥40 Gy a reduced Dmean (≤20 Gy) was beneficial. CONCLUSION: In order to reduce esophagitis after hypofractionated palliative treatment lower doses than those recommended in curative NSCLC settings are preferable. Besides esophageal dose, CRT is the main risk factor for esophagitis. Additional work is needed to confirm that steroids are able to modify the risk (or to rule out confounding effects of baseline variables not included in our database).

Mid-position treatment strategy for locally advanced lung cancer: a dosimetric study.

OBJECTIVE: The internal target volume (ITV) strategy generates larger planning target volumes (PTVs) in locally advanced non-small cell lung cancer (LA-NSCLC) than the Mid-position (Mid-p) strategy. We investigated the benefit of the Mid-p strategy regarding PTV reduction and dose to the organs at risk (OARs). METHODS: 44 patients with LA-NSCLC were included in a randomized clinical study to compare ITV and Mid-p strategies. GTV were delineated by a physician on maximum intensity projection images and on Mid-p images from four-dimensional CTs. CTVs were obtained by adding 6 mm uniform margin for microscopic extension. CTV to PTV margins were calculated using the van Herk's recipe for setup and delineation errors. For the Mid-p strategy, the mean target motion amplitude was added as a random error. For both strategies, three-dimensional conformal plans delivering 60-66 Gy to PTV were performed. PTVs, dose-volume parameters for OARs (lung, esophagus, heart, spinal cord) were reported and compared. RESULTS: With the Mid-p strategy, the median of volume reduction was 23.5 cm3 (p = 0.012) and 8.8 cm3 (p = 0.0083) for PTVT and PTVN respectively; the median mean lung dose reduction was 0.51 Gy (p = 0.0057). For 37.1% of the patients, delineation errors led to smaller PTV with the ITV strategy than with the Mid-p strategy. CONCLUSION: PTV and mean lung dose were significantly reduced using the Mid-p strategy. Delineation uncertainty can unfavorably impact the advantage. ADVANCES IN KNOWLEDGE: To the best of our knowledge, this is the first dosimetric comparison study between ITV and Mid-p strategies for LA-NSCLC.

Definitive chemoradiotherapy for squamous cell carcinoma of the esophagus: outcomes for borderline-resectable disease.

Definitive chemoradiotherapy (dCRT) is the standard treatment for unresectable esophageal cancer. Induction chemotherapy has been actively investigated for borderline-resectable and unresectable disease, but the superiority over dCRT has yet to be confirmed. The purpose of this study was to evaluate the outcome of dCRT with special interest in borderline-resectable disease. Patients with esophageal cancer treated with dCRT between January 2004 and November 2016 were included in this retrospective analysis. Chemotherapy consisted of two cycles of cisplatin (70-75 mg/m2) on day 1 and 5-fluorouracil (700-1000 mg/m2 per day) on days 1-4 or low-dose cisplatin (10 mg/m2 per day) and 5-fluorouracil (175 mg/m2 per day) for 20 days. Radiotherapy was given with a daily fraction of 1.8-2 Gy to a total dose of 50-70 Gy. A total of 104 patients were included: 34 were resectable, 35 were borderline-resectable and 35 were unresectable. Complete response was achieved in 44 patients (42%). Eighteen patients (17%) suffered Grade 2 or greater cardiopulmonary toxicity and seven patients (7%) suffered Grade 3 cardiopulmonary toxicity. At the time of this analysis, 59 patients were dead and 45 were censored. The 3-year overall survival proportions for resectable, borderline-resectable and unresectable patients were 64%, 46% and 21%, respectively. The overall survival for borderline-resectable patients with complete response and noncomplete response was significantly different (P < 0.001), with 3-year survival of 70% and 8%, respectively. The overall survival for complete response patients with borderline-resectable disease was encouraging. Further investigation to find a subgroup fit for esophagus-preserving treatment is warranted.

Exploring the Relationship of Radiation Dose Exposed to the Length of Esophagus and Weight Loss in Patients with Lung Cancer.

PURPOSE: We investigate whether esophageal dose-length parameters (Ldose) can robustly predict significant weight loss-≥5% weight loss during radiation therapy (RT) compared with the weight before RT-in patients with lung cancer treated with definitive intent. METHODS AND MATERIALS: Patients with lung cancer treated with conventionally fractionated RT between 2010 and 2018 were retrospectively identified. LFdose and LPdose, the length of full- and partial-circumferential esophagus receiving greater than a threshold dose in Gy, respectively, were created. Multivariate logistic regression examined the associations between individual Ldose and weight loss after adjusting for clinical parameters and correcting for multiple comparisons. Ridge logistic regression examined the relative importance of Ldose compared with dose-volume (Vdose), mean dose (Dmean), and clinical parameters in determining weight loss. Univariate logistic regression examined the unadjusted probability of weight loss for important Ldose parameters. RESULTS: Among the 214 patients identified, median age was 66.9 years (range, 31.5-88.9 years), 50.5% (n = 108) were male, 68.2% (n = 146) had stage III lung cancer, median RT dose was 63 Gy (range, 60-66 Gy), and 88.3% (n = 189) received concurrent chemotherapy. Esophagus lengths receiving high full-circumferential (LF50-LF60) and high partial-circumferential doses (LP60) were associated with significant weight loss (P ≤ .05). LF65 and LP65 reached near significance (P = .06 and .053, respectively). LF65 > LF60 > LP65 were the most important dose parameters in determining weight loss compared with other Ldose, Vdose, and Dmean parameters. CONCLUSIONS: Esophageal Ldose parameters are an efficient way of interpreting complex dose parameters in relation to weight loss toxicity among patients with lung cancer receiving definitive RT.

External beam patient dose verification based on the integral quality monitor (IQM®) output signals.

BACKGROUND: The Integral Quality Monitor (IQM®) can essentially measure the integral fluence through a segment and provide real-time information about the accuracy of radiation delivery based on comparisons of measured segment signals and pre-calculated reference values. However, the present IQM chamber cannot calculate the dose in the patient. AIM: This study aims to make use of IQM field output signals to calculate the number of monitor units (MUs) delivered through an arbitrary treatment field in order to convert Monte Carlo (MC)-generated dose distributions in a patient model into absolute dose. METHODS: XiO and Monaco treatment planning systems (TPSs) were used to define treatment beam portals for cervix and esophagus conformal radiotherapy as well as prostate intensity-modulated radiotherapy for the translation of patient and beam setup information from DICOM to DOSXYZnrc. The planned beams were simulated in a patient model built from actual patient CT images and each simulated integral field/segment was weighted with its MUs before summation to get the total dose in the plan. The segment beam weights (MUs) were calculated as the ratio of the open-field IQM measured signal and the calculated signal per MU extracted from chamber sensitivity maps. These are the actual MUs delivered not just MUs set. The beam weighting method was evaluated by comparing weighted MC doses with original planned doses using profile and isodose comparisons, dose difference maps, γ analysis and dose-volume histogram (DVH) data. RESULTS: γ pass rates of up to 98% were found, except for the esophagus plan where the γ pass rate was below 45%. DVH comparisons showed good agreement for most organs, with the largest differences observed in low-density lung. However, these discrepancies can result from differences in dose calculation algorithms or differences in MUs used for dose weighting planned by the TPS and MUs calculated using IQM field output signals. To test this, a 4-field box DOSXYZnrc MC simulation weighted with planned (XiO) MUs was compared with the same simulation weighted with IQM-based MUs. Dose differences of up to 5% were found on the isocentre slice. For XiO versus MC, up to 7% dose differences were found, indicating additional error due to limitations of XiO's superposition algorithm. Dose differences between MC Monaco and MC EGSnrc were less than 3%. CONCLUSIONS: The most valuable comparison was MC versus MC as it eliminated algorithm discrepancies and evaluated dose differences precisely according to beam weighting. For XiO TPS, care must be taken as dose differences may also arise due to limitations in XiO's planning software, not merely due to differences in MUs. Overall, the IQM was successfully used to compute beam dose weights to accurately reconstruct the patient dose using unweighted MC beams. Our technique can be used for pre-treatment QA provided each segment output is known and an accurate linac source model is available.

Predicting High-Grade Esophagus Toxicity After Treating Central Lung Tumors With Stereotactic Radiation Therapy Using a Normal Tissue Complication Probability Model.

PURPOSE: The treatment of central lung tumors with stereotactic body radiation therapy (SBRT) is challenged by the risk of excessive esophageal toxicity. To improve clinical decision making, we aimed to derive normal tissue complication probability (NTCP) models in a patient cohort with central lung tumors treated with SBRT and to evaluate the currently used esophagus dose constraints. METHODS AND MATERIALS: Patients with a central lung tumor who received SBRT (8 fractions of 7.5 Gy or 12 fractions of 5 Gy) were included. Doses were recalculated to an equivalent dose of 2 Gy with an α/ß-ratio of 10 Gy for acute and 3 Gy for late toxicity (the cut-off was 3 months). The esophagus was manually delineated. NTCP modeling based on logistic regression was used to relate dose-volume histogram parameters (Dmax, D1cc, D2cc, D5cc) to acute and late toxicity. Parameters with a P < .05 were included in the model. Based on the NTCP models, we determined the probability of toxicity for the currently used dose constraints: D1cc ≤40 Gy for 8 fractions and D1cc ≤48 Gy for 12 fractions. RESULTS: For this study, 188 patients with 203 tumors were eligible. Esophagus toxicity occurred in 33 patients (18%). Late high-grade toxicity consisted of 2 possible treatment-related deaths (grade 5) and 2 patients with grade 3 toxicity. Acute toxicity consisted of only grade 1 (n = 19) and grade 2 toxicity (n = 10). All investigated dose-volume histogram parameters were significantly correlated to acute and late toxicity. The probability of late high-grade toxicity is 1.1% for 8 fractions and 1.4% for 12 fractions when applying the current dose constraints. CONCLUSIONS: High-grade esophageal toxicity occurred in 2.1% of the patients, including 2 possible treatment-related deaths. The currently used dose constraints correspond to a low risk of high-grade toxicity.