Lung Dose-volume Histogram Research Articles

P1.17-20 Excluding PTV From Lung Volume May Better Predict Radiation Pneumonitis For IMRT Treated Lung Cancer Patients

Lung dose-volume histogram(DVH) could be calculated from multiple normal lung definitions. These dose differences have a direct impact on lung cancer radiotherapy treatment planning. Earlier study from 3D conformal radiation therapy suggested dose computation from total normal lung excluding gross tumor volume (GTV) may be more accurate than that of excluding planning target volume (PTV). It is unclear which definition should be used to more accurately predict radiation pneumonitis (RP) in lung cancer patients treated with intensity-modulated radiation therapy (IMRT). We aim to determine a superior normal lung volume to more accurately predict symptomatic RP in lung cancer patients treated with IMRT. This is a retrospective study. All patients treated with IMRT with at least 3 months follow-up are eligible. The normal lungs are defined by total lung volume excluding GTV, PTV or directly using the total lung volume. V5, V20, and MLD have been extracted for all three definitions. RP was diagnosed and graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.03. The primary endpoint was grade 2 or higher RP (RP2). Correlation between RP2 and dose parameters were analyzed by logistic regression. We compared RP prediction performance of each lung volume using area under the receiver operating characteristic curve (AUC). A total of 184 consecutive patients treated between January 2014 and October 2017 were eligible, 26 patients (14%) developed RP2 within 3 months after treatment. Significant dosimetric difference was found between any 2-paired lung volumes (Ps<0.0001). All dose parameters from Lung-PTV method had significant correlation with RP2, with greater AUCs than the other two definitions. The best RP prediction performance was found in Lung-PTV volume MLD (AUC=0.649), which is significantly better than Lung-GTV volume MLD (AUC=0.611, P=0.006). There were significant dosimetric differences from various normal lung definitions. Excluding PTV method may accurately predict acute symptomatic radiation pneumonitis for IMRT treated lung cancer patients.

Using benchmarked lung radiation dose constraints to predict pneumonitis risk: Developing a nomogram for patients with mediastinal lymphoma

PurposeWe identified lung dosimetric constraints to assist in predicting the radiation pneumonitis (RP) risk in patients with mediastinal lymphoma and then identified the clinical prognostic factors that were associated with the achievement of key dosimetric constraints. Methods and MaterialsIn 190 patients who received mediastinal intensity modulated radiation therapy, we used univariate χ2 and multivariate logistic models to identify the predictors of RP and achievement of lung dose-volume histogram (DVH) constraints and build a predictive nomogram for RP. ResultsAn increased risk of RP was strongly associated with mean lung dose (MLD) > 13.5 Gy (odds ratio [OR]: 8.13; 95% confidence interval [CI], 3.01-21.93; P < .001) and the percent of lung volume receiving ≥5 Gy (V5) > 55% (OR: 7.01; 95% CI, 2.94-16.72; P < .001). Therefore, patients had low RP risk (8%) if both MLD ≤13.5 and V5 ≤55 constraints were achieved, moderate risk (24%) if only MLD was achieved, and the highest risk (48%) if MLD was not achieved. Deep-inspiration breath-hold (DIBH) technique during treatment strongly prognosticated achieving MLD and V5 DVH constraints (OR,3.88; 95% CI, 1.84-8.19; P < .001). Specifically, 86% of patients who were treated with DIBH versus 63% without DIBH achieved DVH constraints (P < .001). This translated into a “number needed to treat” with DIBH of 4 patients to enable 1 additional patient to achieve both constraints. In comparison, the clinical characteristics were marginal prognosticators: DVH constraints were more likely achieved in nonbulky disease (OR: 3.01; 95% CI, 0.89-4.53; P = .09) and patients who had not previously received salvage chemotherapy (OR, 2.44; 95% CI, 0.98-6.11; P = .06). Nomogram-predicted risks of RP ranged from 4% to 60% on the basis of MLD and V5, total radiation dose, and use of salvage chemotherapy. ConclusionsAchieving mean lung and V5 DVH constraints is critical to reduce RP risk in patients with lymphoma who receive mediastinal intensity modulated radiation therapy. The use of the DIBH technique is a promising risk-modifying treatment approach in patients with mediastinal lymphoma and especially in patients with a history of nonmodifiable risk factors for RP such as bulky disease and salvage chemotherapy.

Investigating the impact of treatment delivery uncertainties on treatment effectiveness for lung SABR.

To quantify the impact of treatment delivery uncertainties on lung stereotactic ablative body radiotherapy (SABR) plans for step-and-shoot intensity-modulated radiotherapy (ssIMRT) and volumetric modulated arc therapy (VMAT). Baseline ssIMRT and VMAT treatment plans were generated for a cohort of 18 lung SABR patients. Modified plans were generated for each baseline plan by systematically varying gantry and collimator angles between -5 and +5 degrees, as well as multi-leaf collimator (MLC) leaf position errors of magnitude between 1 and 5 mm in both directions (i.e. leaf banks shifted either in the same (Type 1) or opposite (Type 2) directions). Planning target volume (PTV), spinal cord and healthy lung dose-volume histogram (DVH) metrics were compared between the modified and baseline plans. Collimator and gantry angle uncertainties did not significantly impact any of the PTV DVH metrics considered. MLC shifts of 5 mm resulted in average V95% changes of [Formula: see text] (Type 1) and [Formula: see text] (Type 2) and average [Formula: see text] changes of [Formula: see text] (Type 1) and [Formula: see text] (Type 2) for ssIMRT and VMAT plans. Comparatively, MLC shifts of - 2 mm resulted in average [Formula: see text] changes of [Formula: see text] (Type 1) and [Formula: see text] (Type 2) and average [Formula: see text] changes of [Formula: see text] (Type 1) and [Formula: see text] (Type 2) for ssIMRT and VMAT plans. ssIMRT gantry angle uncertainties impacted spinal cord DVH metrics the most, with increases in [Formula: see text] of [Formula: see text] occurring for a 1 degree shift. Type 2 MLC modifications impacted all OAR DVH metrics substantially with differences in spinal cord [Formula: see text] (ssIMRT) and healthy lung [Formula: see text] (VMAT) exceeding [Formula: see text] for 5 mm shifts. Uncertainties in MLC leaf positions affected target and OAR DVH metrics more than collimator or gantry angle uncertainties for lung SABR plans. Less patient-to-patient variation occurred from delivery uncertainties in VMAT than ssIMRT.

Thoracic radiation-induced pleural effusion and risk factors in patients with lung cancer.

The risk factors and potential practice implications of radiation-induced pleural effusion (RIPE) are undefined. This study examined lung cancer patients treated with thoracic radiation therapy (TRT) having follow-up computed tomography (CT) or 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT. Increased volumes of pleural effusion after TRT without evidence of tumor progression was considered RIPE. Parameters of lung dose-volume histogram including percent volumes irradiated with 5-55 Gy (V5-V55) and mean lung dose (MLD) were analyzed by receiver operating characteristic analysis. Clinical and treatment-related risk factors were detected by univariate and multivariate analyses. 175 out of 806 patients receiving TRT with post-treatment imaging were included. 51 patients (24.9%) developed RIPE; 40 had symptomatic RIPE including chest pain (47.1%), cough (23.5%) and dyspnea (35.3%). Female (OR = 0.380, 95% CI: 0.156–0.926, p = 0.033) and Caucasian race (OR = 3.519, 95% CI: 1.327–9.336, p = 0.011) were significantly associated with lower risk of RIPE. Stage and concurrent chemotherapy had borderline significance (OR = 1.665, p = 0.069 and OR = 2.580, p = 0.080, respectively) for RIPE. Patients with RIPE had significantly higher whole lung V5-V40, V50 and MLD. V5 remained as a significant predictive factor for RIPE and symptomatic RIPE (p = 0.007 and 0.022) after adjusting for race, gender and histology. To include, the incidence of RIPE is notable. Whole lung V5 appeared to be the most significant independent risk factor for symptomatic RIPE.

Lymphopenia association with planning target volume and lung V5 and its effect on survival of esophageal cancer receiving neoadjuvant chemo-radiation with Dutch CROSS regime

Introduction: Radiation has a strong lympholytic effect. This effect has been overlooked for decades until recently. As immunotherapy is becoming one of the main systemic treatment of various cancer, it is important to adopt best radiation technique to preserve lymphocyte numbers. Radiation-induced lymphopenia has been reported to be adversely associated with overall survival and recurrence free survival in various cancers including lung, pancreatic and head and neck cancer. Data of lymphopenia effect on esophageal cancer is lacking. We therefore sought to study the association of lymphopenia and overall survival in esophageal cancer patients who have undergone neoadjuvant chemo-radiation according to Dutch CROSS trial regime. One of the possible mechanism of severe lymphopenia in radiotherapy is the large volume of low dose bath killing large number of circulating lymphocytes in both systemic and pulmonary circulation. As there is report of relationship of low dose lung dosimetry parameters with lymphopenia in NSCLC, we also aim to study this relationship in esophageal cancer. Methods: All esophageal cancer patients from June 2012 to April 2015 in our tertiary university hospital who have received neoadjuvant chemo-radiation according to Dutch CROSS trial regime has been retrospectively reviewed. Total subjects eligible for review is 51. One subject has died before the start of chemo-radiation and thus was excluded from analysis. Lymphocyte nadir was defined as the minimum lymphocyte value measured between the start of neoadjuvant chemo-radiation and the operation date. Relationships between lymphocyte nadirs with overall survival (OS) and recurrence free survival (RFS) were evaluated with Cox-regression analysis. Association between Planning Target volume (PTV) and lung dose- volume histogram (DVH) parameters were analysed with Pearson correlation coefficients. Results: 48 out of 50 subjects have normal baseline lymphocyte counts. Low lymphocyte nadir is found to have negative effect on patient's overall survival (OS). On multi-variable Cox regression with backward elimination analysis, patients with higher lymphocyte nadirs exhibited significantly improved OS (hazard ratio [HR] Z = 0.656 per 0.1 x 10^9 lymphocytes/L, p = 0.009). Of note, no significant relationships with OS were seen in baseline total white cell count, lymphocyte count and neutrophil count. Analyses of lung DVH parameters revealed significant correlations at lower doses (lung V1-V15: P < 0.001). The absolute value Pearson correlation coefficient incrementally decreased and became nonsignificant at higher doses (lung V25: P>.05). For instance, the correlation coefficient of V1, V5 and V10 were -0.566, -0.495 and -0.419 respectively. Larger PTV was also associated with lower lymphocyte nadir (r= -0.367 P = 0.008). Conclusion: Lower lymphocyte nadir is associated with poorer overall survival in this group of patients. Higher low dose lung DVH and larger PTV are associated with lower lymphocyte nadir. These findings shall be confirmed with prospective data in future studies. This also suggests immune preserving radiation strategy in radiation by suppressing low dose lung DVH may improve OS in this group of patients.

Pulmonary Function Changes After Radiotherapy for Lung or Esophageal Cancer: A Systematic Review Focusing on Dose-Volume Parameters.

Despite technical developments in treatment delivery, radiation-induced lung toxicity (RILT) remains a crucial problem in thoracic radiotherapy. Clinically based RILT scores have their limitations, and more objective measures such as pulmonary functions tests (PFTs) might help to improve treatment strategies. To summarize the available evidence about the effect of dose to the lung in thoracic radiotherapy on forced expiratory volume in one second (FEV1) and diffusion capacity (DLCO) in patients with lung and esophageal cancer treated with curative intent. A systematic review following the PRISMA guidelines was performed, using MEDLINE and including clinical studies using (chemo)radiotherapy (CRT) or stereotactic ablative radiotherapy (SABR) for lung or CRT for esophageal cancer that reported both lung dose-volume histogram (DVH) parameters and changes in PFT results. Search terms included lung and esophageal neoplasms, respiratory function tests, and radiotherapy. Fifteen studies met the inclusion criteria. Seven out of 13 studies on lung cancer reported significant declines (defined as a p value < .05) in PFT results. Both esophageal studies reported significant DLCO declines. One SABR study found a correlation between low lung-dose parameters and FEV1 decline. Relations between decline of FEV1 (three studies) or decline of DLCO (five studies), respectively, and DVH parameters were found in eight studies analyzing CRT. Furthermore, a heterogeneous range of clinical risk factors for pulmonary function changes were reported in the selected studies. There is evidence that pulmonary function declines after RT in a dose-dependent manner, but solid data about lung DVH parameters predicting changes in PFT results are scarce. A major disadvantage was the wide variety of methods used, frequently lacking multivariable analyses. Studies using prospective high-quality data, analyzed with appropriate statistical methods, are needed. The Oncologist 2017;22:1257-1264 IMPLICATIONS FOR PRACTICE: Radiation-induced lung toxicity remains crucial in thoracic radiotherapy. To prevent this toxicity in the future and individualize patient treatment, objective measures of pulmonary toxicity are needed. Pulmonary function tests may provide such objective measures. This systematic review, included all available clinical studies using external beam radiotherapy for lung or esophageal cancer reporting pulmonary function combined with dose-volume histogram parameters. There is preliminary evidence that pulmonary function declines post radiotherapy in a dose-dependent manner. Data quality and analyses were generally limited. Analyses of high-quality data are therefore urgently needed to improve individualization of advanced radiation therapy.

Inclusion of Incidental Radiation Dose to the Cardiac Atria and Ventricles Does Not Improve the Prediction of Radiation Pneumonitis in Advanced-Stage Non-Small Cell Lung Cancer Patients Treated With Intensity Modulated Radiation Therapy

To evaluate whether inclusion of incidental radiation dose to the cardiac atria and ventricles improves the prediction of grade ≥3 radiation pneumonitis (RP) in advanced-stage non-small cell lung cancer (AS-NSCLC) patients treated with intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT). Using a bootstrap modeling approach, clinical parameters and dose-volume histogram (DVH) parameters of lungs and heart (assessing atria and ventricles separately and combined) were evaluated for RP prediction in 188 AS-NSCLC patients. After a median follow-up of 18.4months, 26 patients (13.8%) developed RP. Only the median mean lung dose (MLD) differed between groups (15.3Gy vs 13.7Gy for the RP and non-RP group, respectively; P=.004). The MLD showed the highest Spearman correlation coefficient (Rs) for RP (Rs=0.21; P<.01). Most Rs of the lung DVH parameters exceeded those of the heart DVH parameters. After predictive modeling using a bootstrap procedure, the MLD was always included in the predictive model for grade ≥3 RP, whereas the heart DVH parameters were seldom included in the model. Incidental dose to the cardiac atria and ventricles did not improve RPriskprediction in our cohort of 188 AS-NSCLC patients treated with IMRT or VMAT.

Comparison between different boost dose delivery techniques to the tumor bed of right sided breast cancer patients.

Comparisons between three different techniques by which the boost dose was delivered to the tumor bed were carried out , aiming to present the best technique of treatment for right breast cancer patients.In this study, ten right sided breast cancer computed tomography (CT) scans were selected for ten early right breast cancer patients. We made three different treatment plans for each patient CT using three different irradiation techniques to deliver a prescribed boost dose of 10 Gy in 5 fractions to the boost PTV. In the first technique, two tangential photon beams were used, in the second technique we, two oblique photon beams were used and in the third technique, a single electron beam was used. The comparative analyses between the three techniques were performed by comparing the boost PTV- dose volume histograms (DVHs), the ipsilateral breast (right breast) DVHs, the ipsilateral lung (right lung) DVHs and the heart DVHs of the three techniques for each patient. Furthermore the dose that covering 100% , 95% of the volume (D100% , D95%) and the volume covered by 95% of the dose (V95%)of the boost PTV of all techniques, were calculated for each patient to investigate the dose coverage of the target.Results showed that there were variations of the dose received by tumor bed, right breast and OARs depending on the technique used and the target location and size. A decrease of D100% than 90% of the prescribed dose was observed with the 3rd technique for patients 8, 9 and 10, and was observed with the 2nd technique for patient 5. A reduction of right breast dose was observed when the 3rd technique was use in comparison with the 1st and the 2nd techniques for patients 1, 2, 3, 4, 6 and 8. Also reduction of right breast was observed when the 2nd technique used in comparison with 1st technique. An increase of lung dose was observed with the 3rd technique for patients 1, 2, 5 and 6, also was observed with 2nd technique in patient 3, 5 and 7. A decrease of lung dose was observed with the 1st technique for patients 2, 4, 5, 6, 7, 8 and 9An individualized treatment, several plans using different irradiation techniques should be developed for each patient individually to reach the best boost PTV dose coverage with minimal OARs’ dose.Â

SU-G-TeP1-11: Predictors of Cardiac and Lung Dose Sparing in DIBH for Left Breast Treatment

Purpose: This retrospective study of left sided whole breast radiation therapy (RT) patients investigates possible predictive parameters correlating to cardiac and left lung dose sparing by deep inspiration breath-hold (DIBH) technique compared to free-breathing (FB). Methods: Thirty-one patients having both DIBH and FB CT scans were included in the study. All patients were planned with a standard step-and-shoot tangential technique using MV photons, with prescription of 50Gy or 50.4Gy. The displacement of the breath hold sternal mark during DIBH, the cardiac contact distances of the axial (CCDax) and parasagittal (CCDps) planes, and lateral-heart-to-chest (LHC) distance on FB CT scans were measured. Lung volumes, mean dose and dose-volume histograms (V5, V10 and V20) were analyzed and compared for heart and left lung for both FB and DIBH techniques. Correlation analysis was performed to identify the predictors for heart and left lung dose sparing. Two-tailed Student's t-test and linear regression were used for data analysis with significance level of P≤0.05. Results: All dosimetric metrics for the heart and left lung were significantly reduced (P<0.01) with DIBH. Breath hold sternal mark displacement ranged from 0.4–1.8 cm and correlated with mean (P=0.05) and V5 (P=0.02) of heart dose reduction by DIBH. FB lung volume showed correlation with mean lung dose reduction by DIBH (P<0.01). The FB-CCDps and FB-LHC distance had strong positive and negative correlation with FB mean heart dose (P<0.01) and mean heart dose reduction by DIBH (P<0.01), respectively. FB-CCDax showed no correlation with dosimetric changes. Conclusion: DIBH technique has been shown to reduce dose to the heart and left lung. In this patient cohort, FB-CCDps, FB-LHC distance, and FB lung volume served as significant predictors for heart and left lung. These parameters can be further investigated to be used as a tool to better select patients who will benefit from DIBH.

Impact of heart and lung dose on early survival in patients with non-small cell lung cancer treated with chemoradiation

Background and purposeTo determine whether the impact of heart dose on early overall survival (OS) reported in RTOG 0617 could be confirmed in an independent cohort. Materials and methodsHeart and lung dose-volume histogram data were retrospectively extracted for patients with stage IIIA-IIIB non-small cell lung cancer (NSCLC) who had received radiotherapy using 3D CRT, IMRT or proton therapy delivered with concurrent chemotherapy between 1999 and 2010. Potential associations between clinical and dosimetric factors and OS up to 24months after start of treatment were assessed in univariate and multivariate analyses with log-rank tests or Cox proportional hazards models. Results468 patients met inclusion criteria. Factors associated with increased risk of early death in univariate analyses were performance status (PS), stage, treatment with 3D conformal radiotherapy, lower tumor dose and larger gross tumor volume (GTV), mean heart dose (MHD), heart V5, mean lung dose (MLD) and lung V5. Factors retaining significance in multivariate analysis were PS, GTV, and MLD. There was a strong correlation between MHD and heart V5 with MLD. However, no evidence was found that heart doses had an independent effect on OS during the first 2years. ConclusionsIn a large group of patients treated with chemoradiation for locally advanced NSCLC, heart dose was not found to be associated with early survival outcomes when lung dose was taken into account. Nevertheless, based on the known adverse effects of radiotherapy on vasculature and cardiac function, dose to the heart should be minimized during radiotherapy planning.

Extracting the normal lung dose–response curve from clinical DVH data: a possible role for low dose hyper-radiosensitivity, increased radioresistance

In conventionally fractionated radiation therapy for lung cancer, radiation pneumonitis’ (RP) dependence on the normal lung dose-volume histogram (DVH) is not well understood. Complication models alternatively make RP a function of a summary statistic, such as mean lung dose (MLD). This work searches over damage profiles, which quantify sub-volume damage as a function of dose. Profiles that achieve best RP predictive accuracy on a clinical dataset are hypothesized to approximate DVH dependence.Step function damage rate profiles R(D) are generated, having discrete steps at several dose points. A range of profiles is sampled by varying the step heights and dose point locations. Normal lung damage is the integral of R(D) with the cumulative DVH. Each profile is used in conjunction with a damage cutoff to predict grade 2 plus (G2+) RP for DVHs from a University of Michigan clinical trial dataset consisting of 89 CFRT patients, of which 17 were diagnosed with G2+ RP.Optimal profiles achieve a modest increase in predictive accuracy—erroneous RP predictions are reduced from 11 (using MLD) to 8. A novel result is that optimal profiles have a similar distinctive shape: enhanced damage contribution from low doses (<20 Gy), a flat contribution from doses in the range ~20–40 Gy, then a further enhanced contribution from doses above 40 Gy. These features resemble the hyper-radiosensitivity / increased radioresistance (HRS/IRR) observed in some cell survival curves, which can be modeled using Joiner’s induced repair model.A novel search strategy is employed, which has the potential to estimate RP dependence on the normal lung DVH. When applied to a clinical dataset, identified profiles share a characteristic shape, which resembles HRS/IRR. This suggests that normal lung may have enhanced sensitivity to low doses, and that this sensitivity can affect RP risk.

SU‐E‐T‐711: Study of the Correlation Between the Anatomic Features of PTV and the Whole Lung DVH in Esophagus Cancer IMRT Plans

Purpose:To quantitatively detect the correlation between the anatomic features of plan target volume (PTV) and the whole lung dose‐volume histogram (DVH) in esophagus cancer (EC) intensity‐modulated radiotherapy (IMRT) plans.Methods:50 patients with EC underwent IMRT protocol were retrospectively studied. The PTV of EC contained esophagus gross target volume (GTV) and the positive neck lymph nodes. 7 fixed gantry IMRT plans were designed by senior planners for each patient using treatment planning system‐Eclipse 10.0 (Varian Medical Systems, Palo Alto, CA). The doses of all organ at risks (OARs) met clinical standard. The valuable morphological parameters of PTV under positive neck lymph nodes, such as the volume, the surface area, the ratio of PTV volume to whole lung volume, the fraction of whole lung volume overlapping with PTV (overlap volume), the length, and the torsion, were extracted. The correlation between every anatomic feature parameter of PTV and the whole lung DVH of EC plans were counted. Finally we acquired a curve about the whole lung doses and every morphological parameter using data fitting.Results:The morphological parameters of PTV under positive neck lymph nodes can be described quite well. Valuable anatomic feature parameters, such as the ratio of PTV volume to whole lung volume, the overlap volume, and the length, impact the whole lung DVH significantly. With these parameters value increasing, dosimetric parameters (such as V5, V10, V20, V30, V40, the mean dose of whole lung) will raise. Especially, the low‐dose regions are more obvious.Conclusion:The results highlight that the anatomical features parameters of PTV and dosimetric indexes of whole lung DVH can be correlated quantitatively in EC IMRT plans, and which offers a potential use in study and prediction of whole lung doses in EC radiotherapy.

Predicting radiation-induced valvular heart damage

Purpose. To develop a predictive multivariate normal tissue complication probability (NTCP) model for radiation-induced heart valvular damage (RVD). The influence of combined heart-lung irradiation on RVD development was included.Material and methods. Multivariate logistic regression modeling with the least absolute shrinkage and selection operator (LASSO) was used to build an NTCP model to predict RVD based on a cohort of 90 Hodgkin lymphoma patients treated with sequential chemo-radiation therapy. In addition to heart irradiation factors, clinical variables, along with left and right lung dose-volume histogram statistics, were included in the analysis. To avoid overfitting, 10-fold cross-validation (CV) was used for LASSO logistic regression modeling, with 50 reshuffled cycles. Model performance was assessed using the area under the receiver operating characteristic (ROC) curve (AUC) and Spearman's correlation coefficient (Rs).Results. At a median follow-up time of 55 months (range 12–92 months) after the end of radiation treatment, 27 of 90 patients (30%) manifested at least one kind of RVD (mild or moderate), with a higher incidence of left-sided valve defects (64%). Fourteen prognostic factors were frequently selected (more than 100/500 model fits) by LASSO, which included mainly heart and left lung dosimetric variables along with their volume variables. The averaged cross-validated performance was AUC-CV = 0.685 and Rs = 0.293. The overall performance of a final NTCP model for RVD obtained applying LASSO logistic regression to the full dataset was satisfactory (AUC = 0.84, Rs = 0.55, p < 0.001).Conclusion. LASSO proved to be an improved and flexible modeling method for variable selection. Applying LASSO, we showed, for the first time, the importance of jointly considering left lung irradiation and left lung volume size in the prediction of subclinical radiation-related heart disease resulting in RVD.

The prognostic value of irradiated lung volumes on the prediction of intra-/ post-operative mortality in patients after neoadjuvant radiochemotherapy for esophageal cancer. A retrospective multicenter study.

Purpose: To assess the association between dosimetric factors of the lung and incidence of intra- and postoperative mortality among esophageal cancer (EC) patients treated with neoadjuvant radiochemotherapy (N-RCT) followed by surgery (S).Methods and Materials: Inclusion criteria were: age < 85 years, no distant metastases at the time of diagnosis, no induction chemotherapy, conformal radiotherapy, total dose ≤ 50.4 Gy, and available dose volume histogram (DVH) data. One-hundred thirty-five patients met our inclusion criteria. Median age was 62 years. N-RCT consisted of 36 - 50.4 Gy (median 45 Gy), 1.8 - 2 Gy per fraction. Concomitant chemotherapy consisted of 5-Fluoruracil (5-FU) and cisplatin in 113 patients and cisplatin and taxan-derivates in 15 patients. Seven patients received a single cytotoxic agent. In 130 patients an abdominothoracal and in 5 patients a transhiatal resection was performed. The following dosimetric parameters were generated from the total lung DVH: mean dose, V5, V10, V15, V20, V30, V40, V45 and V50. The primary endpoint was the rate of intra- and postoperative mortality (from the start of N-RCT to 60 days after surgical resection).Results: A total of ten postoperative deaths (7%) were observed: 3 within 30 days (2%) and 7 between 30 and 60 days after surgical intervention (5%); no patient died during the operation. In the univariate analysis, weight loss (≥10% in 6 months prior to diagnosis, risk ratio: 1.60, 95%CI: 0.856-2.992, p=0.043), Eastern Cooperative Oncology Group-performance status (ECOG 2 vs. 1, risk ratio: 1.931, 95%CI: 0.898-4.150, p=0.018) and postoperative pulmonary plus non-pulmonary complications (risk ratio: 2.533, 95%CI: 0.978-6.563, p=0.004) were significantly associated with postoperative mortality. There was no significant association between postoperative mortality and irradiated lung volumes. Lung V45 was the only variable which was significantly associated with higher incidence of postoperative pulmonary plus non-pulmonary complications (Exp(B): 1.285, 95%CI 1.029-1.606, p=0.027), but not with the postoperative pulmonary complications (Exp(B): 1.249, 95%CI 0.999-1.561, p=0.051).Conclusions: Irradiated lung volumes did not show relevant associations with intra- and postoperative mortality of patients treated with moderate dose (36 - 50.4 Gy) conventionally fractionated conformal radiotherapy combined with widely used radiosensitizers. Postoperative mortality was significantly associated with greater weight loss, poor performance status and development of postoperative complications, but not with treatment-related factors. Limiting the volume of lung receiving higher radiation doses appears prudent because of the observed association with risk of postoperative complications.

Complication Probability Models for Radiation-Induced Heart Valvular Dysfunction: Do Heart-Lung Interactions Play a Role?

PurposeThe purpose of this study is to compare different normal tissue complication probability (NTCP) models for predicting heart valve dysfunction (RVD) following thoracic irradiation.MethodsAll patients from our institutional Hodgkin lymphoma survivors database with analyzable datasets were included (n = 90). All patients were treated with three-dimensional conformal radiotherapy with a median total dose of 32 Gy. The cardiac toxicity profile was available for each patient. Heart and lung dose-volume histograms (DVHs) were extracted and both organs were considered for Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP model fitting using maximum likelihood estimation. Bootstrap refitting was used to test the robustness of the model fit. Model performance was estimated using the area under the receiver operating characteristic curve (AUC).ResultsUsing only heart-DVHs, parameter estimates were, for the LKB model: D50 = 32.8 Gy, n = 0.16 and m = 0.67; and for the RS model: D50 = 32.4 Gy, s = 0.99 and γ = 0.42. AUC values were 0.67 for LKB and 0.66 for RS, respectively. Similar performance was obtained for models using only lung-DVHs (LKB: D50 = 33.2 Gy, n = 0.01, m = 0.19, AUC = 0.68; RS: D50 = 24.4 Gy, s = 0.99, γ = 2.12, AUC = 0.66). Bootstrap result showed that the parameter fits for lung-LKB were extremely robust. A combined heart-lung LKB model was also tested and showed a minor improvement (AUC = 0.70). However, the best performance was obtained using the previously determined multivariate regression model including maximum heart dose with increasing risk for larger heart and smaller lung volumes (AUC = 0.82).ConclusionsThe risk of radiation induced valvular disease cannot be modeled using NTCP models only based on heart dose-volume distribution. A predictive model with an improved performance can be obtained but requires the inclusion of heart and lung volume terms, indicating that heart-lung interactions are apparently important for this endpoint.

Differences and radiation pneumonitis prediction of lung dosimetric parameters based on three normal lung definitions in 3DCRT treatment planning

Objective To compare lung dose-volume histogram (DVH) parameters based on commonly used normal lung definitions,i.e.,lungs-gross tumor volume (GTV),lungs-clinical target volume (CTV),and lungs-planning target volume (PTV),in three-dimensional conformal radiotherapy (3 DCRT) and to determine to what extent they differ in predicting radiation pneumonitis (RP).Methods A total of 147 non-small cell lung cancer patients treated with concurrent chemotherapy and 3DCRT from 2006 to 2010 were collected.RP was diagnosed according to RTOG criteria.Lung DVHs were generated with exclusion of GTV,CTV,or PTV.Independent-samples t test was used to compare DVH parameters based on different normal lung definitions,and the predictive values of these parameters for RP were evaluated with the receiver operating characteristic (ROC) curve.Results There were significant differences in minimum lethal dose (MLD) between lungs-GTV and lungs-CTV/lungs-PTV ((1.16 ± 0.96) Gy vs.(3.45 ± 1.43) Gy).The biggest difference in MLD for the same patient based on different definitions was 8.73 Gy.MLD based on lungs-GTV had a better predictive value for grades ≥2 and ≥3 RP than MLD based on lungs-CTV and lungs-PTV,with larger areas under the ROC curve (lungs-GTV ∶ area =0.614,P=0.024;area =0.678,P=0.056;lungs-CTV∶area =0.556,P=0.269;area =0.602,P=0.226 ; lungs-PTV ∶ area =0.551,P =0.317 ; area =0.616,P =0.167).We drew a similar conclusion when analyzing lung V5-V50.Conclusions There are significant differences between DVH parameters based on various normal lung definitions,which cannot be neglected in the clinical setting.DVH parameters based on lungs-GTV may be the most accurate in predicting RP. Key words: Carcinoma, non-small cell lung/radiotherapy; Radiotherapy, three-dimensional conformal ; Radiation pneumonitis ; Dosimetry

Predictors of Site-Specific Distant Metastasis After Definitive Radiation Therapy in Non-Small Cell Lung Cancer and the Impact of Metastatic Location on Survival

Purpose/Objective(s): Systemic lymphocyte count has been established as prognostic in numerous cancer types. Of relevance is the ability of low dose radiation therapy (RT) to induce death in circulating lymphocytes despite the mitotic inactivity of this cell type. We sought to investigate the potential causes of RT-induced lymphopenia and its associations with patient outcomes in non-small cell lung cancer (NSCLC). Materials/Methods: Subjects were 711 patients who had received definitive RT for NSCLC with 2 lymphocyte measurements during RT. A lymphocyte nadir was defined as the minimum systemic lymphocyte value during RT. Associations between gross tumor volumes (GTVs) and lung dose-volume histogram (DVH) parameters with lymphocyte nadirs were assessed with Spearman’s correlations. Relationships between lymphocyte nadirs with overall survival (OS) and event free survival (EFS) were evaluated with Kaplan-Meier analysis and log-rank tests. Stepwise multivariate regression was conducted with linear and Cox regressions. All variables were analyzed as continuous if possible. Results: Analyses of lung DVH parameters revealed significant correlation with lymphocyte nadir at lower doses (lung v5-10: P 0.05). Lung v5 were lower in patients receiving proton therapy (Median: 30.4%) compared with 3D conformal (Median: 55.6%, P<0.0001) and intensity modulated (Median: 55.4%, P<0.0001) RT. Similarly, larger GTVs were correlated with lower lymphocyte nadirs regardless of concurrent chemotherapy receipt (with concurrent: r Z –0.26, P<0.0001; without: r Z –0.48, P<0.0001). GTV and lung DVH parameters were not associated with other treatment nadirs in other hematopoietic populations (total leukocyte, neutrophil, or monocyte) nor were they associated with pre-RT lymphocyte count. Multivariate analysis revealed GTV (P<0.0001), lung v5 (P<0.0001), receipt of concurrent chemotherapy (P Z 0.001), and twice-daily fractionation (P Z 0.0002) to be associated with lower lymphocyte nadirs. With regard to patient outcomes, univariate analyses revealed lower lymphocyte nadirs to be associated with worse OS (hazard ratio [HR] Z 1.96 per 10 lymphocytes/mL, P Z 0.01) and EFS (HR Z 2.17 per 10 lymphocytes/mL, P<0.0001). Differences held on multivariate analyses controlling for disease and treatment characteristics including GTV. Conclusions: GTV and Lung v5 were associated with lower lymphocyte nadirs, while lower lymphocyte nadirs were predictive of worse patient outcomes. If validated, further investigations should focus on techniques that minimize this “low dose bath.” Author Disclosure: C. Tang: None. Z. Liao: None. D. Gomez: None. L. Levy: None. Z. Yan: None. X. Ting: None. Q. Nguyen: None. R. Komaki: None. J. Welsh: None.

Lymphopenia Association With Gross Tumor Volume and Lung V5 and Its Effects on Non-Small Cell Lung Cancer Patient Outcomes

Radiation therapy (RT) can both suppress and stimulate the immune system. We sought to investigate the mechanisms underlying radiation-induced lymphopenia and its associations with patient outcomes in non-small cell lung cancer (NSCLC). Subjects consisted of 711 patients who had received definitive RT for NSCLC. A lymphocyte nadir was calculated as the minimum lymphocyte value measured during definitive RT. Associations between gross tumor volumes (GTVs) and lung dose-volume histogram (DVH) parameters with lymphocyte nadirs were assessed with Spearman correlation coefficients. Relationships between lymphocyte nadirs with overall survival (OS) and event free survival (EFS) were evaluated with Kaplan-Meier analysis and compared with log-rank test results. Multivariate regressions were conducted with linear and Cox regression analyses. All variables were analyzed as continuous if possible. Larger GTVs were correlated with lower lymphocyte nadirs regardless of concurrent chemotherapy receipt (with concurrent: r = -0.26, P<.0001; without: r=-0.48, P<.0001). Analyses of lung DVH parameters revealed significant correlations at lower doses (lung V5-V10: P<.0001) that incrementally decreased and became nonsignificant at higher doses (lung V60-V70: P>.05). Of note, no significant associations were detected between GTV and lung DVH parameters with total leukocyte, neutrophil, or monocyte nadirs during RT or with lymphocyte count prior to RT. Multivariate analysis revealed larger GTV (P<.0001), receipt of concurrent chemotherapy (P<.0001), twice-daily radiation fractionation (P=.02), and stage III disease (P=.05) to be associated with lower lymphocyte nadirs. On univariate analysis, patients with higher lymphocyte nadirs exhibited significantly improved OS (hazard ratio [HR] = 0.51 per 10(3) lymphocytes/μL, P=.01) and EFS (HR = 0.46 per 10(3) lymphocytes/μL, P<.0001). These differences held on multivariate analyses, controlling for common disease and treatment characteristics including GTV. Lower lymphocyte nadirs during definitive RT were associated with larger GTVs and worse patient outcomes.

The impact of inter-fraction set-up errors on the probability of pulmonary and cardiac complication in left-sided breast cancer patients

AbstractPurposeThis study evaluated the impact of patient set-up errors on the probability of pulmonary and cardiac complications in the irradiation of left-sided breast cancer.Methods and materialsUsing the CMS XiO Version 4·6 radiotherapy planning system's normal tissue complication probability (NTCP) algorithm and the Lyman–Kutcher–Burman model, we calculated the dose–volume histograms (DVH) indices for the ipsilateral lung and heart and the resultant NTCP for radiation-induced pneumonitis and excess cardiac mortality in 12 left-sided breast cancer patients.ResultsIsocentric shifts in the posterior direction had the greatest effect on the lung V20, heart V25, and mean and maximum doses to the lung and the heart. DVH results show that the ipsilateral lung V20 tolerance was exceeded in 58% of the patients after 1 cm posterior shifts. Similarly, the heart V25 tolerance was exceeded after 1 cm antero-posterior and left–right isocentric shifts in 70% of the patients. The baseline NTCPs for radiation-induced pneumonitis ranged from 0·73% to 3·4%, with a mean value of 1·7%. The maximum reported NTCP for radiation-induced pneumonitis was 5·8% (mean 2·6%) after 1 cm posterior isocentric shift. The NTCP for excess cardiac mortality were 0% in 100% of the patients (n = 12) before and after set-up error simulations.ConclusionsSet-up errors in left-sided breast cancer patients have a statistically significant impact on the Lung NTCPs and DVH indices. However, with a central lung distance of 3 cm or less (CLD &lt; 3 cm), and a maximum heart distance of 1·5 cm or less (MHD &lt; 1·5 cm), the treatment plans could tolerate set-up errors of up to 1 cm without any change in the NTCP to the heart.

Is there an impact of heart exposure on the incidence of radiation pneumonitis? Analysis of data from a large clinical cohort

Background. The goal of the present study was to determine, in a large clinical cohort, whether incidental radiation exposure to the heart during definitive radiotherapy of inoperable non-small cell lung cancer (NSCLC) detectably increased the risk of radiation pneumonitis (RP) beyond that resulting from radiation exposure to lung. Material and methods. Data were analyzed from all patients who received definitive three-dimensional (3D) concurrent radiotherapy or intensity-modulated radiotherapy for the treatment of NSCLC over a 10-year period at our institution, except those who had previous lung cancer or for whom radiation treatment plans were unavailable for calculation of heart and lung dose-volume histograms (DVHs). Parameters computed from heart and lung DVHs included mean lung dose (MLD), effective lung dose computed using volume parameter n = 0.5 (Deff), mean heart dose (MHD), percentage of heart receiving > 65 Gy (V65), and minimum dose to the hottest 10% of heart (D10). Univariate and multivariate normal-tissue complication probability (NTCP) models were used to analyze incidence of Grade ≥ 2 or Grade ≥ 3 RP as a function of these and other parameters. Results. The study cohort included 629 patients, with crude rates of Grade ≥ 2 RP and Grade ≥ 3 RP of N = 263 (42%) and N = 124 (20%), respectively. Univariate NTCP models based on dosimetric lung parameters (MLD and Deff) fit the data better than models based on univariate heart parameters (heart D10, heart V65 or MHD). In multivariate modeling, incorporation of heart parameters did not significantly improve the fit of RP risk models based on lung parameters alone (p > 0.38 in each case). Conclusions. In this large clinical cohort, there was no evidence that incidental heart exposure during radiotherapy of NSCLC had a detectable impact on the occurrence of moderate or severe RP.