Lung Dose-volume Histogram Research Articles

Evaluation of Radiation Pneumonitis in a Phase II Study of Consolidation Immunotherapy with Nivolumab and Ipilimumab or Nivolumab Alone Following Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-Small Cell Lung Cancer (NSCLC): Big Ten Cancer Research Consortium BTCRC-LUN16-081

Purpose/Objective(s)The addition of immunotherapy (IO) after concurrent chemoradiation (CCRT) for unresectable non-small cell lung cancer (NSCLC) has become common practice in eligible patients. Approaches to further improve outcomes and reduce treatment-related toxicity for these patients are needed. This study evaluates the risk of radiation pneumonitis after CCRT and its correlation with the radiation dose distribution, immunotherapy regimen (nivolumab vs nivolumab plus ipilimumab), and patient demographics across BTCRC-LUN16-081. Materials/MethodsPatients with unresectable stage III NSCLC after completion of CCRT were enrolled on BTCRC-LUN16-081, a randomized phase II trial to assess efficacy and tolerability of consolidative nivolumab versus nivolumab plus ipilimumab for six months. Radiation dose parameters, patient demographics, and toxicity events were evaluated among treatment arms for risk and severity of pneumonitis. ResultsOne-hundred and five patients were enrolled into two treatment arms, 54 patients received nivolumab alone and 51 patients received nivolumab plus ipilimumab. Of these, 104 patients had dose volume histogram (DVH) information available. Within this cohort, 65 patients (62.5%) had stage IIIA and 39 patients (37.5%) had stage IIIB NSCLC disease per AJCC 7th edition. During the study, 29 patients (27.9%) were diagnosed with grade 2 or greater pneumonitis. Utilizing logistic regression and evaluating different cut-offs for lung V20, patients with V20 >23% demonstrated significantly higher grade 2 or greater pneumonitis rates (37.1% vs. 16.2%, P = .031). No significant difference in rates of pneumonitis between arms were identified. Traditional lung DVH cut-offs (V5 of >65%, V20 of >35%, mean >20 Gy) were not associated with pneumonitis. ConclusionIn patients receiving nivolumab or nivolumab plus ipilimumab after definitive CCRT, lung V20 of >23% was associated with an increased risk of grade 2 or greater pneumonitis. Radiation dose constraints for lungs in patients receiving consolidative IO after CCRT should continue to be evaluated and optimized when feasible.

Evaluation of Pneumonitis in a Phase II Study of Consolidation Immunotherapy with Nivolumab and Ipilimumab or Nivolumab Alone following Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-small Cell Lung Cancer (NSCLC)

Unresectable stage III Non-Small-Cell-Lung-Cancer (NSCLC) has had an evolving landscape of treatment options with the approvals of immuno-oncologic (IO) therapy. There have been relatively few studies that have evaluated the risk of pneumonitis in patients receiving IO after concurrent chemoradiation treatment (CCRT). This study is to evaluate the relationship of pneumonitis and radiation dose in patients receiving consolidative IO with Nivolumab or Nivolumab plus ipilimumab. Patients with stage III NSCLC who underwent CCRT were enrolled on BTCRC-LUN16-081, a randomized phase II trial assessing the efficacy of nivolumab or nivolumab plus ipilimumab as consolidation therapy. These patients were evaluated for radiation dose parameters and correlation with pneumonitis was examined. After CCRT, patients were enrolled to receive consolidative IO therapy on BTCRC-LUN16-081, and 104 patients had Dose Volume Histogram (DVH) information available for analysis. Of these patients, 58 (55.8%) had stage IIIA and 46 (44.2%) had stage IIIB disease according to 7th edition IASLC. During this period 29 patients (27.9%) had at least grade 2 pneumonitis. Utilizing logistic regression and evaluating different cut offs for lung V20, patients receiving a V20 of greater than 23% had a higher risk of grade 2 or greater pneumonitis (p-value 0.0246, 38% vs. 16%). There was no significant difference in rates of pneumonitis between the two different IO regimens. Traditional lung DVH cutoffs (V5>65%, V20>35%, mean >20 Gy) were not associated with pneumonitis in this study. The use of nivolumab or nivolumab plus ipilimumab after definitive CCRT is safe and effective. Lung V20 > 23% was associated with a higher risk of Grade 2 or higher pneumonitis. Radiation dose constraints for lungs in patients receiving consolidative IO after CCRT should continue to be evaluated and optimized when feasible.

Pulmonary fibrosis prevalence after adjuvant radiotherapy of Iranian patients with breast cancer: A single-center cross-sectional study.

This study aims to investigate the incidence rate of pulmonary fibrosis as a late radiotherapy complication and identify the associated dosimetric and demographic factors using radiological findings between Iranian patients with breast cancer. Breast cancer patients treated at the education hospital of Shohada-e Tajrish Hospital, Tehran, Iran, from 2017 to 2021 were considered. Patients have included for whom a secondary chest CT scan was available at least six months after radiotherapy. Dose-volume histogram (DVH) parameters of three-dimensional conformal radiotherapy (3D-CRT) treatment plans were exported. Demographic features and data on underlying lung diseases, diabetes, and smoking history were extracted. A total of 250 patients were included in the study with a mean age of 46.1 ± 7.5 yrs and a mean body mass index (BMI) of 24.5 ± 4.2 kg/m2. Pulmonary fibrosis was detected for sixty-two cases. A significant relationship was obtained between the ipsilateral lung DVH parameters of patients with pulmonary fibrosis (P value < 0.05). The V5Gy, V10Gy, V13Gy, V20Gy, V30Gy, MLD, and DMax for individuals with pulmonary fibrosis were significantly higher than those without this injury. Pulmonary fibrosis was distinguished for 25% of the breast cancer cases at least six months after adjuvant radiotherapy. A significant relationship between the DVH parameters, underlying lung disease, diabetes, radiotherapy fields (i.e., Breast + LN + SC or Breast/Chest-wall only), age, and BMI with the frequency of the ipsilateral pulmonary fibrosis was obtained. V13Gy and V30Gy of the ipsilateral lung may be the most predictor of pulmonary fibrosis incidence.

Neural network based ensemble model to predict radiation induced lymphopenia after concurrent chemo-radiotherapy for non-small cell lung cancer from two institutions

The use of adjuvant Immune Checkpoint Inhibitors (ICI) after concurrent chemo-radiation therapy (CCRT) has become the standard of care for locally advanced non-small cell lung cancer (LA-NSCLC). However, prolonged radiotherapy regimens are known to cause radiation-induced lymphopenia (RIL), a long-neglected toxicity that has been shown to correlate with response to ICIs and survival of patients treated with adjuvant ICI after CCRT.In this study, we aim to develop a novel neural network (NN) approach that integrates patient characteristics, treatment related variables, and differential dose volume histograms (dDVH) of lung and heart to predict the incidence of RIL at the end of treatment. Multi-institutional data of 139 LA-NSCLC patients from two hospitals were collected for training and validation of our suggested model. Ensemble learning was combined with a bootstrap strategy to stabilize the model, which was evaluated internally using repeated cross validation.The performance of our proposed model was compared to conventional models using the same input features, such as Logistic Regression (LR) and Random Forests (RF), using the Area Under the Curve (AUC) of Receiver Operating Characteristics (ROC) curves. Our suggested model (AUC=0.77) outperformed the comparison models (AUC=0.72, 0.74) in terms of absolute performance, indicating that the convolutional structure of the network successfully abstracts additional information from the differential DVHs, which we studied using Gradient-weighted Class Activation Map.This study shows that clinical factors combined with dDVHs can be used to predict the risk of RIL for an individual patient and shows a path toward preventing lymphopenia using patient-specific modifications of the radiotherapy plan.

Incidence and Treatment Outcome of Radiation Pneumonitis in Patients With Limited-stage Small Cell Lung Cancer Treated With Concurrent Accelerated Hyperfractionated Radiation Therapy and Chemotherapy

PurposeThis study aimed to clarify the characteristics of and evaluate the risk factors for radiation pneumonitis (RP) induced by chemoradiation therapy (CRT) using accelerated hyperfractionated (AHF) radiation therapy (RT) in patients with limited-stage small cell lung cancer (LS-SCLC). Methods and MaterialsBetween September 2002 and February 2018, 125 patients with LS-SCLC were treated with early concurrent CRT using AHF-RT. Chemotherapy was comprised of carboplatin/cisplatin with etoposide. RT was administered twice daily (45 Gy/30 fractions). We collected data regarding onset and treatment outcomes for RP, and analyzed the relationship between RP and total lung dose–volume histogram findings. Uni- and multivariate analyses were performed to assess patient- and treatment-related factors for grade ≥2 RP. ResultsThe median age of patients was 65 years, and 73.6% of participants were men. In addition, 20% and 80.0% of participants presented with disease stage II and III, respectively. The median follow-up time was 73.1 months. Grades 1, 2, and 3 RP were observed in 69, 17, and 12 patients, respectively. Grades 4 to 5 RP were not observed. RP was treated with corticosteroids in patients with grade ≥2 RP, without recurrence. The median time from initiation of RT to onset of RP was 147 days. Three patients developed RP within 59 days, 6 within 60 to 89 days, 16 within 90 to 119 days, 29 within 120 to 149 days, 24 within 150 to 179 days, and 20 within ≥180 days. Among the dose–volume histogram parameters, the percentage of lung volume receiving >30 Gy (V30) was most strongly related to the incidence of grade ≥2 RP, and the optimal threshold to predict RP incidence was V30 ≥20%. On multivariate analysis, V30 ≥20% was an independent risk factor for grade ≥2 RP. ConclusionsThe incidence of grade ≥2 RP correlated strongly with a V30 of ≥20%. Contrarily, the onset of RP induced by concurrent CRT using AHF-RT may occur later. RP is manageable in patients with LS-SCLC.

Anatomy-based prediction method for determining ipsilateral lung doses in postoperative breast radiation therapy assisted by diagnostic computed tomography images.

BackgroundThis study aimed to investigate whether ipsilateral lung doses (ILDs) could be predicted by anatomical indexes measured using diagnostic computed tomography (CT) prior to the planning stage of breast radiation therapy (RT).Materials and methodsThe thoracic diameters and the length of lines drawn manually were measured on diagnostic CT images. The parameters of interest were the skin maximum lung distance (sMLD), central lung distance (CLD), Haller index (HI), and body mass index (BMI). Lung dose-volume histograms were created with conformal planning, and the lung volumes receiving 5–40 Gy (V5–V40) were calculated. Linear regression models were used to investigate the correlations between the anatomical indexes and dose differences and to estimate the slope and 95% confidence intervals (CIs).ResultsA total of 160 patients who had undergone three-dimensional conformal RT after breast-conserving surgery were included. Univariable analysis revealed that the sMLD (p < 0.001), CLD (p < 0.001), HI (p = 0.002), and BMI (p < 0.001) were significantly correlated with the V20. However, multivariable analysis revealed that only the sMLD (slope: 0.147, p = 0.001, 95% CI: 0.162–0.306) and CLD (0.157, p = 0.005, 0.048–0.266) were strongly correlated with the V20. The p-value for the sMLD was the lowest among the p-values for all indexes, thereby indicating that the sMLD had the best predictive power for ILD.ConclusionssMLD and CLD are anatomical markers that can be used to predict ILD in whole breast RT. An sMLD > 20.5 mm or a CLD > 24.3 mm positively correlated with a high ILD.

Dosimetric Evaluation of 4 Field Three-Dimensional Conformal Radiation Therapy and 7 Field Intensity Modulated Radiation Therapy in Esophageal Cancer Treated with Definitive Chemoradiation

Background: The present study aimed to evaluate dosimetrically and correlate the lung and heart dose volume histogram (DVH) of the 4 Field three-dimensional conformal radiotherapy (3DCRT) with 7 field intensity modulated radiotherapy (IMRT) in patients with oesophageal cancers. Method: This retrospective dosimetric study considered 20 oesophagus cancer patients treated with definitive chemoradiation with IMRT technique. In the 7 field IMRT technique, the first phase delivered a dose of 36Gy/18fr followed by 18Gy/9fr in two weeks in the second phase. In the 3DCRT technique, the first phase was planned with 4 field technique with two parallel opposed and two posterior oblique fields, followed by the 3 field technique in the second phase. The assessments of the techniques were performed using Differential DVH analysis of the right and left lungs, heart, and the spinal cord. The values of the mean dose, V20 (Volume receiving 20 Gy), and V30 (volume receiving 30 Gy) were assessed for any correlations. Results: The DVH of V20 in IMRT showed 5 % less lung volume irradiation compared to the 3DCRT plans and over 20% less V30 for irradiated heart volume. The study demonstrated a statistical advantage of using 7 field IMRT over 4 field 3DCRT in reducing the mean percentage dose to both lungs, heart, and spinal cord. Conclusion: 7 field IMRT is superior to 4 field 3DCRT plans in significantly reducing the average percentage of irradiated volume of both the lung and heart in esophageal cancer radiation therapy.

Correlation between gastric volume and organs at risk dose in adjuvant radiotherapy for left breast cancer.

BackgroundThe role of the gastric volume on the dose-effect relationship for these organs has not been investigated. The aim of the study was to evaluate the correlation between gastric volume and dose-volume histogram (DVH) parameters of the heart, left lung and stomach during left breast cancer radiotherapy (RT).Materials and methodsNinety-nine left breast cancer patients who got adjuvant radiotherapy were included. Study was classified into two groups based on treatment field arrangements: 1) breast tangential fields only (T) and 2) breast tangential and supraclavicular fields (TS). Organs DVHs were extracted. Descriptive statistics, Pearson correlation, linear regression analyses, and receiver operating characteristic (ROC) analyses were performed.ResultsThere is a direct but not significant correlation between the gastric volume and doses to the stomach and left lung. For a 100-cc increase in the gastric volume, the stomach maximum dose and the V50 increased by 3 Gy and 4%, respectively. For the left lung, V4 and V5 increased by 1% for TS cases. Considering ROC analysis results, one can make a decision for about 74% of patients due to their left lung DVH parameters, using gastric volume as a known input data. The correlation between gastric volume and heart dose was not significant.ConclusionsThe gastric volume of about 170 cc or less can result in lower dose to the stomach and ipsilateral lung during left breast cancer radiotherapy, especially for TS cases. To reach this gastric volume threshold, patients should be fast for 2 hours before the procedure of CT simulation and treatment.

P18.04 Individualized Fraction Regimen of SBRT Patients with Non-small Cell Lung Cancer Based on Uncomplicated and Cancer-free Control Probability

Stereotactic body radiotherapy (SBRT) currently adopts non-discriminative prescription regimen. This study attempts to investigate an individualized fraction regimen (IFR) method for SBRT patients with non-small cell lung cancer (NSCLC) based on Uncomplicated and Cancer-free Control Probability (UCFCP). Twenty patients with NSCLC were retrospectively prescribed with forty regimens, ranging from 8Gy×5f to 12Gy×5f in step of 0.1 Gy, and forty plans were correspondingly generated for each of the patients. The dose volume histograms (DVHs) of PTV, total lung, chest wall and rib were extracted from the treatment planning system (TPS) with the resolution of 1cGy. Taking into consideration of the age and the BMI index of each patient as well, the tumor control probability (TCP), the normal tissue complication probability (NTCP) of the total lung, chest wall and rib, and the secondary cancer probability (SCP) of the total lung were calculated for each plan of the patients. For the forty regimens, the UCFCP was calculated and the maximum value of UCFCP was the one corresponding to the IFR of the specified patient. In addition, IFR of UCP approach which only took account of the TCP and NTCP was also derived and to be compared with the IFR based on the UCFCP method. For all the patients, the UCFCP value showed a bell-shaped trend with the change of prescription dose. Among the 20 patients, the IFRs of 16 patients were different from the original fixed regimen. Of the 16 patients, the IFR of five patients exhibited slight changes between UCP and UCFCP methods. The patients with smaller target volume could be benefited from increased fractional dose to some extent, while patients with larger target or with target closer to the chest wall might be better off with properly reduced fractional dose. The method based on the maximum value of UCFCP function may be helpful to provide IFR for specific SBRT patients with NSCLC, differentiating the patient specific characteristics such as anatomical structures and locations, ages and BMI indexes. Further validation in clinical samples is required.

A Multi-Institutional Analysis of Radiation Dosimetric Predictors of Toxicity After Trimodality Therapy for Esophageal Cancer

PurposeThis multi-institutional review explored associations between radiation dose-volume histogram (DVH) parameters and cardiopulmonary toxicities with trimodality therapy for esophageal cancer. Methods and MaterialsWe reviewed 465 consecutive patients with esophageal cancer treated with chemoradiation therapy followed by surgery at 2 tertiary-care institutions between 2007 and 2013. Using logistic regression, we assessed associations between lung and heart DVH parameters and cardiopulmonary toxicities and survival. Statistically significant variables were subsequently included in multivariable models, which incorporated age, smoking history, previous history of heart disease, and type of chemotherapy. ResultsThe median age of the patients was 61 years (interquartile range, 54-68 years), and 86% were men. At baseline, 60% of the patients had known cardiac risk factors, 64% were current or former smokers, and 10% had other pulmonary comorbidities. Most patients had stage II to III (96%) adenocarcinoma (94%) of the distal esophagus. The radiation therapy (RT) modalities used were 3-dimensional conformal RT (38%), intensity modulated RT (41%), and proton therapy (20%). An increased heart dose was associated with increased risk of cardiac toxicity on univariable analysis (V20 Gy: odds ratio [OR], 1.20; 95% CI, 1.08-1.33; P = .001) (V30 Gy: OR, 1.24; 95% CI, 1.11-1.38; P < .0001) (V40 Gy: OR, 1.18; 95% CI, 1.03-1.35; P = .018). No lung DVH metrics were associated with lung toxicity. Heart V30 Gy was associated with adverse events on multivariable analysis (OR, 1.15; 95% CI, 1.04-1.26; P = .0047). ConclusionsWe observed an association between heart dose and cardiac toxicity for esophageal cancer. The risk of cardiac toxicity was 5%, 10%, and 15% when the heart V30 Gy dose was 14%, 20%, and 30%, respectively. For every 10% increase in V30 Gy, there was a corresponding 24% increase in the relative risk of cardiac toxicity.

Repeat Thoracic Stereotactic Body Radiation Therapy (SBRT) for Nonsmall Cell Lung Cancer: Long-Term Outcomes, Toxicity, and Dosimetric Considerations

PurposeLung reirradiation for nonsmall cell lung cancer (NSCLC) is common for either recurrent disease or new primary cancer. Dose volume tolerance of the lung after multiple courses of radiation therapy (RT) is unknown. We review our experience with lung reirradiation for patients with NSCLC in a single community setting using stereotactic body radiation therapy (SBRT) to report lung cumulative doses, survival, and toxicity. Methods and MaterialsForty-four patients who received at least 2 curative courses of lung RT with the second course delivered between January 2012 and December 2017 were eligible. All patients had NSCLC and were treated with SBRT for reirradiation. Cumulative lung dose volume histograms for all courses were generated, summated, and converted into cumulative equivalent dose in 2 Gy fractions (EQD2). Actuarial overall survival (OS), local control, and toxicity is reported, including a subset of patients who received more than 2 courses of SBRT. ResultsMedian age of the group was 71 years (range, 51-87). Median survival of the entire group from diagnosis, first, and second courses of RT was 3.94, 3.03, and 2.03 years. Three-year actuarial OS for the entire group was 34.1% from second course of RT. The mean EQD2 Gy3 mean lung dose for all courses was 12.35 Gy (range, 2.7-26.52). The mean EQD2 Gy3 V5Gy, V10Gy, V20Gy, V30Gy, and V40Gy were 40.9%, 25.5%, 14.7%, 10.2%, and 7.7%. Six-year actuarial freedom from grade ≥3 complications was 86.3%. The rate of grade ≥3 lung toxicity was 4.5% (2 of 44). Other late toxicities included grade 3 recurrent laryngeal nerve damage (n = 1) and grade 3 chest wall pain/rib fracture (n = 1). Overall, 32% of patients had more than 2 courses of RT to the lung (range, 3-7). ConclusionsLong-term OS is possible with multiple RT courses to the lung for NSCLC with low toxicity.

Impact of positioning errors in the dosimetry of VMAT left-sided post mastectomy irradiation

BackgroundVolumetric modulated arc therapy (VMAT) adopted in post-mastectomy radiation therapy (PMRT) has the capacity to achieve highly conformal dose distributions. The research aims to evaluate the impact of positioning errors in the dosimetry of VMAT left-sided PMRT.MethodsA total of 18 perturbations where introduced in 11 VMAT treatment plans that shifted the isocenter from its reference position of 3, 5, 10 mm in six directions. The thoracic wall and supraclavicular clinical target volumes (CTVs), the heart and the left lung dose volume histograms (DVHs) of 198 perturbed plans were calculated. The absolute differences (∆) of the mean dose (Dm) and DVH endpoints Vx and Dy (percentage volume receiving x Gy, and dose covering y% of the volume, respectively) were used to compare the dosimetry of the reference vs perturbed plans.ResultsIsocenter shifts in the anterior and lateral directions lead to maximum disagreement between the CTVs dosimetry of perturbed vs reference plans. Isocenter shifts of 10 mm shown a decrease of D95, D98 and Dm of 12.8, 18.0, and 2.9% respectively, for the CTVs. For 5 mm isocenter shifts, these differences decreased to 3.2, 5.2, and 0.9%, respectively, and for 3 mm shifts to 1.0, 1.7, and 0.6%, respectively. For the organs at risk (OARs), only isocenter shifts in the right, posterior and inferior directions worsen the plan dosimetry, nevertheless not negligible lung ∆ V20 of + 2.6%, and heart ∆ V25 of + 1.6% persist for 3 mm shifts.ConclusionsInaccuracy in isocenter positioning for VMAT left-sided PMRT irradiation may impact the dosimetry of the CTVs and OARs to a different extent, depending on the directions and magnitude of the perturbation. The acquired information could be useful for planning strategies to guarantee the accuracy of the treatment delivered.

Dose-volume parameters predict radiation pneumonitis after induction chemoradiotherapy followed by surgery for non-small cell lung cancer: a retrospective analysis

BackgroundThe relationship between lung dose-volume histogram (DVH) parameters and radiation pneumonitis (RP) associated with induction concurrent chemoradiotherapy (CCRT) followed by surgery in patients with non-small cell lung cancer (NSCLC) is unclear, particularly when concerning irradiation of the whole lung prior to resection. We performed this study to identify factors associated with grade ≥ 2 RP in such patients.MethodsPatients who received induction CCRT (chemotherapy: cisplatin and docetaxel; radiotherapy: 46 Gy/23 fractions) between May 2003 and May 2017 were reviewed. The mean lung dose (MLD) and the percentage of the lung volume that received ≥5 Gy (V5) and ≥ 20 Gy (V20) were calculated. Factors associated with the development of grade ≥ 2 RP were analyzed.ResultsOne hundred and eight patients were included in this study, 34 (31.5%) of whom experienced grade ≥ 2 RP. A V20 ≥ 21%, an MLD ≥10 Gy, and a lower lobe tumor location were significant predictors of grade ≥ 2 RP on univariate analysis (p = 0.007, 0.002, and 0.004, respectively). Moreover, an MLD ≥10 Gy and lower lobe location were significant predictors of grade ≥ 2 RP on multivariate analysis (p = 0.026 and 0.0043, respectively). The cumulative incidence rates of grade ≥ 2 RP at 6 months were 15.7 and 45.6% in patients with MLDs < 10 Gy and ≥ 10 Gy, respectively, and were 23.5 and 55.6% in patients with upper/middle lobe- vs. lower lobe-located tumors, respectively.ConclusionsMLD and lower lobe location were predictors of grade ≥ 2 RP in patients who received induction CCRT. It is necessary to reduce the MLD to the greatest extent possible to prevent the occurrence of this adverse event.

Lung organ-at-risk volumes: A survey of practice and the need for a consistent definition in the 4DCT era.

In the 4DCT era, the definition of lung organ-at-risk (OAR) volumes for dose-volume histogram (DVH) calculation is unclear, introducing potential for variability in practice. We aimed to identify definitions used clinically and evaluate the magnitude of DVH differences between these. We surveyed Australian & New Zealand departments about lung radiotherapy protocols including lung OAR volume definition. We used these definitions to calculate lung DVHs on 10 patients prescribed lung IMRT (60-66Gy/30-33 fractions). We calculated mean lung dose (MLD), V20 and V30 for 'Lungs - PTV', 'Lungs - CTV', 'Lungs - iGTV' (internal GTV in all respiratory phases) and 'Lungs - GTV_EX' (expiratory phase). The response rate was 39% (34/88). 14% and 29% of departments did not have a departmental protocol for OAR and tumour volume delineation, respectively. All permutations for lung OAR volumes were used with no clear preference. For conventional radiotherapy (n=27), this included Lungs alone (n=1), Lungs - PTV (n=6), Lungs - CTV (n=2), Lungs - iGTV (n=6), Lungs - GTV in single phase (n=5) and individual clinician preference (n=7). The different lung OAR volumes resulted in MLD difference ranging from 0.9 to 4.15Gy, V20 from 1.5% to 6.6% and V30 from 1.34% to 7.11%. The largest differences between subtraction of GTV_EX and iGTV were 0.32Gy, 0.43% and 0.46% for MLD, V20 and V30, respectively. A significant number of departments lacked lung cancer radiotherapy contouring protocols. Lung OAR volume definition was variable between and within departments. Potentially clinically significant differences in lung DVH parameters were seen according to the volume used.

Dose-volume Factors Predicting Radiation Pneumonitis after SBRT for Ultra-central Lung Tumors

The safety of SBRT is uncertain for ultra-central tumors (near the proximal airways or esophagus). Predictors of toxicity in this population are urgently needed. We therefore studied dose-volume correlates of radiation pneumonitis after ultra-central SBRT. 88 patients with tumors abutting proximal bronchial tree (PBT) or PTVs overlapping esophagus (n = 76 and 23; 11 met both criteria) were included. 53 (60%) had primary/locally recurrent lung cancer, and 35 had lung metastases. All had 5, 8 or 15 fractions of image-guided radiotherapy with BED ≥84Gy (α/β=10). Primary endpoints were grade ≥2/3 radiation pneumonitis (RP2+/RP3+) using CTCAE 4.0. Dose-volume histograms (DVHs) using linear-quadratic equivalent doses in 2 Gy fractions (ED) were calculated for lung and heart (α/β= 3 Gy). Volumes of these organs exposed to equivalent doses (VEDX) were tested for correlation with RP2+/RP3+ using Cox proportional hazards models with ED values of 2.5 Gy, then from 5-70 Gy in 5 Gy steps. Age, gender, KPS, COPD, radiographic ILD, smoking, anti-VEGF agents, and GTV size were also tested and included in multivariate analysis with the most significant lung and heart DVH variables. Median follow up was 14.3 months. There were 24 (27%) and 9 (10%) cases of RP2+ and RP3+. Four patients (4.5%) died of RP. Univariately, significant correlations with RP2+ were seen for lung ED from 2.5-70 Gy (p < 0.002), with strongest correlations for ED from 10-20Gy(p < 10-5). One-year rates of RP2+ with Lung VED15< or > 14.7% (the median) were 13% and 46% respectively. Correlations with RP2+ were seen for heart ED from 2.5-50 Gy, with the strongest correlation for VED5(p=0.0001). Significant correlations with RP3+ were seen for lung ED from 2.5-35 Gy, with strongest correlations for VED10(p = 0.005). Correlations with RP3+ were also seen for heart ED from 2.5-15 Gy, with the strongest correlation for VED2.5(p=0.03). One-year rates of RP3+ with Lung VED10< or > 18% (the median) were 5% and 18% respectively. No clinical variables save ILD were significantly correlated with RP2+/RP3+ (p = 0.002 and 0.0001 respectively). Though ILD was statistically significant, only 2 patients in the cohort had ILD (both had RP3+, and one died of RP). The most significant lung and heart DVH variables were correlated with each other (p < 10-4). Multivariate models of RP2+ and RP3+ using Lung VED15and ILD were significant (p <10-5and p=0.02 respectively, for RP2+; p=0.02 and 0.001 respectively, for RP3+). We observed a high rate (27%) of RP after ultra-central SBRT, with a 4.5% rate of fatal RP. Lung dose-volume factors are highly correlated with RP. Presence of ILD warrants extreme caution. Our analysis suggests that RP3+ can be limited to 5% by keeping Lung VED10< 18%, and that RP2+ can be limited to 13% by keeping Lung VED15<14.7%.

Evaluating risk factors of radiation pneumonitis after stereotactic body radiation therapy in lung tumor: Meta-analysis of 9 observational studies.

BackgroundIn this study, we assessed the association of SBRT (stereotactic body radiotherapy) dose and volume with radiation pneumonitis (RP) risk in lung tumor.MethodsRelevant articles were identified up to April 2018, using following databases; Medline, EMBASE, Cochrane Library, and China National Knowledge Infrastructure (CNKI). The pooled OR (odds ratio) with 95% CI (confidence interval) data [mean ± SD (standard deviation)] obtained from different studies was analyzed by statistical analysis using a fixed-effects model or a random-effects model when appropriate.ResultsThe analysis was based on nine observational studies, which were identified based on the study selection criteria. Between RP and non-RP patients, no difference was observed based on age, but significant differences were observed based on planning target volume (PTV), mean ipsilateral lung dose (MLD), total MLD, and V5, V10, V20 and V40 (the percentage of lung volume exceeding 5, 10, 20 and 40 Gy). In addition, PTV >145 cm3, total MLD ≥4.7 Gy, V5 ≥26.8%, V10 >12% and V20 ≥5.8 were associated with RP risk. Overall, the grade assessments of V5 and V20 revealed moderate quality evidence.ConclusionThe present study indicated V5 and V20 as major risk factors for RP after SBRT treatment in lung tumor. In addition, it was observed that lung DVH (Dose Volume Histogram) patterns should be assessed more carefully, while predicting RP incidence after SBRT.

113. Eligibility and feasibility of adjuvant breast cancer treatments with pencil beam scanning (PBS) proton therapy. An inter-institutional study

Purpose Proton therapy reduces lung dose and mean heart dose in breast cancer irradiation in adjuvant breast cancer, in particular with nodal involvement [1] . In this work we compare 10 selected intensity modulated photon therapy (IMXT) treatment cases selected from the sending institution with PBS proton therapy. Methods and materials The eligibly criteria of the sending institution were: poor coverage of the target volumes, unfavourable dose volume histograms (DVH) to the organs at risk (OAR) lung and heart or wide irradiated volume (IV) with static IMXT. The type of case were heterogeneous as shown in Table 1. All plans were performed on the CT and volumes send applying a class solution of 3 proton field with range shifter with treatment planning system (TPS) Raystation. All plans were performed in robust Single Field Optimization technique (rSFO) optimizing the target and the OAR heart and the ipsilateral lung. The optimization was done with clinical pencil beam algorithm and 5 mm geometrical robust optimization tool provided by the TPS. No robust optimization of the range was applied. Results Comparing the proton and photon plans there was a significant improvement in at least one of the following parameter: IV, DVH of lung, DVH of heart for each case (e.g. Fig. 1). Conclusion The results of this study are promising. The heuristic eligibility method provide positive answer in 100% of the cases. Further work are necessary to assess role of range errors of proton peak.

A Multi-institutional Analysis of Dosimetric Predictors of Toxicity Following Trimodality Therapy for Esophageal Cancer

Abstract Purpose This multi-institutional review explored associations between radiation dose-volume histogram (DVH) parameters and cardiopulmonary toxicities with trimodality therapy for esophageal cancer. Methods and Materials We reviewed 465 consecutive patients with esophageal cancer treated with chemoradiation therapy followed by surgery at 2 tertiary-care institutions between 2007 and 2013. Using logistic regression, we assessed associations between lung and heart DVH parameters and cardiopulmonary toxicities and survival. Statistically significant variables were subsequently included in multivariable models, which incorporated age, smoking history, previous history of heart disease, and type of chemotherapy. Results The median age of the patients was 61 years (interquartile range, 54-68 years), and 86% were men. At baseline, 60% of the patients had known cardiac risk factors, 64% were current or former smokers, and 10% had other pulmonary comorbidities. Most patients had stage II to III (96%) adenocarcinoma (94%) of the distal esophagus. The radiation therapy (RT) modalities used were 3-dimensional conformal RT (38%), intensity modulated RT (41%), and proton therapy (20%). An increased heart dose was associated with increased risk of cardiac toxicity on univariable analysis (V20 Gy: odds ratio [OR], 1.20; 95% CI, 1.08-1.33; P = .001) (V30 Gy: OR, 1.24; 95% CI, 1.11-1.38; P Conclusions We observed an association between heart dose and cardiac toxicity for esophageal cancer. The risk of cardiac toxicity was 5%, 10%, and 15% when the heart V30 Gy dose was 14%, 20%, and 30%, respectively. For every 10% increase in V30 Gy, there was a corresponding 24% increase in the relative risk of cardiac toxicity.

NTCP Model for Radiation Pneumonitis after Stereotactic Body Radiation Therapy in Non-Small Cell Lung Cancer Patients

Radiation pneumonitis (RP) is a dose limiting toxicity in stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC). Currently there is no consensus on which lung dosimetric parameter would best predict RP. This study aimed to determine the optimal lung dosimetric parameter for predicting RP in SBRT using a lung normal tissue complication probability (NTCP) model. A total of 339 early-stage NSCLC patients with SBRT were included in the study. Total lung minus gross tumor volume was used to calculate lung dose volume histogram. V5Gy, V10Gy, V20Gy, V30Gy, as well as generalized equivalent uniform dose (EUD) with “a”=1 to 6 were calculated as representative lung dosimetric parameters. RP1 (RP>=1), RP2 (RP>=2), RP3 (RP>=3) were used as the toxicity endpoint, respectively. Maximum log likelihood (MLL) was used to determine the optimal lung dosimetric parameter for the logistic NTCP model with D50 and γ50 as fitting parameters. The RP>=1 was reported in 91 (27%) patients, RP>=2 in 34 (10%) patients and RP>=3 in 19 (6%) patients. V20Gy was the best lung dosimetric parameter for predicting RP>=1, with V50=16.5 % ± 95% CI (8.6%, 24.3%). EUD (a=5) was the best parameter for RP>=2, with D50=46.7 (Gy) ± 95% CI (30.8 Gy, 62.5 Gy). EUD (a=3) was the best for RP>=3, with D50=30.9 (Gy) ± 95% CI (24.4 Gy, 37.4 Gy). Considering 30%, 15% and 10% of RP for RP1, RP2, and RP3 as the acceptable toxicity rate, respectively, the cutting lung dosimetric parameter should be V20Gy < 7.2%, EUD (a=5) < 28.3 Gy, and EUD (a=3) < 19.0 Gy. With the NTCP analysis of RP endpoints, V20Gy, EUD (a=5), and EUD (a=3) appear to be the best predictors for RP1, RP2 and RP3 following SBRT for NSCLC patients. The cutting off dosimetric parameters for 30% RP1, 15% RP2 and 10% RP3 are 7.2%, 28.3 Gy and 19.0 Gy, respectively.

Modeling Variability for at Risk Lung Functionality by Location of Esophageal Cancer Radiation Therapy Fields

Dose volume histogram (DVH) parameters are used to assess lung tolerance for esophageal cancer radiotherapy. Although lung functionality is heterogeneous, DVH evaluation treats all lungs as equivalent. We modeled variability of ventilation in lung exposed to radiotherapy by site of esophageal cancer. We developed simulated 3D conformal 4-field radiation treatment plans for gastroesophageal junction and mid-thoracic esophagus patients from 9 individual 4D CT scans. Standard expansions were used (4 cm superiorly/inferiorly and 1cm radially for clinical target volume and then 5mm in all directions for planning target volume (PTV)). Radiation dose was 5,040 cGy in 28 fractions to the PTV. We then determined points in the lung that were at the superior and inferior edges of the radiation fields for each plan and measured the displacement of those points from full exhalation to full inhalation as a surrogate for lung expansion. P-values were determined through the Wilcoxon Rank Sum test and t-tests. Lung displacement as measured by points at the superior and inferior edges of the gastroesophageal and mid-thoracic fields were 12.1 mm (± 6.7), 19.2 mm (± 5.9), 3.8 mm (± 1.3), and 7.1 mm (± 2.5), respectively, between full exhalation and full inhalation. Points in the superior aspect of the gastroesophageal fields moved significantly more than points in the superior aspect of the mid-thoracic fields (p=0.0078). Displacement was generally lateral and caudal in direction. There was a difference in displacement in the simulated tumors as well, with the mid-thoracic tumors moving a mean distance of 6.7 mm caudally and the gastroesophageal tumors moving a mean distance of 10.0 mm ventrally and caudally (p=0.039). There was also a difference in dose to the inferior aspects of the lung that displaced the most during the breathing cycle between the gastroesophageal and mid-thoracic fields, 3,541 cGy and 580 cGy, respectively (p=0.0001). This difference in dose to the most expansive part of the lung was not well expressed through the mean lung dose, V5, V10, or V30. The V5 to the total lung volume was higher for mid-thoracic plans than for gastroesophageal plans (63% vs 43%; p=0.0078) as was V10 (52.2% vs 36.9%; p=0.0039), while V30 was higher for gastroesophageal plans (17% vs 11%; p=0.039). The mean lung dose was numerically higher at 1,540 cGy for mid-thoracic plans versus 1,320 cGy for gastroesophageal plans although not statistically significant (p=0.18). Gastroesophageal junction fields have superior lung DVH parameters but are treating more ventilated lung versus mid-thoracic esophagus fields. Further study of differences in pulmonary outcomes based on location of tumor and ventilation of treated lung are warranted. In conjunction with tumor movement results, gastroesophageal junction tumors would appear to be more amenable to advanced planning techniques managing movement and functional lung avoidance.