Higher Mean Lung Dose Research Articles

Real-World Acute Toxicity and 90-Day Mortality in Patients With Stage I NSCLC Treated With Stereotactic Body Radiotherapy

IntroductionStereotactic body radiotherapy (SBRT) has firmly established its role in stage I NSCLC. Clinical trial results may not fully apply to real-world scenarios. This study aimed to uncover the real-world incidence of acute toxicity and 90-day mortality in patients with SBRT-treated stage I NSCLC and develop prediction models for these outcomes. MethodsProspective data from the Dutch Lung Cancer Audit for Radiotherapy (DLCA-R) were collected nationally. Patients with stage I NSCLC (cT1-2aN0M0) treated with SBRT in 2017 to 2021 were included. Acute toxicity was assessed, defined as grade greater than or equal to 2 radiation pneumonitis or grade greater than or equal to 3 non-hematologic toxicity less than or equal to 90 days after SBRT. Prediction models for acute toxicity and 90-day mortality were developed and internally validated. ResultsAmong 7279 patients, the mean age was 72.5 years, with 21.6% being above 80 years. Most were male (50.7%), had WHO scores 0 to 1 (73.3%), and had cT1a-b tumors (64.6%), predominantly in the upper lobes (65.2%). Acute toxicity was observed in 280 (3.8%) of patients and 90-day mortality in 122 (1.7%). Predictors for acute toxicity included WHO greater than or equal to 2, lower forced expiratory volume in 1 second and diffusion capacity for carbon monoxide, no pathology confirmation, middle or lower lobe tumor location, cT1c-cT2a stage, and higher mean lung dose (c-statistic 0.68). Male sex, WHO greater than or equal to 2, and acute toxicity predicted higher 90-day mortality (c-statistic 0.73). ConclusionsThis nationwide study revealed a low rate of acute toxicity and an acceptable 90-day mortality rate in patients with SBRT-treated stage I NSCLC. Notably, advanced age did not increase acute toxicity or mortality risk. Our predictive models, with satisfactory performance, offer valuable tools for identifying high-risk patients.

Real World Rates and Predictive Factors of Pneumonitis in Advanced, Non-Resectable NSCLC Treated with Concurrent Chemoradiation and Durvalumab

<h3>Purpose/Objective(s)</h3> Real world outcomes related to pneumonitis in patients with locally advanced (LA) non-resectable non-small cell lung cancer (NSCLC) treated with concurrent chemoradiation (chemoRT) and consolidative durvalumab (D) may differ from those seen in prospective trials given selection biases and other variables in clinical trials. We aimed to assess the real-world incidence of pneumonitis for LA NSCLC patients and identify clinical or dosimetric predictors of pneumonitis. <h3>Materials/Methods</h3> We retrospectively identified consecutive patients with locally advanced NSCLC treated with chemoRT and D at a single institution from 4/2017 to 6/2019 from our prospectively maintained institutional database. The actuarial incidence of pneumonitis was estimated using the Kaplan-Meier method and compared using log-rank tests. Toxicity was evaluated via retrospective examination of clinical documents and prescription records (i.e., steroids or oxygen) and graded according to Common Terminology Criteria for Adverse Events, version 5.0. Logistic regression was used to assess associations between pneumonitis and relevant clinical and dosimetric variables. Patients were followed with clinical examination and surveillance computed tomography scans every 3 months for 2 years and every 6 months afterwards. <h3>Results</h3> We identified 61 patients with locally advanced NSCLC that were consecutively treated with a median RT dose of 66 Gy (range 60-70Gy). Median follow up was 29 months (range 4-55). Intensity-modulated radiation therapy (IMRT) was used in 36 (59%) patients, and 25 (41%) patients received 3D-conformal RT (3DCRT). Twenty-three (37.7%) patients developed pneumonitis. Highest grade pneumonitis was 2 (n=17, 27.9%), and 3 (n=5, 8.2%). Of patients who developed pneumonitis, the median time to onset was 3.2 months from completion of RT (range 1.2-9.1), with a 1-year actuarial rate of 43.5% for all grade pneumonitis. On logistic regression, significant predictors of any grade pneumonitis were higher mean lung dose, V5, V10, V15, V20 and V25. There was no association between time to pneumonitis and the volume of the planning target volume (PTV) or use of 3DCRT vs IMRT (p > 0.05). <h3>Conclusion</h3> In real-world patients with locally advanced NSCLC treated with concurrent chemoRT and consolidative durvalumab, the incidence of any grade and grade 3 pneumonitis may be higher than previously observed in prospective clinical trials. Several dosimetric parameters (MLD, V5, V10, V15, V20 and V25) predicted development of pneumonitis, emphasizing the global importance of minimizing dose to normal lung tissue.

Analysis of early respiratory-related mortality after radiation therapy of non-small-cell lung cancer: feasibility of automatic data extraction for dose–response studies

Purpose: To examine the feasibility of automatic data extraction from clinical radiation therapy (RT) databases at four hospitals to investigate the impact of mean lung dose (MLD) and age on the risk of early respiratory-related death and early overall death for patients treated with RT for non-small-cell lung cancer (NSCLC).Material and methods: We included adult patients with NSCLC receiving curatively intended RT between 2002 and 2017 at four hospitals. A script was developed to automatically extract RT-related data. The cause of death for patients deceased within 180 days of the start of RT was retrospectively assessed. Using logistic regression, the risks of respiratory-related death and of overall death within 90 and 180 days were investigated using MLD and age as variables.Results: Altogether, 1785 patients were included in the analysis of early overall mortality and 1655 of early respiratory-related mortality. The respiratory-related mortalities within 90 and 180 days were 0.9% (15/1655) and 3.6% (60/1655). The overall mortalities within 90 and 180 days were 2.5% (45/1785) and 10.6% (190/1785). Higher MLD and older age were associated with an increased risk of respiratory-related death within 180 days and overall death within 90 and 180 days (all p<.05). For example, the risk of respiratory-related death within 180 days and their 95% confidence interval for patients aged 65 and 75 years with MLDs of 20 Gy was according to our logistic model 3.8% (2.6–5.0%) and 7.7% (5.5–10%), respectively.Conclusions: Automatic data extraction was successfully used to pool data from four hospitals. MLD and age were associated with the risk of respiratory-related death within 180 days of the start of RT and with overall death within 90 and 180 days. A model quantifying the risk of respiratory-related death within 180 days was formulated.

Prognosis and Risk Factors of Radiation-Induced Lymphopenia in Early-Stage Lung Cancer Treated With Stereotactic Body Radiation Therapy.

Background: To investigate the role of stereotactic body RT (SBRT) in decreased total peripheral lymphocyte count (TLC) in patients with early-stage lung cancer and to explore possible risk factors for RT-induced lymphopenia.Materials and Methods: We analyzed the TLCs and lymphocyte subsets of 76 patients in our prospective clinical database who received SBRT for early-stage lung cancer treatment. Relationships between clinical factors or dosimetric parameters and TLC were evaluated using Spearman's correlation analysis and Chi-square tests for continuous and categorical variables, respectively. Multivariate linear regression analysis was used to control for confounding factors. Kaplan–Meier analysis with a log-rank test and a multivariate Cox regression model were used for survival analysis.Results: Most patients (64/76, 84.2%) experienced decreased absolute lymphocyte counts following SBRT, as well as shifts in lymphocyte subset distributions. Spearman's correlation coefficients between post-SBRT TLC and the percentage of the lung and heart receiving 5 to 50 Gy (in 5 Gy increments) shown that most lung DVH parameters [V(10)-V(50)] were significantly negatively correlated with post-SBRT TLC, while only heart V(5), V(20), V(25), V(30), and V(45) were significant. Univariate analyses revealed that a lower Pre-SBRT TLC level, higher mean lung dose, longer treatment duration, and longer TBT were significantly associated with a lower Post-SBRT TLC level (all P < 0.05). Stepwise multivariate linear regression, which incorporated all of the significantly clinical variables and SBRT-related parameters in univariate analysis, revealed that lower pre -SBRT TLC (P < 0.001), higher heart V5 (P = 0.002), and longer total beam-on time (TBT) (P = 0.001) were the independent risk factors for decrease in post-SBRT TLC. Patients with lower post-SBRT TLC and longer TBT exhibited significantly inferior progression-free survival (PFS) (P < 0.001 and P = 0.013) and overall survival (P = 0.006 and P = 0.043).Conclusions: G2 and more severe lymphopenia after SBRT might be an independent prognostic factor for poorer outcome in early-stage lung cancer. Lowering heart V5 and TBT when designing SBRT plans may spare circulating lymphocytes and have the potential to further improve survival outcomes.

Clinical results of proton beam therapy for elderly patients with non-small cell lung cancer

BackgroundThe purpose of the present study was to evaluate retrospectively the efficacy and safety of proton beam therapy for elderly patients (≥80 years of age) with non-small cell lung cancer.MethodsPatients diagnosed with T1–4 N0 M0 non-small cell lung cancer and treated with proton beam therapy between January 2009 and 2015 were recruited from our database retrospectively. Toxicity was evaluated using The Common Terminology Criteria for Adverse Events version 4.0.ResultsThirty-five patients, including 25 (71%) with clinically inoperable lung cancer, were administered proton beam therapy. The median age was 82 years (range: 80–87 years), and the median follow-up time was 34 months (range: 10–72 months). The median dose of proton beam therapy was 80.0 Gy relative biological effectiveness (RBE) (range: 60.0–80.0 Gy [RBE]), and all patients completed the treatments. All patients were followed for at least 23 months or until their death. The 3-year overall survival rate was 67.2% (90.0% in patients with operable lung cancer, and 58.2% in those with inoperable lung cancer). The 3-year local control rate was 86.5%. Two patients presented with grade 2 pneumonitis. The occurrence rate of grade 2 pneumonitis was significantly correlated with a high lung V20 (p = 0.030), and a high mean lung dose (p = 0.030), and a low ratio of lung volume spared from 0.05 Gy (RBE) dose (total lung volume minus lung volume irradiated at least 0.05 Gy [RBE]) (p = 0.030). However, there were no cases of grade 3 or higher radiation pneumonitis.ConclusionsThis study suggests that the proton beam therapy was feasible for elderly patients with non-small cell lung cancer and can be considered as one of the treatment choices for elderly patients with lung cancer.

Polymorphisms in BMP2/BMP4, with estimates of mean lung dose, predict radiation pneumonitis among patients receiving definitive radiotherapy for non-small cell lung cancer.

Single nucleotide polymorphisms (SNPs) in TGFβ1 can predict the risk of radiation pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) after definitive radiotherapy. Here we investigated whether SNPs in TGFβ superfamily members BMP2 and BMP4 are associated with RP in such patients. In total, we retrospectively analyzed 663 patients given ≥ 60 Gy for NSCLC. We randomly assigned 323 patients to the training cohort and 340 patients to the validation cohort. Potentially functional and tagging SNPs of BMP2 (rs170986, rs1979855, rs1980499, rs235768, rs3178250) and BMP4 (rs17563, rs4898820, rs762642) were genotyped. The median of mean lung dose (MLD) was 17.9 Gy (range, 0.15–32.74 Gy). Higher MLD was strongly associated with increased risk of grade ≥ 2 RP (hazard ratio [HR]=2.191, 95% confidence interval [CI] = 1.680–2.856, P < 0.001) and grade ≥ 3 RP (HR = 4.253, 95% CI = 2.493–7.257, P < 0.001). In multivariate analyses, BMP2 rs235768 AT/TT was associated with higher risk of grade ≥ 2 RP (HR = 1.866, 95% CI = 1.221–2.820, P = 0.004 vs. AA) both in training cohort and validation cohort. Similar results were observed for BMP2 rs1980499. BMP2 rs3178250 CT/TT was associated with lower risk of grade ≥ 3 RP (HR = 0.406, 95% CI = 0.175–0.942, P = 0.036 vs. CC) in the pooled analysis. Adding the rs235768 and rs1980499 SNPs to a model comprising age, performance status, and MLD raised the Harrell's C for predicting grade ≥ 2 RP from 0.6117 to 0.6235 (P = 0.0105). SNPs in BMP2 can predict grade ≥ 2 or 3 RP after radiotherapy for NSCLC and improve the predictive power of MLD model. Validation is underway through an ongoing prospective trial.

Detection of early radiotherapy-induced changes in intrinsic myocardial contractility by ultrasound tissue characterization in patients with early-stage breast cancer.

Increased cardiovascular morbidity and mortality are major late complications after radiotherapy (RT) in the thoracic region. Ultrasound tissue characterization (UTC) is a noninvasive method for the identification of myocardial changes. The aim of this prospective clinical trial was to assess whether the analysis of cyclic variation of integrated backscatter (CVIBS) can detect early RT-induced myocardial alterations. Seventy-three eligible patients with early-stage breast cancer were evaluated before and immediately after adjuvant RT. Twenty and 53 patients had right-sided and left-sided breast cancer, respectively. None of the patients received chemotherapy. Comprehensive echocardiographic examination included three-dimensional (3D) measurements and UTC analysis of the left ventricular (LV) septum and posterior wall. RT reduced CVIBS in a dose-dependent manner. The mean heart radiation dose over two gray (Gy) reduced the septal CVIBS from 12.0±3.4 to 9.6±2.5 dB (P<.001) and the posterior wall CVIBS from 12.8±2.7 to 11.3±2.4 dB (P=.007). The CVIBS remained unchanged when the mean heart RT dose was below 2Gy. Multivariate analysis showed an independent association with a change in septal CVIBS and the use of aromatase inhibitor (β=2.986, P=.001) and body mass index (β=-0.241, P=.014). The posterior values were worse with higher mean lung dose (β=-.485, P=.018) and with nonsmoking status (β=-2.411, P=.009). Echocardiography parameters showed increased myocardial mass but conventional measurements of the LV systolic function remained unchanged. Cyclic variation of integrated backscatter analysis seems to be a sensitive method to detect early RT-induced myocardial changes. Hence, it may be useful in screening of patients needing closer follow-up.

Therapeutic effects of intensity-modulated radiotherapy and three-dimensional conformal radiotherapy in patients with stage III N (+ ) esophageal cancer: a comparative study

Objective To investigate the therapeutic effects and adverse effects of three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) in patients with stage Ⅲ N (+ ) esophageal cancer. Methods A total of 428 patients with esophageal cancer who were treated from 2003 to 2012 and met the inclusion criteria were enrolled, and among these patients, 293 received 3DCRT and 135 received IMRT. The median radiation dose was 60 Gy. The Kaplan-Meier method was used to calculate survival rates and the log-rank test was used for survival difference analysis. Results The 1-, 3-, and 5-year local control rates in 3DCRT group and IMRT group were 65.1%/40.6%/37.5% and 70.0%/57.0%/49.4%, respectively (P=0.025). The 1-, 3-, and 5-year overall survival (OS) rates in 3DCRT group and IMRT group were 56.0%/22.3%/15.7% and 53.3%/29.2%/17.8%, respectively (P=0.394). Compared with the 3DCRT group, the IMRT group had a significantly higher mean lung dose (P=0.001) and significantly lower lung V20, V25, V30, and V35(P=0.007, 0.000, 0.000, and 0.000). Compared with the 3DCRT group, the IMRT group had significantly higher incidence rates of grade Ⅱ and Ⅲ acute radiation esophagitis and grade Ⅱ acute radiation pneumonitis (P=0.000, 0.006, and 0.043). Of all patients, 343 patients died, and the main cause of death was local factors (60.6%), followed by distant metastasis (25.1%). The IMRT group had a significantly lower proportion of patients who died of local factors than the 3DCRT group (51.0% vs. 64.5%, P=0.021). Conclusions IMRT is effective in the treatment of esophageal cancer, and compared with 3DCRT, it significantly improves the local control rate. However, IMRT does not improve the long-term OS rate. The main cause of death is local factors, followed by distant metastasis. The patients receiving IMRT have a significantly lower proportion of those who die of local factors than the patients receiving 3DCRT. Key words: Esophageal neoplasms/radiotherapy; Radiotherapy, three-dimensional conformal; Radiotherapy, intensity-modulated; Prognosis

673P - Interstitial Pulmonary Disorder in Patients with Esophageal Squamous Cell Carcinoma Treated with Docetaxel after Chemoradiotherapy

ABSTRACT Background and aims Docetaxel (DOC) is a key drug in second-line chemotherapy after the failure of chemoradiotherapy (CRT) for esophageal cancer. Interstitial pulmonary disorder (IPD) is one of the fatal adverse effects of DOC, but its frequency and risk factors have not been clarified. The aim of this study was to determine the frequency of and risk factors for IPD in patients with esophageal squamous cell carcinoma (ESCC), who were treated with DOC after the failure of CRT. Patients and methods We retrospectively reviewed the clinical data for 115 patients with ESCC who had been treated with CRT at Kyoto University Hospital from April 2007 to March 2011. Thirty-seven of these patients had been treated with DOC after CRT (D group) and 78 had not been treated with DOC (non-D group). We compared the incidence of IPD in the two groups and also identified the risk factors for IPD. Results The incidence of grade 3/4 IPD in the D and non-D groups was 10.8% (4/37) and 1.3% (1/78), respectively (P = 0.035). A median of 4 cycles of DOC was administered (range, 2–7). The median total radiation dose was 60 Gy. The mean value for V20 (% total lung volume receiving ≥20Gy) in patients with grade 3/4 IPD was greater than that in patients without IPD (20.0% vs 12.3%, respectively; P = 0.012). The V20 value was greater than 20% in 80% (4/5) of patients with grade 3/4 IPD. The mean lung dose (MLD) in patients with grade 3/4 IPD was also greater than that in patients without IPD (11.1 Gy vs 6.6 Gy, respectively; P Conclusion The incidence of grade 3/4 IPD was 10.8% in patients who received DOC after CRT. IPD must be considered when DOC is administered to patients who have already received radiotherapy with high V20 and MLD in their first-line CRT. Disclosure All authors have declared no conflicts of interest.

Incorporating Single-nucleotide Polymorphisms Into the Lyman Model to Improve Prediction of Radiation Pneumonitis

To determine whether single-nucleotide polymorphisms (SNPs) in genes associated with DNA repair, cell cycle, transforming growth factor-β, tumor necrosis factor and receptor, folic acid metabolism, and angiogenesis can significantly improve the fit of the Lyman-Kutcher-Burman (LKB) normal-tissue complication probability (NTCP) model of radiation pneumonitis (RP) risk among patients with non-small cell lung cancer (NSCLC). Sixteen SNPs from 10 different genes (XRCC1, XRCC3, APEX1, MDM2, TGFβ, TNFα, TNFR, MTHFR, MTRR, and VEGF) were genotyped in 141 NSCLC patients treated with definitive radiation therapy, with or without chemotherapy. The LKB model was used to estimate the risk of severe (grade≥3) RP as a function of mean lung dose (MLD), with SNPs and patient smoking status incorporated into the model as dose-modifying factors. Multivariate analyses were performed by adding significant factors to the MLD model in a forward stepwise procedure, with significance assessed using the likelihood-ratio test. Bootstrap analyses were used to assess the reproducibility of results under variations in the data. Five SNPs were selected for inclusion in the multivariate NTCP model based on MLD alone. SNPs associated with an increased risk of severe RP were in genes for TGFβ, VEGF, TNFα, XRCC1 and APEX1. With smoking status included in the multivariate model, the SNPs significantly associated with increased risk of RP were in genes for TGFβ, VEGF, and XRCC3. Bootstrap analyses selected a median of 4 SNPs per model fit, with the 6 genes listed above selected most often. This study provides evidence that SNPs can significantly improve the predictive ability of the Lyman MLD model. With a small number of SNPs, it was possible to distinguish cohorts with >50% risk vs <10% risk of RP when they were exposed to high MLDs.

Helical Tomotherapy for Solitary Lung Tumor: Feasibility Study and Dosimetric Evaluation of Treatment Plans

The purpose of this study is to evaluate the feasibility of and treatment plans for helical tomotherapy (HT) for solitary lung tumors. Nine patients with stage IA non-small-cell lung cancer (NSCLC) and three patients with solitary lung metastasis were treated with HT. All patients were immobilized with the BodyFIX system, and the target volume shown on computed tomography in the 3 respiration phases were superimposed onto the 3-dimensional radiation treatment planning system to represent the internal target motion. All patients were treated with 54-60 Gy in 12 fractions over 8 to 13 days. The median follow-up time was 14 months (range: 3-16 months). The overall response rate was 92%. The local control rate at 1 year was 100% with no difference between NSCLC and metastasis. Of 12 patients, one patient experienced Grade 2 radiation pneumonitis (RP), and the other patient with severe interstitial pneumonia and emphysema experienced Grade 5 RP. The mean lung dose (MLD) and the dose-volume histogram (DVH) for the normal lung volumes were converted into normalized total dose with an alpha/beta ratio of 3 Gy. The DVH of the normal lung volumes demonstrated that the mean volumes of V(10), V(30), V(50), and V(70) were 40.4 +/- 9.4%, 21.3 +/- 6.4%, and 12.8 +/- 4.6%, and 9.3 +/- 4.2% in all patients, 28.8%, 18.7%, 12.3%, and 10.5% in the patient with Grade 2 RP, and 29.3%, 17.9%, 7.7%, and 5.4% in the patient with Grade 5 RP. The mean MLD of all patients was 13.5 +/- 3.9 Gy, and those values of patients with Grade 2 and 5 RP were 12.9 and 21.8 Gy, respectively. Our study found that only the MLD was significantly correlated with RP >Grade 2 (p = 0.030) using the Student's t-test. Our study found the conformity index value of 1.48 +/- 0.15 and the homogeneity index value of 1.066 +/- 0.023, which suggested the feasibility of using HT to treat lung tumors with hypofractionation. In conclusion, HT is a feasible non-invasive technique for treating solitary lung tumors and achieves high accuracy in terms of dose conformity and homogeneity. The decision of the indications for HT might be required caution in cases in which a severe pulmonary toxicity is predicted from the high MLD, especially in cases involving a severe pulmonary comorbidity.

A prospective study of pulmonary function in Hodgkin’s lymphoma patients

BackgroundTo prospectively study changes in lung function in Hodgkin's lymphoma (HL) patients and to explore predictors for these changes over time. MethodsIn all, 52 patients with HL receiving bleomycin-based chemotherapy with (n = 23) or without (n = 29) mediastinal radiotherapy were enrolled. Pretreatment pulmonary function tests were carried out. These were repeated at 1 month, 6 months, and 1 year after therapy. ResultsWith chemotherapy alone, the median %DLCO declined significantly at 1 month but returned to baseline by 6 months. The median %DLCO did not further decrease with radiotherapy, but remained persistently reduced at 1 year. In patients who received radiotherapy, having >33% of lung volume receive 20 Gy (V20) and a mean lung dose (MLD) of >13 Gy significantly predicted for persistently reduced %DLCO at 6 months (P = 0.035). Smoking significantly predicted for a persistently reduced %DLCO at 1 year (P = 0.036). On multivariable analysis, significant predictors for decline in %DLCO at 1 year were higher baseline %DLCO (P = 0.01), higher MLD (P = 0.02), and a smoking history (P = 0.02). ConclusionsSeveral factors contribute to decline in %DLCO in HL patients who received bleomycin-based computed tomography. The identification of threshold radiation dosimetric parameters for reduced lung function may provide guidance in the radiation planning of these patients.

Using patient data similarities to predict radiation pneumonitis via a self-organizing map

This work investigates the use of the self-organizing map (SOM) technique for predicting lung radiation pneumonitis (RP) risk. SOM is an effective method for projecting and visualizing high-dimensional data in a low-dimensional space (map). By projecting patients with similar data (dose and non-dose factors) onto the same region of the map, commonalities in their outcomes can be visualized and categorized. Once built, the SOM may be used to predict pneumonitis risk by identifying the region of the map that is most similar to a patient's characteristics. Two SOM models were developed from a database of 219 lung cancer patients treated with radiation therapy (34 clinically diagnosed with Grade 2+ pneumonitis). The models were: SOMall built from all dose and non-dose factors and, for comparison, SOMdose built from dose factors alone. Both models were tested using ten-fold cross validation and Receiver Operating Characteristics (ROC) analysis. Models SOMall and SOMdose yielded ten-fold cross-validated ROC areas of 0.73 (sensitivity/specificity = 71%/68%) and 0.67 (sensitivity/specificity = 63%/66%), respectively. The significant difference between the cross-validated ROC areas of these two models (p < 0.05) implies that non-dose features add important information toward predicting RP risk. Among the input features selected by model SOMall, the two with highest impact for increasing RP risk were: (a) higher mean lung dose and (b) chemotherapy prior to radiation therapy. The SOM model developed here may not be extrapolated to treatment techniques outside that used in our database, such as several-field lung intensity modulated radiation therapy or gated radiation therapy.

Investigation of clinical and dosimetric factors associated with postoperative pulmonary complications in esophageal cancer patients treated with concurrent chemoradiotherapy followed by surgery

To assess the association of clinical and especially dosimetric factors with the incidence of postoperative pulmonary complications among esophageal cancer patients treated with concurrent chemoradiation therapy followed by surgery. Data from 110 esophageal cancer patients treated between January 1998 and December 2003 were analyzed retrospectively. All patients received concurrent chemoradiotherapy followed by surgery; 72 patients also received irinotecan-based induction chemotherapy. Concurrent chemotherapy was 5-fluorouracil-based and in 97 cases included taxanes. Radiotherapy was delivered to a total dose of 41.4-50.4 Gy at 1.8-2.0 Gy per fraction with a three-dimensional conformal technique. Surgery (three-field, Ivor-Lewis, or transhiatal esophagectomy) was performed 27-123 days (median, 45 days) after completion of radiotherapy. The following dosimetric parameters were generated from the dose-volume histogram (DVH) for total lung: lung volume, mean dose to lung, relative and absolute volumes of lung receiving more than a threshold dose (relative V(dose) and absolute V(dose)), and absolute volume of lung receiving less than a threshold dose (volume spared, or VS(dose)). Occurrence of postoperative pulmonary complications, defined as pneumonia or acute respiratory distress syndrome (ARDS) within 30 days after surgery, was the endpoint for all analyses. Fisher's exact test was used to investigate the relationship between categorical factors and incidence of postoperative pulmonary complications. Logistic analysis was used to analyze the relationship between continuous factors (e.g., V(dose) or VS(dose)) and complication rate. Logistic regression with forward stepwise inclusion of factors was used to perform multivariate analysis of those factors having univariate significance (p < 0.05). The Mann-Whitney test was used to compare length of hospital stay in patients with and without lung complications and to compare lung volumes, VS5 values, and absolute and relative V5 values in male vs. female patients. Pearson correlation analysis was used to determine correlations between dosimetric factors. Eighteen (16.4%) of the 110 patients developed postoperative pulmonary complications. Two of these died of progressive pneumonia. Hospitalizations were significantly longer for patients with postoperative pulmonary complications than for those without (median, 15 days vs. 11 days, p = 0.003). On univariate analysis, female gender (p = 0.017), higher mean lung dose (p = 0.036), higher relative volume of lung receiving > or = 5 Gy (V5) (p = 0.023), and smaller volumes of lung spared from doses > or = 5-35 Gy (VS5-VS35) (p < 0.05) were all significantly associated with an increased incidence of postoperative pulmonary complications. No other clinical factors were significantly associated with the incidence of postoperative pulmonary complications in this cohort. On multivariate analysis, the volume of lung spared from doses > or = 5 Gy (VS5) was the only significant independent factor associated with postoperative pulmonary complications (p = 0.005). Dosimetric factors but not clinical factors were found to be strongly associated with the incidence of postoperative pulmonary complications in this cohort of esophageal cancer patients treated with concurrent chemoradiation plus surgery. The volume of the lung spared from doses of > or = 5 Gy was the only independent dosimetric factor in multivariate analysis. This suggests that ensuring an adequate volume of lung unexposed to radiation might reduce the incidence of postoperative pulmonary complications.