Pretreatment Pulmonary Function Tests Research Articles

Investigating risk factors and treatment options for severe, partially steroid responsive, and steroid-refractory checkpoint inhibitor pneumonitis.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer care with incredible reductions in mortality. One of the most devastating complications of treatment is ICI-related pneumonitis (ICI-p). Despite this, little is known regarding risk factors for severe pneumonitis and treatment effectiveness of various therapeutic options for steroid-refractory disease. To address this, we conducted a retrospective study on patients with cancer who developed ICI-p. We examined consecutive patients who received ICIs and developed ICI-p. Risk factors of interest for severe disease and steroid-refractory ICI-p, including pre-treatment pulmonary function tests (PFTs) and chest imaging, were compared between patients with severe (grades 3-5) and mild (grades 1-2) pneumonitis. The clinical and treatment courses for patients with steroid-refractory ICI-p were recorded. A total of 132 patients developed ICI-p, with 60 patients having mild and 72 with severe disease. We found that lower forced vital capacity percent predicted (66.24 vs 85.05, P = .05), lower total lung capacity percent predicted (85.23 vs 99.71, P = .13), and specific radiographic patterns on pre-treatment chest imaging were predictors of severe disease. Initial corticosteroid dose of less than 1 milligram per kilogram prednisone equivalent (P = .14) was correlated with partially steroid-responsive or steroid-refractory ICI-p. Ten patients had steroid refractory ICI-p, and those who received IVIG alone as the immune suppressant beyond corticosteroids had improved survival (P = 05). We are the first to identify pre-treatment PFTs and chest imaging abnormalities as risk factors for severe ICI-p. We also found that lower corticosteroid doses were associated with partially steroid-responsive and steroid-refractory ICI-p. Larger, prospective studies are needed to validate our results.

Association between pre-treatment chest imaging and pulmonary function abnormalities and immune checkpoint inhibitor pneumonitis.

Immune checkpoint inhibitors (ICIs) are a first-line treatment for various metastatic solid tumors. Pneumonitis is a potentially devastating complication of ICI treatment and a leading cause of ICI-related mortality. Here, we evaluate whether abnormal pre-treatment pulmonary function tests (PFTs) or interstitial abnormalities on computed tomography of the chest (CT chest) prior to ICI are associated with the development of ICI-pneumonitis (ICI-p). We conducted a retrospective cohort study of consecutive patients who received at least one dose of ICI from 2011 to 2017 at The Ohio State University. Potential risk factors for ICI-p, including abnormal PFTs and CT chest, were recorded. These risk factors were compared between patients with and without pneumonitis. In total, 1097 patients were included, 46 with ICI-p and 1051 without. Ninety percent of patients had pre-treatment chest imaging, while only 10% had pre-treatment PFTs. On multivariable analysis, interstitial abnormalities and reduced total lung capacity (TLC) were significantly associated with development of ICI-p (hazard ratio of 42.42 [95% CI; 15.04-119.67] and hazard ratio of 4.04 [95% CI; 1.32-12.37]), respectively. No other PFT abnormality was associated with increased risk of ICI-p. There was no significant difference in overall survival in patients who did or did not develop ICI-p (p = 0.332). Pre-existing interstitial abnormalities on CT chest and reduced TLC were strongly associated with developing ICI-p. Prospective studies are warranted to further explore the role of PFTs as a potential tool for identifying patients at highest risk for developing ICI-p.

Predictive Model of Progression in Early Stage Non Small Cell Lung Cancer Treated with Stereotactic Ablative Radiation Therapy

There is an emerging interest for combining stereotactic ablative radiotherapy (SABR) with immunotherapy in the management of early stage non small cell lung cancer (ES-NSCLC). To help best select which patients may benefit from immunotherapy in future trials, we aimed to determine the predictive factors of progression free survival (PFS) and time to progression (TTP) in a large cohort of ES-NSCLC patients treated with SABR. A retrospective analysis of patients with stage I–II NSCLC treated with SABR from 2004 to 2015 was conducted. SABR doses of 34-70 Gy in 1-10 fractions were delivered. Cox proportional hazard ratio models were used for analysis of potential predictive variables. The following variables were included in the model: patient age, gender, ECOG performance status, Charlson co-morbidity index, pre-treatment pulmonary function tests (percent forced expiratory volume in 1 second [%FEV1]) and percent diffusing lung capacity for carbon monoxide [%DLCO]), tumor stage, size, histology, location and maximum standardized uptake value (SUVmax) on FDG/PET. Variables with significant association with PFS and TTP in univariate analysis were used for subsequent recursive partitioning analysis (RPA) to identify appropriate cut-off points. A total of 912 patients with a median age of 72 years (range, 46-91) were included. Median follow-up was 59.3 months. Local recurrence, regional recurrence, distant metastasis and second primary lung cancer developed in 10.0%, 11.5%, 20.1% and 7.5% of patients, at a median time to recurrence of 14.9 months (range, 1.5–91.9), 10.5 months (range 1.4–70.7), 11.6 months (range, 0.2–91.9 months) and 23.6 months (range, 1.2–122.4), respectively. Actuarial 3- and 5-year PFS were 52.7% and 39.1%, and 3- and 5-year TTP were 72.2% and 66.7%, respectively. On univariate analysis, age (p=0.0009), ECOG (p<0.0001), Charlson score (p=0.0001), %DLCO (p<0.0001), %FEV1 (p=0.007), non-adenocarcinoma histology (p<0.0001), tumor size (p=0.01) and tumor SUVmax (p=0.0002) were associated with PFS, while %DLCO (p=0.002), tumor size (p=0.002) and tumor SUVmax (p=0.01) were associated with TTP. RPA identified age ≥ 78 years, Charlson score ≥ 5, %DLCO < 71%, %FEV1 < 65%, tumor size ≥ 3 cm and SUVmax ≥ 12 as significant cut-offs for adverse PFS outcome. RPA identified %DLCO < 71%, tumor size ≥ 3 cm and SUVmax ≥ 12 as significant cut-offs for adverse TTP. On multivariate analysis, age (p=0.05), Charlson score (p=0.03), %DLCO (p=0.00001), non-adenocarcinoma histology (p=0.02), and tumor size (p=0.002) remained predictive of PFS. Correlations with biological markers are currently on-going. Age ≥ 78 years, Charlson score≥ 5, %DLCO < 71%, tumor size ≥ 3 cm and non-adenocarcinoma histology were found to be independent predictors of PFS. Patients with %DLCO < 71%, tumor size ≥ 3 cm and SUVmax ≥ 12 had adverse TTP outcomes, suggesting that they may benefit from treatment intensification. A predictive model is being develop and will be presented.

P1.16-25 A Propensity Score Model for Appropriate Treatment Selection (Sublobar Resection vs. SBRT) In Patients With cStage I NSCLC

Stereotactic body radiotherapy (SBRT) and sublobar resection (SLR) are current treatment options for patients with cStage I non-small-cell lung cancer (NSCLC) who are operable, but at high risk for lobectomy. However, optimal selection of the two treatments remains controversial. Purposes of this study are to identify pre-treatment factors affecting treatment decision and to evaluate their impact on outcomes. We retrospectively reviewed patients who underwent SBRT or SLR for cStage I NSCLC because of medical comorbidity between 2003 and 2009. Patients who were with performance status of 2 or worse, those who had no data on pre-treatment pulmonary function test, or those who had no histological confirmation of NSCLC were excluded. A propensity score (PS) model of treatment decision (0 toward SBRT, and 1 toward SLR) was generated using stepwise logistic regression incorporating pre-treatment factors. Ninety-two and 65 patients who underwent SBRT and SLR, respectively, were enrolled into this analysis. Median potential follow-up period was 8.6 years. The following factors remained in the PS model after stepwise selection: age, sex, Charlson comorbidity index (CCI), body mass index (BMI), forced expiratory volume in 1 second (FEV1) and tumor diameter. Old age, male, CCI of 1 or more, underweight BMI and large tumor had coefficients toward SBRT (Table). In a cohort with PS of 0.5 or more, overall survival was significantly better in SLR patients than in SBRT patients (79.5% and 47.5% at 5 years, respectively; P = 0.004). In a cohort with PS<0.5, whereas, overall survival was similar between SLR and SBRT (43.3% and 39.7% at 5 years, respectively; P = 0.805). The PS model would help appropriate treatment selection for high-risk operable patients. Although patients with PS of 0.5 or more benefit from SLR, SBRT provides comparable outcomes for patients with PS<0.5.

Pulmonary Function in Patients With Germ Cell Cancer Treated With Bleomycin, Etoposide, and Cisplatin

For patients with germ cell cancer, various pulmonary toxicity risk factors have been hypothesized for treatment with bleomycin, etoposide, and cisplatin (BEP). Because existing studies have shortcomings, we present a large, unselected cohort of patients who have undergone close monitoring of lung function before, during, and after treatment with BEP to disclose valid pulmonary toxicity risk factors. All patients who were treated with BEP at Rigshospitalet, Copenhagen, Denmark, from 1984 to 2007, were included. Pulmonary function tests (PFTs) that measured the diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in 1 second, and forced vital capacity were performed systematically before, during, and after treatment with BEP for 5 years of follow-up. According to local protocol, bleomycin was discontinued if hemoglobin-corrected DLCO (DLCOc) decreased ≥ 25% compared with pretreatment value. Covariates of possible importance were evaluated with a multiple regression analysis for pretreatment PFTs and with a mixed model for follow-up PFTs. Bleomycin was adjusted on the basis of PFT results and was thus omitted as covariate. Overall, 565 patients were evaluated with a PFT before or after treatment with BEP. During BEP, 15 patients died of progressive disease or toxicity, including one patient from bleomycin-induced pneumonitis. Post-treatment DLCOc decreased significantly, with a rebound during follow-up. Forced expiratory volume in 1 second and forced vital capacity remained unchanged after BEP but increased significantly to levels above pretreatment during follow-up. International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic group, mediastinal primary, pulmonary metastases, and smoking all significantly influenced baseline PFT results. Pulmonary surgery, pulmonary embolism, IGCCCG poor prognosis, and smoking influenced PFT during follow-up. Mediastinal primary, pulmonary metastases, age, or doses of cisplatin and etoposide had no influence on follow-up PFT, and renal function did not influence PFT. After 5 years of follow-up, pulmonary impairment in patients with germ cell cancer who were treated with BEP was limited. Exceptions were patients treated with pulmonary surgery, those who suffered pulmonary embolism, and those in the IGCCCG poor prognostic group.

Impact of pulmonary nontuberculous mycobacterial treatment on pulmonary function tests in patients with and without established obstructive lung disease

There is relatively little data regarding pulmonary function test (PFT) findings and impact of treatment on PFT in pulmonary nontuberculous mycobacterial (pNTM) disease. We performed a retrospective study on pNTM patients. Clinical, radiographical, microbiological and PFT data were reviewed. Patients were divided into three groups based on pre-existing obstructive lung disease: (i) normal (no chronic obstructive pulmonary disease (COPD) or asthma); (ii) asthma; and (iii) COPD. We studied pre-treatment PFT and assessed for PFT changes after anti-mycobacterial therapy. A total of 96 patients fulfilled ATS disease criteria and had pre-treatment PFT (54 'normal', 18 asthma, 24 COPD). Most common causative NTM was Mycobacterium avium complex (76%), and radiographical disease type was nodular bronchiectasis (71%). Before therapy, all groups had PFT abnormalities, including obstruction, gas trapping and at least mildly low diffusion capacity of carbon monoxide (DLCO). Pre-treatment PFT abnormalities were more pronounced among patients with asthma and COPD. A total of 44 patients had >12 months anti-mycobacterial therapy and post-treatment PFT. There tended to be small and generally not statistically significant reductions in spirometry and DLCO in most groups. Among the nine asthmatic patients, there was a small reduction in residual volume (RV) (1.5% predicted, P = 0.01) and RV/total lung capacity (by 7% predicted, P = 0.06). Patients with pNTM have abnormal PFT, and treatment was not associated with substantial changes therein. Asthmatics may experience some improvements in gas trapping after NTM therapy, but because the sample size and the observed change were both small, this requires further investigation.

Stereotactic Body Radiation Therapy for Non-Small Cell Lung Cancer Tumors Greater Than 5 cm: Safety and Efficacy

The purpose of this study was to determine outcomes of patients with node-negative medically inoperable non-small cell lung cancer (NSCLC) whose primary tumors exceeded 5 cm and were treated with stereotactic body radiation therapy (SBRT). We surveyed our institutional prospective lung SBRT registry to identify treated patients with tumors >5 cm. Treatment outcomes for local control (LC), locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) were assessed by Kaplan-Meier estimates. Toxicities were graded according to Common Terminology Criteria for Adverse Events version 4. Mean pretreatment pulmonary function test values were compared to mean posttreatment values. From December 2003 to July 2014, 40 patients met study criteria. Median follow-up was 10.8 months (range: 0.4-70.3 months). Median age was 76 years (range: 56-90 years), median body mass index was 24.3 (range: 17.7-37.2), median Karnofsky performance score was 80 (range: 60-90), and median Charlson comorbidity index score was 2 (range: 0-5). Median forced expiratory volume in 1 second (FEV1) was 1.41 L (range: 0.47-3.67 L), and median diffusion capacity (DLCO) was 47% of predicted (range: 29%-80%). All patients were staged by fluorodeoxyglucose-positron emission tomography/computed tomography staging, and 47.5% underwent mediastinal staging by endobronchial ultrasonography. Median tumor size was 5.6 cm (range: 5.1-10 cm), median SBRT dose was 50 Gy (range: 30-60 Gy) in 5 fractions (range: 3-10 fractions). Eighteen-month LC, LRC, DFS, and OS rates were 91.2%, 64.4%, 34.6%, and 59.7%, respectively. Distant failure was the predominant pattern of failure (32.5%). Three patients (7.5%) experienced grade 3 or higher toxicity. Mean posttreatment FEV1 was not significantly reduced (P=.51), but a statistically significant absolute 6.5% (P=.03) reduction in DLCO was observed. Lung SBRT for medically inoperable node-negative NSCLC with primary tumors larger than 5 cm is safe and provides excellent local control with limited toxicity. The predominant pattern of failure in this population was distant failure.

Influence of patient's physiologic factors and immobilization choice with stereotactic body radiotherapy for upper lung tumors.

The purpose of the present study was to compare the impact of pulmonary function, body habitus, and stereotactic body radiation therapy (SBRT) immobilization on setup and reproducibility for upper lung tumor. From 2008 through 2011, our institution's prospective SBRT database was searched for patients with upper lung tumors. Two SBRT immobilization strategies were used: full‐length BodyFIX and thermoplastic S‐frame. At simulation, free‐breathing, four‐dimensional computed tomography was performed. For each treatment, patients were set up to isocenter with in‐room lasers and skin tattoos. Shifts from initial and subsequent couch positions with cone‐beam computed tomography (CBCT) were analyzed. Accounting for setup uncertainties, institutional tolerance of CBCT‐based shifts for treatment was 2, 2, and 4 mm in left–right, anterior–posterior, and cranial–caudal directions, respectively; shifts exceeding these limits required reimaging. Each patient's pretreatment pulmonary function test was recorded. A multistep, multivariate linear regression model was performed to elucidate intervariable dependency for three‐dimensional calculated couch shift parameters. BodyFIX was applied to 76 tumors and S‐frame to 17 tumors. Of these tumors, 41 were non–small cell lung cancer and 15 were metastatic from other sites. Lesions measured <1(15%), 1.1 to 2 (50%), 2.1 to 3 (25%), and >3(11%) cm. Errors from first shifts of first fractions were significantly less with S‐frame than BodyFIX (p<0.001). No difference in local control (LC) was found between S‐frame and BodyFIX (p=0.35); two‐year LC rate was 94%. Multivariate modeling confirmed that the ratio of forced expiratory volume in the first second of expiration to forced vital capacity, body habitus, and the immobilization device significantly impacted couch shift errors. For upper lung tumors, initial setup was more consistent with S‐frame than BodyFIX, resulting in fewer CBCT scans. Patients with obese habitus and poor lung function had more SBRT setup uncertainty; however, outcome and probability for LC remained excellent.PACS number: 89.20.‐a

Is There a Lower Limit of Pretreatment Pulmonary Function for Safe and Effective Stereotactic Body Radiotherapy for Early-Stage Non-small Cell Lung Cancer?

To evaluate the influence of pretreatment pulmonary function (PF) on survival, early and late pulmonary toxicity after stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer. Four hundred eighty-three patients with 505 tumors of early-stage non-small cell lung cancer cT1-3 cN0 were treated with image-guided SBRT at five international institutions (1998-2010). Sixty-four percent of the tumors were biopsy-proven and 18F-fluorodeoxyglucose-positron emission tomography was performed for staging in 84%. Image-guided SBRT was performed with a median of three fractions to a median total dose of 54 Gy. Pretreatment PF was available for 423 patients, and 617 posttreatment PF tests from 270 patients were available. A large variability of pretreatment PF was observed: the 90% range of forced expiratory volume in 1 second and diffusing capacity for carbon monoxide was 29 to 109% and 5.5 to 19.1 ml/min/mmHg, respectively. PF was significantly correlated with overall survival but not cause-specific survival: diffusing capacity for carbon monoxide of 11.2 ml/min/mmHg differentiated between 3-year overall survival of 66% and 42%. Radiation-induced pneumonitis grade ≥II occurred in 7% of patients and was not increased in patients with lower PF. A significant and progressive change of PF was observed after SBRT: PF decreased by 3.6% and 6.8% on average within 6 and 6 to 24 months after SBRT, respectively. Changes of PF after SBRT were significantly correlated with pretreatment PF: PF improved for worst pretreatment PF and the largest loss was observed for best pretreatment PF. Image-guided SBRT is safe in terms of acute and chronic pulmonary toxicity even for patients with severe pulmonary comorbidities. SBRT should be considered as a curative treatment option for inoperable patients with pretreatment PF as reported in this study.

Predictive factors for symptomatic radiation pneumonitis in 293 consecutively treated non-small cell lung cancer (NSCLC) patients receiving definitive radiation therapy.

7041 Background: Radiation pneumonitis is a potentially fatal complication in NSCLC patients treated with definitive radiotherapy. The ability to identify patients at risk for this complication would be of value to clinicians. The objective of this study was to identify significant predictors of grade 2 or higher radiation pneumonitis. Methods: Consecutive NSCLC patients receiving definitive non-stereotactic radiotherapy at the University of Pennsylvania between January 2003 to July 2010 were graded for post-treatment radiation pneumonitis using RTOG criteria. Demographic and treatment data were collected on all patients. Univariate and mutivariate analysis was used to determine predictors of grade 2 or higher pneumonitis. Results: Of 293 patients treated in this period, 47% were male, 52% received concurrent chemotherapy. Median prescription dose was 66.6Gy, median gross tumor volume was 91cc, and the median mean lung dose (MLD) was 16Gy. On univariate analysis, concurrent chemoradiation (p = 0.002; OR 2.7), MLD (p = 0.0001, OR = 1.14/Gy), KPS (p = 0.045, OR = 1.04/point), and N2/3 disease (p = 0.026, OR = 2.51) were significant predictors of pneumonitis. A multivariate analysis including all significant predictors on univariate analysis was performed and only MLD (p = 0.031, OR = 1.10/Gy) proved significant. The median MLD cutoff of 16Gy had a sensitivity/specificity of 72% and 55% respectively and positive and negative predictive value of 55% and 87% respectively. Of note, V20 (volume of lung receiving 20Gy or higher), smoking status, and pre-treatment pulmonary function tests including FEV1 and DLCO were not significant predictors of pneumonitis. Conclusions: MLD was a significant predictor of grade 2 or higher radiation pneumonitis in patients with NSCLC receiving definitive radiotherapy, while V20 was not. Additionally, the poor positive predictive value and specificity of MLD limits the clinical utility of this variable. This study underscores the need for more robust predictors of radiation pneumonitis.

Pulmonary Function Testing After Stereotactic Body Radiotherapy to the Lung

Surgical resection remains the standard of care for operable early-stage non-small-cell lung cancer (NSCLC). However, some patients are not fit for surgery because of comorbidites such as chronic obstructive pulmonary disease (COPD) and other medical conditions. We aimed to evaluate pulmonary function and tumor volume before and after stereotactic body radiotherapy (SBRT) for patients with and without COPD in early-stage lung cancer. A review of prospectively collected data of Stage I and II lung cancers, all treated with SBRT, was performed. The total SBRT treatment was 60 Gy administered in three 20 Gy fractions. The patients were analyzed based on their COPD status, using their pretreatment pulmonary function test cutoffs as established by the American Thoracic Society guidelines (forced expiratory volume [FEV]% ≤ 50% predicted, FEV%/forced vital capacity [FVC]% ≤ 70%). Changes in tumor volume were also assessed by computed tomography. Of a total of 30 patients with Stage I and II lung cancer, there were 7 patients in the COPD group (4 men, 3 women), and 23 in t he No-COPD group (9 men, 14 women). At a mean follow-up time of 4 months, for the COPD and No-COPD patients, pretreatment and posttreatment FEV% was similar: 39 ± 5 vs. 40 ± 9 (p = 0.4) and 77 ± 0.5 vs. 73 ± 24 (p = 0.9), respectively. The diffusing capacity of the lungs for carbon monoxide (DL(CO)) did significantly increase for the No-COPD group after SBRT treatment: 60 ± 24 vs. 69 ± 22 (p = 0.022); however, DL(CO) was unchanged for the COPD group: 49 ± 13 vs. 50 ± 14 (p = 0.8). Although pretreatment tumor volume was comparable for both groups, tumor volume significantly shrank in the No-COPD group from 19 ± 24 to 9 ± 16 (p < 0.001), and there was a trend in the COPD patients from 12 ± 9 to 6 ± 5 (p = 0.06). SBRT did not seem to have an effect on FEV(1) and FVC, but it shrank tumor volume and improved DL(CO) for patients without COPD.

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.

Pretreatment pulmonary function tests predict risk of mortality following fractionated total body irradiation without lung dose reduction prior to stem cell transplant

6550 Background: Peripheral blood stem cell transplantation (PBSCT) is a key component in the treatment of various malignancies. Preparatory regimens for PBSCT often include total body irradiation (TBI). Pulmonary toxicity is often prominent, and is felt to be related to total lung dose and dose rate. The Radiation Oncology Branch of the National Institute of Health initially administered TBI without lung shielding, however shielding was added in 2002. Pulmonary function testing (PFT) was undertaken both before and after stem cell transplant and TBI for all patients. The PFT results were analysed to test the hypothesis that TBI patients with pre-treatment combined ventilation/diffusion capacity deficits, defined as both FEV1 and DLCO below 100% predicted, would benefit most from reduction of lung dose. Methods: From 1997–2004, 146 consecutive patients with hematologic malignancies received fractionated TBI before PBSCT. The first 85 patients were treated without lung dose reduction to 13.6 Gray (Gy). Thereafter, total body dose was decreased to 12 Gy (1.5 Gy BID for 4 days). Initially, lung dose was limited to 9 Gy by use of lung shielding. Later lung dose was reduced to 6 Gy. All patients received PFTs prior to treatment, 90 days after treatment, and annually. Results: Median F/U was 44 months (range 12–90 months). Sixty-one patients had combined ventilation/diffusion capacity deficits defined as both a forced expiratory volume in the first second (FEV1) and a diffusion capacity of carbon dioxide (DLCO) less than 100% predicted. Of these 61, 27 had lung dose reduction and 34 did not. One-year survival was 71% versus 50% with and without lung dose reduction respectively (log rank test p=0.042). Eighty-five patients had FEV1 and/or DLCO greater than or equal to 100% predicted; 34 were treated with lung dose reduction and 51 without. In both groups, 1 year survival was 70%. Conclusions: Among patients treated without lung dose reduction, survival was significantly worse among those with pretreatment combined ventilation/diffusion capacity deficits. Among those with combined ventilation/diffusion capacity deficits, lung dose reduction significantly improved survival. No significant financial relationships to disclose.

Characteristics of Patients Who Developed Radiation Pneumonitis Requiring Steroid Therapy After Stereotactic Irradiation for Lung Tumors

To find possible risk factors for symptomatic radiation pneumonitis (RP) after stereotactic irradiation (STI) for peripheral non-small cell lung cancer (NSCLC), pre-treatment pulmonary function test and dose volume statistics in patients who developed RP requiring steroid intake were retrospectively compared with statistics of those who did not develop RP. From 1996 to 2002, 156 patients with Stage I NSCLC received STI at 5 hospitals in Japan. Of those patients, 12 were medicated with steroids for RP after treatment (RP group). For comparison, 31 patients were randomly selected from the remaining 144 patients who received STI but did not receive steroids (control group). There were no statistical differences in age, sex, tumor size, performance status, forced expiratory volume in 1 sec (FEV1.0%), or percent vital capacity (%VC) between patients medicated with steroids for RP and those who did not have RP and received no steroids. V20 (%) was 7 to 18% (median 8%) in patients medicated with steroids for RP and 2 to 16% (median 7%) in those who did not have RP. No difference was observed in V20, the biologically effectively dose (BED) at the periphery of the planning target volume, or the dose per fraction between the two groups. Pre-treatment pulmonary function test (%VC, FEV1.0%), and dose volume statistics V20, total dose, BED, dose per fraction, peripheral dose) were not predictive of RP requiring steroid intake after STI for stage I NSCLC.

Impaired diffusion capacity predicts for decreased treatment tolerance and survival in limited stage small cell lung cancer patients treated with concurrent chemoradiation.

To determine if stratification of limited stage small cell lung cancer (LSCLC) patients by pre-treatment pulmonary function test (PFT) prognostic indicators predicts for treatment-related toxicity risks and survival following concurrent chemoradiation. From 1989 to 1999, 215 LSCLC patients received six cycles of alternating cyclophosphamide/doxorubicin/vincristine and etoposide/cisplatin (EP). Thoracic radiation (RT) was initiated only with EP and at cycle 2 or 3. RT dose was: 40 Gy/15 fractions/3 weeks or 50 Gy/25 fractions/5 weeks. RT fields encompassed gross and suspected microscopic disease with a 2 cm margin. Pre-treatment PFT values analyzed included forced expiratory volume in 1s (FEV1) (in liter and as % predicted) and diffusion capacity for carbon monoxide (DLCO) (as % predicted). The "marker" for toxicity during concurrent chemoradiation was the duration of any RT breaks initiated for severe hematologic or locoregional symptomatology. Patient outcomes were analyzed for associations between recognized PFT cut-offs (FEV1 <2l, > or =2l; FEV1 <60%, > or =60% predicted; DLCO <60%, > or =60% predicted), toxicity rates, and survival. For the whole study cohort, median, 2- and 5-year overall survivals were: 14.7 months, 22.7 and 7.2%, respectively. Fifty-six patients (26%) required treatment breaks due to toxicity. FEV1 and DLCO results were available for 96 (45%) and 86 (40%) patients, respectively. Two thirds of FEV1s measured were <2l. On statistical analysis, the incidence of toxicity-related interruptions was significant for DLCO<60% (P=0.043), suggestive for FEV1<2l (P=0.1) and non-significant for FEV1<60%. Patients with simultaneous DLCO<60% and FEV1<2l showed a trend toward increase toxicity risk (P=0.1). For selected PFT measures, median overall survivals were: 12.7 months versus 14.8 months for DLCO<60% versus > or =60%; 13.4 months versus 17.7 months for FEV1<2l versus > or =2l; 15.4 months versus 19.9 months for DLCO<60% + FEV1<2l versus DLCO> or =60% + FEV1> or =2l. Although absolute differences favored all patients with PFT values above the prognostic cut-offs, differences were not statistically significant on this analysis. Patients with both a treatment break and a DLCO<60% had the poorest median survival of all patient subsets, at 11.4 months (P=0.09). Impaired DLCO (i.e. <60%) is a novel predictor of increased treatment-related toxicity leading to interruptions. The present study suggests a probable role for DLCO and FEV1 (in l) as prognostic factors for predicting survival but larger patient samples are required for confirmation. Patients with impaired DLCOs experiencing treatment interruptions have the poorest survival. Assessment of pre-treatment PFTs contributes to determining optimal management strategies for LSCLC patients receiving definitive chemoradiation.

853 Poster Pre-treatment pulmonary function tests as predictors of acute treatment toxicity and survival for limited small cell lung cancer (LSCLC) patients receiving chemoradiation

853 Poster Pre-treatment pulmonary function tests as predictors of acute treatment toxicity and survival for limited small cell lung cancer (LSCLC) patients receiving chemoradiation

Do volume metrics predict pulmonary function changes in lung irradiation

Purpose: With conventional doses and field arrangements there is no accurate way to predict the change in pulmonary function, although several volume based metrics do correlate with the risk of pneumonitis. We hypothesized that in a series of patients treated with nonconventional beam arrangements on a dose escalation study for non-small cell lung cancer (NSCLC) that one of these metrics might correlate with late pulmonary function changes as measured by pulmonary function tests (PFTs). Materials and Methods: 42 patients with NSCLC treated on a lung dose escalation study had pre-treatment and post-treatment PFTs 3 or more months after treatment, and were available for evaluation. The study has increased the dose based on the volume of normal lung irradiated by stratifying patients based on the effective volume (Veff) of normal lung irradiated. There was no minimal pulmonary function requirement. Each patient received 2.1 Gy per day in a single fraction, with lung dose inhomogeneity correction. The PTV included the gross tumor plus a 1 cm expansion. The median dose delivered was 76.9 Gy (range 63 to 102.9 Gy). Field arrangements were not specified and varied widely. The median number of fields was 4 with a range from 1 to 6. This cohort had a median age of 66.5 yrs (range 40 to 80). Eight patients received induction chemotherapy with cisplatin and vinorelbine. All patients had the volume of normal lung treated to greater than 20 Gy (V20), the Veff and mean lung dose (MLD) calculated for both lungs. A linear regression analysis was done to determine if there was a correlation between the metrics and changes in FEV1, % Predicted FEV1, and DLCO. Results: The analyzed group had pre-treatment PFTs similar to the entire study group. 42 patients had FEV1 available, 38 had %predicted FEV1 pre-and posttreatment, and 21 had pre- and posttreatment DLCO available. Post-treatment PFTs were measured at a median of 208 days (range 84-471). Median values for Pretreatment PFTs were as follows. FEV1 1.72 (.84to 3.52),%predicted FEV1 65.3 (25 to 117%), DLCO 65.4 (27 to 116). Median values for metrics were Veff .19 (.076 to .43), MLD 15.4 Gy (6.2 to 28.5 Gy, V20 20.6% (0 to 54%). Median posttreatment PFTs were FEV1 1.67 (0.6 to 5.0), % predicted FEV1 60.9 (23 to 119%), DLCO 53.8 (25 to 108). No Patients experienced Grade 3 or 4 pneumonitis. There was no correlation between Veff, V20 or MLD and the change in FEV1, the percent change in FEV1, the change in the % predicted FEV1, the % change in % predicted FEV1, the change in DLCO or the % change in DLCO. Subgroup analyses of patients with and without atelectasis prior to irradiation, induction chemotherapy and stage I or III only patients, were reviewed and there was no correlation between the volume metrics and degree of PFT changes. Conclusions: None of the volume metrics shown to correlate with the risk of pneumonitis were successful in predicting long term changes in pulmonary function as assessed with standard pulmonary function studies in patients treated to high dose using 3D-CRT. A different model and/or parameters are likely necessary to accurately estimate the long-term change in pulmonary function. Tabled 1ParameterMedianRangeDecrease in FEV1.02Decline .9 to increase 3.14%Decrease in FEV12%Decline 45 % to increase 168%%Decrease in %FEV1-2.2%Decline 35 % to increase 56%Decrease in DLCO6.9Decline 9% to increase 31%%Decrease in DLCO10%Decline 28% to increase 29% Open table in a new tab

Changes in plasma TGFβ levels during pulmonary radiotherapy as a predictor of the risk of developing radiation pneumonitis

Purpose : To determine whether plasma transforming growth factor-β (TGF-β) levels measured before and during radical radiotherapy for lung cancer could be used to predict patients at risk for the development of radiation pneumonitis. Methods and Materials : The first eight patients with lung cancer (nonsmall cell: seven, small cell: one) enrolled in a prospective study designed to evaluate physiological and molecular biologic correlates of radiation induced normal tissue injury are described. The study began in June 1991. All patients were treated with radiotherapy with curative intent. Plasma transforming growth factor-R levels were obtained before, weekly during, and at each follow-up after treatment. Pretreatment pulmonary function tests and single photon emission computed tomography scans were obtained to assess baseline lung function and were repeated at follow-up visits. Dose-volume histogram analyses were performed to determine the volume of lung which received ≥ 30 Gy. Patients were assessed at each follow-up visit for signs and symptoms of pneumonitis. Results : Five patients developed signs and/or symptoms of pulmonary injury consistent with pneumonitis and three patients did not. In all three patients not developing pneumonitis, plasma TGF-β levels normalized by the end of radiotherapy. In contrast, four out of five patients who suffered pneumonitis had persistently elevated plasma TGF-β levels by the end of therapy. This finding appeared to be independent of the volume of irradiated lung. Conclusions : These results suggest that plasma TGF-β levels during treatment may be useful to determine which patients are at high risk of developing symptomatic pneumonitis following thoracic radiotherapy. This finding may have implications when planning additional therapy (either chemotherapy or radiotherapy) which may have potentially adverse consequences on the lung.

Usefulness of serial pulmonary function testing as an indicator of amiodarone toxicity

A prospective study was conducted of 189 patients treated with amiodarone, maintained at doses of 400 to 800 mg/day and followed for up to 6 years. Only patients who had life-threatening ventricular arrhythmias unresponsive to conventional therapy were enrolled, and they underwent baseline pretreatment pulmonary function tests, with follow-up testing every 6 months. Morbidity and mortality statistics were confirmed by chart review and patient telephone interview. Of the 189 enrolled patients, 101 are alive, 84 are dead and 4 are lost to follow-up. Amiodarone-induced toxicity to the neurologic system, lungs, thyroid or liver was the primary or complicating cause of death in 12 of the 84 patients who died. The overall prevalence of all these forms of toxicity was 15%. Sixty-nine percent of the patients with amiodarone toxicity had pulmonary toxicity atone or combined with other forms of toxicity. Pulmonary function test abnormalities were noted at baseline in 75% of patients who had amiodarone-induced toxicity. The proportion of abnormal baseline pulmonary function tests was not significantly different among all toxic patients, pulmonary toxic patients and nontoxic patients. An evaluation of the decrease in pulmonary function over time could not distinguish patients who developed toxicity from those who did not. The observed incidence of pulmonary toxicity is consistent with published values; however, contrary to the findings of others, no statistically significant differences in pulmonary function at baseline or in changes over time were found between toxic and nontoxic patients. Differences from previous findings may be reflective of the more severe illness of the present population as evidenced by the high prevalence of abnormal pulmonary function at baseline and a high incidence of subsequent cardiac death. Two findings have not been previously reported: abnormal pulmonary function tests in patients with amiodarone-induced toxicity in nonpulmonary organs, and the frequent finding of concurrent multiple organ involvement in pulmonary toxic patients. The data indicate that pulmonary function tests are only a nonspecific indicator of pulmonary abnormalities in a population with preexisting cardropulmonary disease. In the absence of a specific diagnostic test, diagnosis of amiodarone pulmonary toxicity rests on a constellation of characteristics compiled from pulmonary function tests, chest x-rays, physical signs and a compatible history.

Betaxolol in chronic obstructive pulmonary disease.

We evaluated the effect of betaxolol on the pulmonary function tests of nine patients with glaucoma and chronic obstructive pulmonary disease (COPD) requiring beta-blocker therapy. The results of pre-treatment pulmonary function tests were compared to results after two weeks of betaxolol therapy. The mean ratio of forced expiratory volume in one second (FEV-1) to forced vital capacity (FVC) was 59.33 +/- 13.30%. After two weeks of betaxolol therapy, the resulting mean FEV-1/FVC was 57.89 +/- 13.89%, a statistically insignificant difference (P greater than 0.05). The mean FEV-1 was 1.94 +/- 0.83 liters, compared to 1.91 +/- 0.78 liters after two weeks of betaxolol. The mean FVC was 3.19 +/- 0.91 liters, compared to 3.23 +/- 0.89 liters after two weeks of betaxolol. These differences were, also, not statistically significant (P greater than 0.05). This prospective study supports previous reports suggesting that betaxolol has potential advantages for those patients at risk for developing pulmonary side effects from beta-blocker therapy. This report represents the largest single-center series of patients who have been studied in this fashion.