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Exhaled nitric oxide predicts radiation pneumonitis in esophageal and lung cancer patients receiving thoracic radiation
Radiotherapy and Oncology 101 (2011) 443–448
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Radiation pneumonitis
Exhaled nitric oxide predicts radiation pneumonitis in esophageal and lung cancer patients receiving thoracic radiation Matthew R. McCurdy a, Mohamad W. Wazni b, Josue Martinez c, Mary Frances McAleer d, Thomas Guerrero d,⇑ a c
Division of Radiation Oncology, Baylor College of Medicine, Houston, TX, USA; b Graduate School of Biomedical Sciences at Houston, University of Texas, TX, USA; Department of Statistics, Texas A&M University, TX, USA; d Division of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
a r t i c l e
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Article history: Received 7 April 2011 Received in revised form 24 August 2011 Accepted 26 August 2011 Available online 6 October 2011 Keywords: Radiation pneumonitis Lung cancer Esophageal cancer Exhaled nitric oxide
a b s t r a c t Background and purpose: Radiation pneumonitis is a significant toxicity following thoracic radiotherapy with no method to predict individual risk. Materials and methods: Sixty-five patients receiving thoracic radiation for lung or esophageal cancer were enrolled in a phase II study. Each patient received respiratory surveys and exhaled nitric oxide measurements before, on the last day of, and 30–60 days after completing radiotherapy (RT). Pneumonitis toxicity was scored using the common terminology criteria for adverse events, version 4.0. The demographics, dosimetric factors, and nitric oxide ratio (NOR) of end RT/pre-RT were evaluated for correlation with symptomatic patients (Grade P2). Results: Fifty patients completed the trial. The pneumonitis toxicity score was: Grade 3 for 1 patient, Grade 2 for 6 patients, Grade 1 for 18 patients, and Grade 0 for 25 patients. Dosimetric factors were not predictive of symptoms. The NOR was 3.0 ± 1.8 (range 1.47–6.73) for the symptomatic and 0.78 ± 0.29 (range 0.33–1.37) for the asymptomatic patients (p = 0.006). A threshold NOR of 1.4 separated symptomatic and asymptomatic patients (p < 0.001). The average error was 4%. Conclusions: Elevation in eNO on the last day of radiotherapy predicted subsequent symptomatic radiation pneumonitis weeks to months after treatment. Ó 2011 Published by Elsevier Ireland Ltd. Radiotherapy and Oncology 101 (2011) 443–448
Radiation pneumonitis (RP) is the dose-limiting toxicity in thoracic radiotherapy (RT) for lung cancer [1,2] and is a major toxicity for esophageal cancer [3,4]. Severe RP is often fatal, with a mortality rate approaching 50% in one non-small cell lung cancer series [5]. RP occurs after the initiation of RT up to 6 months after completing a course of RT with cough, shortness of breath, fever and changes in pulmonary function [6,7]. RP has been reported in a wide range of doses to normal lung, including 15 Gy to a unilateral lung for Hodgkin’s disease [8]. Dosimetric parameters, such as the percentage of lung volume irradiated P20 Gy (V20) and the mean lung dose (MLD), provide a guide to assess the risk of RP in the treatment planning process. These parameters have a poor predictive power for individual risk [2,9–12]. The range of V20 and MLD for asymptomatic and symptomatic patients often overlaps [8,12]. In a study of 96
⇑ Corresponding author. Address: Department of Radiation Oncology, Unit 97, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, United States. E-mail address: [email protected] (T. Guerrero). 0167-8140/$ - see front matter Ó 2011 Published by Elsevier Ireland Ltd. doi:10.1016/j.radonc.2011.08.035
patients who received three-dimensional conformal radiotherapy for non-small cell lung cancer, dosimetric factors (MLD, V20, V30) and age (P60 years) were predictive of RP [13]. Rodrigues et al. performed a systematic review of the predictive ability of various dose-volume histogram (DVH) parameters, MLD, and normal tissue complication probability in the incidence of RP. An association between DVH parameters and RP risk was been demonstrated. However, the overall accuracy, sensitivity, specificity, and positive predictive value were generally poor to fair for all three classes of DVH metrics [9]. In a study of 37 esophageal cancer patients treated with radiotherapy with concomitant chemotherapy consisting of 5-fluorouracil and cisplatin, DVH parameters were predictors of symptomatic RP [10]. Current smoking has also been shown to increase the risk of RP [14]. [18F]-2-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET) imaging can also be used to assess pneumonitis. Pulmonary inflammation appears as enhanced 18F-FDG uptake in response to inflammatory stimuli [15–17]. This metabolic response to radiation has been reported [18], beginning early in the RT course [19] and reaching its peak response 63 months after completion [20]. A significant correlation has been found between
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clinical symptoms and the metabolic response measured by 18FFDG imaging [3]. However, this metabolic response occurs concurrently with the clinical symptoms. An inexpensive biomarker that predicts for RP before clinical symptoms is needed. Exhaled nitric oxide (eNO) is an inexpensive noninvasive marker of pulmonary inflammation that may predict the risk of RP for a group of patients at high risk of developing it [21,22]. Within the respiratory system, NO regulates vascular and bronchial tone by promoting dilation of both vessels and airway, helps facilitate the coordinated beating of ciliated epithelial cells, and transmits signals for non-adrenergic and non-cholinergic neurons that course through the bronchial wall [23–26]. NO is produced by a group of enzymes known as nitric oxide synthases (NOS) [27,28]. As a proinflammatory mediator, NO is easily oxidized in biological systems to peroxynitrite (OONO-), a potent epithelial toxin [29]. NO may mediate radiation-induced lung injury by increasing permeability in airway vessels. In lung cancer patients, several cytokines (IL-1b, IL-6, IF-c, TNF-a, TGF-b, etc.) are produced to enhance the production of NO [30]. eNO has been studied in many acute and chronic lung diseases [31,32]. eNO is useful in assessing inflammatory status and response to therapy in patients with moderate to severe asthma and is becoming routine clinical practice in the pediatric asthmatic population [33]. In an irradiated lung mouse model, alveolar macrophages produced NO after RT, and the expression of inducible NO synthase in both alveolar macrophages and alveolar epithelial cells was increased after RT [34,35]. In a prospective patient study of 29 patients undergoing thoracic RT for lung cancer, Koizumi et al. [21] found the eNO level increased >3 times the pretreatment levels in 5 patients. Of these 5 patients, 3 developed symptomatic RP. No other patients showed signs of RP. In a recent study, we reported an elevated eNO in symptomatic patients among a group of 28 patients with esophageal cancer receiving 50.4 Gy with concurrent chemotherapy [22]. In the present study, we evaluated eNO as a predictive biomarker for RP in patients undergoing thoracic radiation for either lung cancer or esophageal cancer in a prospective study. The patient symptoms were surveyed using a standard respiratory questionnaire [36], and they underwent exhaled NO measurements before, at the completion of, and 30–60 days after thoracic RT. We hypothesize that eNO would increase during RT as compared to baseline RT in all symptomatic RT patients.
Materials and methods Eighty-two patients scheduled to begin esophageal cancer or lung cancer treatment in the Department of Radiation Oncology at the University of Texas M. D. Anderson Cancer Center (MDACC) between March 23, 2009 and June 15, 2010 were enrolled in this MDACC Institutional Review Board approved Phase II prospective study (2008–0632). Each patient signed an informed consent and was entered into the clinical research database prior to study entry. Esophageal cancer patients underwent induction and/or neoadjuvant chemoradiotherapy, interval restaging, and surgery [37]. Lung cancer patients underwent induction or concurrent chemotherapy and interval restaging. Patients received measurement of their concentration of eNO prior to beginning radiotherapy, on the last day of radiotherapy, and at their restaging follow-up visit. Since thoracic surgical intervention would interfere with the interpretation of clinical symptoms, esophageal patients completed this study at their restaging follow-up visit prior to surgery. At each of the three study encounters, they were asked to complete a respiratory questionnaire and confirm their current medications list. A measurement of their exhaled nitric oxide concentration was also made at each visit.
Each patient received a treatment planning session with computed tomography (CT) images of the entire thorax and upper-abdomen. Gross target delineation and margin generation were performed in a consistent manner as our group has reported [38]. The radiation dose was calculated using an average CT calculated from a 4-dimensional CT (4D CT) image set [39,40]. The radiation dose distributions were calculated with lung heterogeneity corrections for all cases [41,42]. Mean lung dose (MLD) and the percentage volume of lung irradiated to 5, 10, 20, and 30 Gy (V5, V10, V20, and V30), were obtained from the radiation treatment plans as dosimetric parameters to estimate the volume of lung irradiated. The patients received eNO testing using the Food and Drug Administration approved NIOX Mino (Aerocrine, New Providence, NJ) within 2 weeks of starting RT, on the day of completion of RT, and on their restaging follow-up visit after RT. The patients received exhaled breath testing using the American Thoracic Society (ATS) guidelines standard techniques [43]. The patients were seated comfortably and a sterile single-use mouthpieces and filter were used for each subject at each session. Each patient inserted the mouthpiece and inhaled over 2–3 s through the mouth to total lung capacity (TLC), or near TLC if TLC was difficult, and then exhaled immediately. Since the NO concentration has a marked dependence on the flow rate, the flow rate is monitored by the NIOX Mino to maintain a 3 L/min flow rate on exhalation. The NIOX Mino creates a mild back pressure (8–10 mmHg) to close the posterior vellum and prevent nasal air contamination. The measurements were made in triplicate, with data acquired during three breaths at each time point and recorded. ENO values were then calculated as the mean of the three values. There were at least 2 min of rest prior to each measurement. Measurements were taken at the start of radiation therapy, during the last week of radiation treatment, and at the follow-up PET imaging session. At each of the three assessment time points, patients enrolled in this study were asked to complete the Americanized St. George’s Respiratory Questionnaire [36]. Their current medications list was confirmed with the patients and the documents entered into the patients’ electronic file for this study. If patients had a surgical resection after completing radiation, the toxicity evaluation ended at the day of the operation. All other patients records were evaluated for 1 year after completing radiation. The clinical and research records were combined to score the pneumonitis toxicity using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (CTCAEv4.0) [44]. Clinically symptomatic pneumonitis was defined as Grade 2 or higher. Continuous variables (mean lung dose, V5, V10, V20, V30, radiation dose, time between radiotherapy and restaging, and age) were summarized in the form of mean (SD; range). Categorical variables (toxicity, tumor location, and tumor histology) were summarized in the form of frequency tables. A Wilcoxon rank sum test was used to compare the dosimetry parameters (MLD, mean lung dose; V5– V30, percentage of lung volume that received >5–30 Gy) between the asymptomatic and symptomatic groups. P-values of 0.05 or less were considered statistically significant. A sensitivity analysis was performed to determine the threshold level of the ratio of eNO at the end of RT to pre-RT that can best predict symptomatic and asymptomatic patients. The area under the relative operating characteristic (ROC) was determined to test the hypothesis that prediction of the events is not equal to random selection [45]. To validate these results, the Wilcoxon rank test was also used to compare eNO ratios of end versus before RT. The eNO ratio of end versus before treatment was tested as classifier to predict symptomatic patients using a k-nearest neighbor classifier with k = 1–5 and an 80/ 20 cross-validation scheme. Simulations were run 1000 times to predict the average error, where 80/20 is the percentage of data used to train/test the classifier.
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Results In this analysis, of the 65 consented patients, 5 patients withdrew from the study prior to completing radiotherapy and their scheduled tests. Nine patients missed one of the evaluation sessions, either due to instrument failure or schedule. One patient did not return for follow-up or restaging visits. The characteristics of the evaluable patients who completed the study are summarized in Table 1. All esophageal patients received 50.4 Gy (or Co60 GE), 13 received proton therapy and the remainder X-ray based intensity modulated radiotherapy (IMRT). One patient received radiation for a head-and-neck primary concomitant with the radiation to the distal esophagus, and the dosimetric parameters from the composite plan were used. The primary esophageal tumors from all cases were mid-thoracic or lower esophageal cancer primaries. Non-small cell lung cancer patients received 63–74 Gy (or Co-60 GE) with 3 patients receiving proton therapy and the remainder receiving IMRT. One small cell lung cancer patient received daily radiation to 61.2 Gy and two patients received 45 Gy with twice daily treatments. Overall, the median time between the completion of radiotherapy and the follow-up visit was 37 days (range: 23–57 days). The median last follow up visit 109 days for esophageal cancer patients (censured at time of esophagectomy) and 322 days for lung cancer patients. eNO concentration measured before, at completion, and at restaging was 18.2 ± 9.8 SD (range, 5–54.7), 15.7 ± 11.4 (5.8– 67.7), and 14.5 ± 6.3 (5.5–29.0) parts per billion, respectively. Ratios for each case were formed with respect to the pre-radiotherapy baseline and are given in histogram format in Fig. 1 for the completion and restaging time points. There is a transient rise in the eNO over baseline at the end of radiotherapy that nearly completely resolves by the restaging visit. Pneumonitis toxicity was assessed from medical records, including a review of the radiographic studies, and the respiratory surveys. The toxicity scores derived using the CTCAEv4.041 were: Grade 0 for 25, Grade 1 for 18, Grade 2 for 6, Grade 3 for 1, and Grade 4 or 5 for none. Three patients had both radiographic and clinical respiratory symptoms affecting their instrumental activities of daily living were given a score of 2. Eighteen patients, who had only radiographic findings within the radiation treatment field or minor clinical symptoms, were scored as Grade 1 toxicity. Patients were stratified based on the clinical score as symptomatic (P2, 7 patients) or asymptomatic (0 or 1, 43 patients). For the seven symptomatic patients, toxicity Grade P2, the times to peak respiratory symptoms were recorded. Five symptomatic patients had esophageal cancer and two patients had lung cancer (Table 3). The dosimetric parameters, the MLD and V5 though V30, for asymptomatic and symptomatic cases are summarized in Table 2. The range of values for the asymptomatic cases included and exceeded the range for the symptomatic cases. There was no statistical difference in the dosimetric parameters detected between the two groups. The eNO ratios, before versus end of radiotherapy, are separated into symptomatic and asymptomatic cases in Fig. 1a. Every symptomatic case was higher than all of the asymptomatic cases, there were no symptomatic cases with a ratio of 61.4 and vice versa. A scatter plot of the time from the end of radiotherapy to peak symptoms versus eNO ratio is given in Fig. 2. For each of these symptomatic cases peak symptoms were defined during a clinical encounter such as hospitalization for dyspnea. For the symptomatic cases, a greater eNO ratio at the end of radiation treatment correlated with a shorter the time to peak symptoms. The eNO ratio was plotted against the MLD and V20 in Fig. 3 for the symptomatic and asymptomatic cases. There was no dosimetric parameter that could meaningfully separate the two groups. A comparison of the eNO ratios (end of RT versus before RT) between
Table 1 Patients characteristics. Characteristics Esophageal cancer Age (y) Median Range Gender Male Female Stage I IIA IIB III IVA IVB Location Middle
n
61 40–84 34 3 1 (2.7) 11 (29.7) 4 (10.8) 16 (43.2) 4 (10.8) 1 (2.7) 5 (13.5)
Middle to GE junction Lower GE junction Histology Adenocarcinoma Squamous cell carcinoma Prescription dose (Gy) Median Range Radiation type IMRT/protons Chemotherapy Induction prior to radiotherapy Concurrent with radiotherapy
13 (35.1) 15 (40.5) 4 (10.8)
Lung cancer Age (y) Median Range Gender Male Female Stage IA IIB IIIA IIIB IV Location Upper lobe Lower lobe Histology Adenocarcinoma Squamous cell carcinoma Small cell carcinoma Prescription dose (Gy) Median Range⁄ Radiation type IMRT/protons Chemotherapy Induction prior to radiotherapy Concurrent with radiotherapy
n
32 (86) 5 (14) 50.4 Gy (or Co-60 GE) 50.4 Gy 24/13 24 (65) 37 (100)
65 51–85 7 6 1 3 6 2 1
(7.7) (23.1) (46.2) (15.4) (7.7)
10 3 7 (54) 3 (23) 3 (23) 70 Gy (or Co-60 GE) 61.2–74 Gy 10/ 3 1(8) 11 (85)
Abbreviations: GE = Gastro-esophageal, Co-60 GE = cobalt-60 gray equivalents. Percentages are presented in parenthesis. ⁄Two patients with small cell lung cancer received 45 Gy using 1.5 Gy twice daily fractionation.
the asymptomatic versus the symptomatic group found that symptomatic patients had a higher ratio than asymptomatic patients (p < 0.006). A sensitivity analysis was performed to determine the level of the ratio of end RT eNO to pre RT eNO that can best predict symptomatic and asymptomatic patients. The threshold level of 1.4 classified between symptomatic and asymptomatic patients. The area under the ROC curve for this analysis is 1 (p < 0.001). The eNO ratio (end versus before) was tested as a classifier to
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Exhaled nitric oxide predicts radiation pneumonitis Table 2 Dosimetric parameters for asymptomatic and symptomatic cases. Parameter
Asymptomatic (n = 43)
Symptomatic (n = 7)
p⁄
MLD V5 V10 V20 V30
9.5 (3.0–20.9) 39.3 (11.9–64.5) 28.4 (8.5–45.6) 18.7 (4.6–35.2) 8.2 (1.3–30.6)
7.3 (4.4–12.0) 30.4 (17.6–56.1) 25.0 (15.3–39.9) 14.5 (11.8–24.5) 6.4 (2.3–12.2)
0.68 0.94 0.93 0.55 0.81
Abbreviations: MLD = mean lung dose; V5 = percentage of lung receiving P5 Gy; V10 = percentage of lung receiving P10 Gy; V20 = percentage of lung receiving P20 Gy; V30 = percentage of lung receiving P30 Gy. Data presented as median with range in parentheses. ⁄p-values calculated using the Wilcoxon rank sum test with p 6 0.05 or less were considered statistically significant.
Table 3 Pneumonitis grade by common toxicity criteria version 4. Toxicity grade Esophageal cancer (n = 37) 0 1 2 3 Lung cancer (n = 13) 0 1 2 3
n 21 (57) 11 (30) 4 (11) 1 (2) 4 7 2 0
(31) (54) (15) (0)
Percentages are presented in parenthesis.
Fig. 1. Frequency distribution of exhaled nitric oxide ratio. (a) A histogram is shown of the ratio of exhaled nitric oxide concentrations at the completion of treatment versus that obtained before radiotherapy (RT) from 50 cases. The symptomatic cases are shown in solid black and the asymptomatic in hashed lines. Symptomatic cases were those with CTCAEv4.0 Grade 2 or higher pneumonitis. (b) A histogram of the ratio of exhaled nitric oxide concentration obtained at the first follow-up visit (23–57 days after RT) versus that obtained before RT from 50 cases.
predict symptomatic patients, and this resulted in a very small average error rate (4%). Discussion In this prospective study, we show that eNO concentration measurements, which are rapid, inexpensive, and point-of-service, predict symptomatic RP. All symptomatic patients had no clinically significant indication of pneumonitis at the end of RT other than an elevated eNO ratio. The elevation in eNO was predictive and occurred weeks to months before peak symptoms developed in each case. This prediction does not necessarily change radiotherapy since the prediction is related to measurements at the end of radiation. Rather, an elevated eNO ratio may indicate that an intervention could be administered to an asymptomatic patient. The patients in this study received differing treatments (timedose-fractionation, dose intensity of chemoradiation, sequence, chemotherapeutics, treatment technique, dose distribution) for two distinct malignancies which may affect the risk of pneumonitis for an individual patient. In addition, this study has a relatively small number of patients. A validation study is needed to further assess NOR in predicting pneumonitis.
Fig. 2. Exhaled nitric oxide versus time to peak symptoms. Scatter plot of time from the end of radiotherapy to peak symptoms versus exhaled NO ratio. The time to peak symptoms was inversely correlated with eNO ratio (p = 0.02). For each of these symptomatic cases peak symptoms were defined during a clinical encounter such as hospitalization for dyspnea.
The present study has shown that all symptomatic cases had an elevated eNO ratio with a pneumonitis incidence of 14%. In the retrospective study of 122 pediatric patients receiving 15 Gy (Hodgkin’s disease) to 70 Gy (sarcoma) for a range of thoracic malignancies, the 1-year cumulative incidence of symptomatic RP was 8.2% with symptomatic cases found even in those receiving 15 Gy to the unilateral lung [8]. The rate of symptomatic pneumonitis was low (14%). This is in the range 13–37% reported in a data review by Rodrigues et al. [9]. In a study of 139 esophageal cancer patients [4], we found a pneumonitis rate of 58% owing to higher lung dose with MLD of 12.3 versus 9.6 Gy in the present study. This difference
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and sputum results were recorded. Every patient in this study with pulmonary symptoms were scored as RP since there was no overwhelming evidence of another cause. A viral infection could have occurred in some patients to cause an elevated NO. Medications can affect NO levels, including steroids and bronchodilators. Medications were recorded at each visit and the time of last administration was recorded. In asthma, airway caliber affects NO, where a larger diameter yields higher NO plateau [51–53]. Post-stenotic obstruction could have reduced NO levels in some patients by reducing output, while adjacent inflammation could have increased NO levels. Current smoking chronically reduces eNO and acutely reduces eNO within 1–2 h of smoking [53,54]. The ratio of NO was chosen instead of absolute values because a change in variation of NO in individuals over time could likely be demonstrated with a smaller study. Each individual acts as their own control, establishing their pretreatment baseline. In asthma patients, medications were titrated based on an individual’s NO level of time before a threshold NO level for the diagnosis of asthma was established since the later required many data points because of the significant overlap of asthma and healthy individuals. eNO is a non-invasive, rapid, point-of-service test to assess airway inflammation. In this study, the test was easy for the patients to perform and was reproducible. The sensitivity and specificity of the ratio of eNO at End RT/ pre-RT could not be fully assessed owing to the limited number of symptomatic cases in the accrual to date. The number of symptomatic cases is small but the classifier chooses subjects at random and attempts to classify with even fewer cases, which makes the findings more robust. The present study was limited by the number of NO measurements made. In an ongoing lung cancer patient cohort, weekly assessments are being made to allow earlier detection of the increase in eNO to aid in total dose determination and delivery of potential therapeutic agents for RP during radiation delivery. Conclusion Fig. 3. Toxicity analysis using exhaled nitric oxide (eNO). (a) Plot of toxicity outcome by eNO ratio and MLD. The dashed line (ratio eNO = 1.4) separates those with Grade 2 or higher toxicity from the asymptomatic cases. (b) Plot of toxicity outcome by eNO ratio and V20. The same line delineates a high risk region for those with Grade 2 or higher radiation pneumonitis toxicity. The two volumetric parameters (MLD & V20) alone or combined had poor predictive power.
in MLD is explained by the use of three-dimensional RT planning and wider planning margins without image guidance in the study of 139 esophageal cancer patients. Amifostine [46] and inhaled beclomethasone [47] may reduce the incidence of RP in locally advanced lung cancer patients receiving thoracic RT. However, the perceived risk of reduced cancer control and medication side effects have resulted in reluctance to prophylactically treat all patients undergoing thoracic RT with these medications. This study identified a group of patients, at the end of RT, at high risk of developing subsequent symptomatic pneumonitis. Now that a high risk group can be identified using eNO, studies are needed to identify methods to mitigate the development of RP in high risk patients. Several patient factors potentially affected NO levels in this study, particularly in the lung cancer patient group. Patients with asthma are known to have elevated NO levels and were excluded from this study. Two lung cancer patients had a diagnosis of chronic obstructive pulmonary disease (COPD), and NO has been reported to be high in exacerbations compared with stable patients [48]. One report suggested that NO falls after inhaled steroids in stable COPD [49]. Viral infections also have been shown to transiently elevate NO [50]. The questionnaire and medical record were used to aid in determining the cause of cough and dyspnea,
In this prospective study, an elevation in eNO at the end of RT predicted subsequent symptomatic RP. All symptomatic patients had a ratio of end of RT eNO to baseline eNO higher than asymptomatic patients. No asymptomatic patient had a ratio greater than 1.4 and vice versa. The interval to the occurrence of peak symptoms was inversely related to the increase in eNO. Serial eNO measurements may aid in identifying a group of patients at high risk of developing symptomatic RP. Conflict of interest statement None declared. Acknowledgments We extend our gratitude to the thoracic radiation oncology faculty, thoracic surgeons, and gastrointestinal medical oncologists at M. D. Anderson whose patients were the focus of this study. The authors thank Dr. Mersiha Hadziahmetovic who performed the initial calibration and clinical acceptance testing of the NO breath analyzer. The authors also thank Mr. Jan Pagilagan who served as the data coordinator for this study and Ms. Toni Williams who provided administrative support. We most sincerely thank the National Institutes of Health (NIH) and the National Cancer Institute (NCI) who provided support for this project through NIH/NCI Grant R21CA141833. Dr. Martinez was supported by a post-doctoral training grant, NCI Grant R25T-CA90301. Additional funding for this study was provided from The University of Texas M. D. Anderson Cancer Center’s Physician Scientist Program.
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Radiation pneumonitis
Exhaled nitric oxide predicts radiation pneumonitis in esophageal and lung cancer patients receiving thoracic radiation Matthew R. McCurdy a, Mohamad W. Wazni b, Josue Martinez c, Mary Frances McAleer d, Thomas Guerrero d,⇑ a c
Division of Radiation Oncology, Baylor College of Medicine, Houston, TX, USA; b Graduate School of Biomedical Sciences at Houston, University of Texas, TX, USA; Department of Statistics, Texas A&M University, TX, USA; d Division of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
a r t i c l e
i n f o
Article history: Received 7 April 2011 Received in revised form 24 August 2011 Accepted 26 August 2011 Available online 6 October 2011 Keywords: Radiation pneumonitis Lung cancer Esophageal cancer Exhaled nitric oxide
a b s t r a c t Background and purpose: Radiation pneumonitis is a significant toxicity following thoracic radiotherapy with no method to predict individual risk. Materials and methods: Sixty-five patients receiving thoracic radiation for lung or esophageal cancer were enrolled in a phase II study. Each patient received respiratory surveys and exhaled nitric oxide measurements before, on the last day of, and 30–60 days after completing radiotherapy (RT). Pneumonitis toxicity was scored using the common terminology criteria for adverse events, version 4.0. The demographics, dosimetric factors, and nitric oxide ratio (NOR) of end RT/pre-RT were evaluated for correlation with symptomatic patients (Grade P2). Results: Fifty patients completed the trial. The pneumonitis toxicity score was: Grade 3 for 1 patient, Grade 2 for 6 patients, Grade 1 for 18 patients, and Grade 0 for 25 patients. Dosimetric factors were not predictive of symptoms. The NOR was 3.0 ± 1.8 (range 1.47–6.73) for the symptomatic and 0.78 ± 0.29 (range 0.33–1.37) for the asymptomatic patients (p = 0.006). A threshold NOR of 1.4 separated symptomatic and asymptomatic patients (p < 0.001). The average error was 4%. Conclusions: Elevation in eNO on the last day of radiotherapy predicted subsequent symptomatic radiation pneumonitis weeks to months after treatment. Ó 2011 Published by Elsevier Ireland Ltd. Radiotherapy and Oncology 101 (2011) 443–448
Radiation pneumonitis (RP) is the dose-limiting toxicity in thoracic radiotherapy (RT) for lung cancer [1,2] and is a major toxicity for esophageal cancer [3,4]. Severe RP is often fatal, with a mortality rate approaching 50% in one non-small cell lung cancer series [5]. RP occurs after the initiation of RT up to 6 months after completing a course of RT with cough, shortness of breath, fever and changes in pulmonary function [6,7]. RP has been reported in a wide range of doses to normal lung, including 15 Gy to a unilateral lung for Hodgkin’s disease [8]. Dosimetric parameters, such as the percentage of lung volume irradiated P20 Gy (V20) and the mean lung dose (MLD), provide a guide to assess the risk of RP in the treatment planning process. These parameters have a poor predictive power for individual risk [2,9–12]. The range of V20 and MLD for asymptomatic and symptomatic patients often overlaps [8,12]. In a study of 96
⇑ Corresponding author. Address: Department of Radiation Oncology, Unit 97, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, United States. E-mail address: [email protected] (T. Guerrero). 0167-8140/$ - see front matter Ó 2011 Published by Elsevier Ireland Ltd. doi:10.1016/j.radonc.2011.08.035
patients who received three-dimensional conformal radiotherapy for non-small cell lung cancer, dosimetric factors (MLD, V20, V30) and age (P60 years) were predictive of RP [13]. Rodrigues et al. performed a systematic review of the predictive ability of various dose-volume histogram (DVH) parameters, MLD, and normal tissue complication probability in the incidence of RP. An association between DVH parameters and RP risk was been demonstrated. However, the overall accuracy, sensitivity, specificity, and positive predictive value were generally poor to fair for all three classes of DVH metrics [9]. In a study of 37 esophageal cancer patients treated with radiotherapy with concomitant chemotherapy consisting of 5-fluorouracil and cisplatin, DVH parameters were predictors of symptomatic RP [10]. Current smoking has also been shown to increase the risk of RP [14]. [18F]-2-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET) imaging can also be used to assess pneumonitis. Pulmonary inflammation appears as enhanced 18F-FDG uptake in response to inflammatory stimuli [15–17]. This metabolic response to radiation has been reported [18], beginning early in the RT course [19] and reaching its peak response 63 months after completion [20]. A significant correlation has been found between
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clinical symptoms and the metabolic response measured by 18FFDG imaging [3]. However, this metabolic response occurs concurrently with the clinical symptoms. An inexpensive biomarker that predicts for RP before clinical symptoms is needed. Exhaled nitric oxide (eNO) is an inexpensive noninvasive marker of pulmonary inflammation that may predict the risk of RP for a group of patients at high risk of developing it [21,22]. Within the respiratory system, NO regulates vascular and bronchial tone by promoting dilation of both vessels and airway, helps facilitate the coordinated beating of ciliated epithelial cells, and transmits signals for non-adrenergic and non-cholinergic neurons that course through the bronchial wall [23–26]. NO is produced by a group of enzymes known as nitric oxide synthases (NOS) [27,28]. As a proinflammatory mediator, NO is easily oxidized in biological systems to peroxynitrite (OONO-), a potent epithelial toxin [29]. NO may mediate radiation-induced lung injury by increasing permeability in airway vessels. In lung cancer patients, several cytokines (IL-1b, IL-6, IF-c, TNF-a, TGF-b, etc.) are produced to enhance the production of NO [30]. eNO has been studied in many acute and chronic lung diseases [31,32]. eNO is useful in assessing inflammatory status and response to therapy in patients with moderate to severe asthma and is becoming routine clinical practice in the pediatric asthmatic population [33]. In an irradiated lung mouse model, alveolar macrophages produced NO after RT, and the expression of inducible NO synthase in both alveolar macrophages and alveolar epithelial cells was increased after RT [34,35]. In a prospective patient study of 29 patients undergoing thoracic RT for lung cancer, Koizumi et al. [21] found the eNO level increased >3 times the pretreatment levels in 5 patients. Of these 5 patients, 3 developed symptomatic RP. No other patients showed signs of RP. In a recent study, we reported an elevated eNO in symptomatic patients among a group of 28 patients with esophageal cancer receiving 50.4 Gy with concurrent chemotherapy [22]. In the present study, we evaluated eNO as a predictive biomarker for RP in patients undergoing thoracic radiation for either lung cancer or esophageal cancer in a prospective study. The patient symptoms were surveyed using a standard respiratory questionnaire [36], and they underwent exhaled NO measurements before, at the completion of, and 30–60 days after thoracic RT. We hypothesize that eNO would increase during RT as compared to baseline RT in all symptomatic RT patients.
Materials and methods Eighty-two patients scheduled to begin esophageal cancer or lung cancer treatment in the Department of Radiation Oncology at the University of Texas M. D. Anderson Cancer Center (MDACC) between March 23, 2009 and June 15, 2010 were enrolled in this MDACC Institutional Review Board approved Phase II prospective study (2008–0632). Each patient signed an informed consent and was entered into the clinical research database prior to study entry. Esophageal cancer patients underwent induction and/or neoadjuvant chemoradiotherapy, interval restaging, and surgery [37]. Lung cancer patients underwent induction or concurrent chemotherapy and interval restaging. Patients received measurement of their concentration of eNO prior to beginning radiotherapy, on the last day of radiotherapy, and at their restaging follow-up visit. Since thoracic surgical intervention would interfere with the interpretation of clinical symptoms, esophageal patients completed this study at their restaging follow-up visit prior to surgery. At each of the three study encounters, they were asked to complete a respiratory questionnaire and confirm their current medications list. A measurement of their exhaled nitric oxide concentration was also made at each visit.
Each patient received a treatment planning session with computed tomography (CT) images of the entire thorax and upper-abdomen. Gross target delineation and margin generation were performed in a consistent manner as our group has reported [38]. The radiation dose was calculated using an average CT calculated from a 4-dimensional CT (4D CT) image set [39,40]. The radiation dose distributions were calculated with lung heterogeneity corrections for all cases [41,42]. Mean lung dose (MLD) and the percentage volume of lung irradiated to 5, 10, 20, and 30 Gy (V5, V10, V20, and V30), were obtained from the radiation treatment plans as dosimetric parameters to estimate the volume of lung irradiated. The patients received eNO testing using the Food and Drug Administration approved NIOX Mino (Aerocrine, New Providence, NJ) within 2 weeks of starting RT, on the day of completion of RT, and on their restaging follow-up visit after RT. The patients received exhaled breath testing using the American Thoracic Society (ATS) guidelines standard techniques [43]. The patients were seated comfortably and a sterile single-use mouthpieces and filter were used for each subject at each session. Each patient inserted the mouthpiece and inhaled over 2–3 s through the mouth to total lung capacity (TLC), or near TLC if TLC was difficult, and then exhaled immediately. Since the NO concentration has a marked dependence on the flow rate, the flow rate is monitored by the NIOX Mino to maintain a 3 L/min flow rate on exhalation. The NIOX Mino creates a mild back pressure (8–10 mmHg) to close the posterior vellum and prevent nasal air contamination. The measurements were made in triplicate, with data acquired during three breaths at each time point and recorded. ENO values were then calculated as the mean of the three values. There were at least 2 min of rest prior to each measurement. Measurements were taken at the start of radiation therapy, during the last week of radiation treatment, and at the follow-up PET imaging session. At each of the three assessment time points, patients enrolled in this study were asked to complete the Americanized St. George’s Respiratory Questionnaire [36]. Their current medications list was confirmed with the patients and the documents entered into the patients’ electronic file for this study. If patients had a surgical resection after completing radiation, the toxicity evaluation ended at the day of the operation. All other patients records were evaluated for 1 year after completing radiation. The clinical and research records were combined to score the pneumonitis toxicity using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (CTCAEv4.0) [44]. Clinically symptomatic pneumonitis was defined as Grade 2 or higher. Continuous variables (mean lung dose, V5, V10, V20, V30, radiation dose, time between radiotherapy and restaging, and age) were summarized in the form of mean (SD; range). Categorical variables (toxicity, tumor location, and tumor histology) were summarized in the form of frequency tables. A Wilcoxon rank sum test was used to compare the dosimetry parameters (MLD, mean lung dose; V5– V30, percentage of lung volume that received >5–30 Gy) between the asymptomatic and symptomatic groups. P-values of 0.05 or less were considered statistically significant. A sensitivity analysis was performed to determine the threshold level of the ratio of eNO at the end of RT to pre-RT that can best predict symptomatic and asymptomatic patients. The area under the relative operating characteristic (ROC) was determined to test the hypothesis that prediction of the events is not equal to random selection [45]. To validate these results, the Wilcoxon rank test was also used to compare eNO ratios of end versus before RT. The eNO ratio of end versus before treatment was tested as classifier to predict symptomatic patients using a k-nearest neighbor classifier with k = 1–5 and an 80/ 20 cross-validation scheme. Simulations were run 1000 times to predict the average error, where 80/20 is the percentage of data used to train/test the classifier.
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Results In this analysis, of the 65 consented patients, 5 patients withdrew from the study prior to completing radiotherapy and their scheduled tests. Nine patients missed one of the evaluation sessions, either due to instrument failure or schedule. One patient did not return for follow-up or restaging visits. The characteristics of the evaluable patients who completed the study are summarized in Table 1. All esophageal patients received 50.4 Gy (or Co60 GE), 13 received proton therapy and the remainder X-ray based intensity modulated radiotherapy (IMRT). One patient received radiation for a head-and-neck primary concomitant with the radiation to the distal esophagus, and the dosimetric parameters from the composite plan were used. The primary esophageal tumors from all cases were mid-thoracic or lower esophageal cancer primaries. Non-small cell lung cancer patients received 63–74 Gy (or Co-60 GE) with 3 patients receiving proton therapy and the remainder receiving IMRT. One small cell lung cancer patient received daily radiation to 61.2 Gy and two patients received 45 Gy with twice daily treatments. Overall, the median time between the completion of radiotherapy and the follow-up visit was 37 days (range: 23–57 days). The median last follow up visit 109 days for esophageal cancer patients (censured at time of esophagectomy) and 322 days for lung cancer patients. eNO concentration measured before, at completion, and at restaging was 18.2 ± 9.8 SD (range, 5–54.7), 15.7 ± 11.4 (5.8– 67.7), and 14.5 ± 6.3 (5.5–29.0) parts per billion, respectively. Ratios for each case were formed with respect to the pre-radiotherapy baseline and are given in histogram format in Fig. 1 for the completion and restaging time points. There is a transient rise in the eNO over baseline at the end of radiotherapy that nearly completely resolves by the restaging visit. Pneumonitis toxicity was assessed from medical records, including a review of the radiographic studies, and the respiratory surveys. The toxicity scores derived using the CTCAEv4.041 were: Grade 0 for 25, Grade 1 for 18, Grade 2 for 6, Grade 3 for 1, and Grade 4 or 5 for none. Three patients had both radiographic and clinical respiratory symptoms affecting their instrumental activities of daily living were given a score of 2. Eighteen patients, who had only radiographic findings within the radiation treatment field or minor clinical symptoms, were scored as Grade 1 toxicity. Patients were stratified based on the clinical score as symptomatic (P2, 7 patients) or asymptomatic (0 or 1, 43 patients). For the seven symptomatic patients, toxicity Grade P2, the times to peak respiratory symptoms were recorded. Five symptomatic patients had esophageal cancer and two patients had lung cancer (Table 3). The dosimetric parameters, the MLD and V5 though V30, for asymptomatic and symptomatic cases are summarized in Table 2. The range of values for the asymptomatic cases included and exceeded the range for the symptomatic cases. There was no statistical difference in the dosimetric parameters detected between the two groups. The eNO ratios, before versus end of radiotherapy, are separated into symptomatic and asymptomatic cases in Fig. 1a. Every symptomatic case was higher than all of the asymptomatic cases, there were no symptomatic cases with a ratio of 61.4 and vice versa. A scatter plot of the time from the end of radiotherapy to peak symptoms versus eNO ratio is given in Fig. 2. For each of these symptomatic cases peak symptoms were defined during a clinical encounter such as hospitalization for dyspnea. For the symptomatic cases, a greater eNO ratio at the end of radiation treatment correlated with a shorter the time to peak symptoms. The eNO ratio was plotted against the MLD and V20 in Fig. 3 for the symptomatic and asymptomatic cases. There was no dosimetric parameter that could meaningfully separate the two groups. A comparison of the eNO ratios (end of RT versus before RT) between
Table 1 Patients characteristics. Characteristics Esophageal cancer Age (y) Median Range Gender Male Female Stage I IIA IIB III IVA IVB Location Middle
n
61 40–84 34 3 1 (2.7) 11 (29.7) 4 (10.8) 16 (43.2) 4 (10.8) 1 (2.7) 5 (13.5)
Middle to GE junction Lower GE junction Histology Adenocarcinoma Squamous cell carcinoma Prescription dose (Gy) Median Range Radiation type IMRT/protons Chemotherapy Induction prior to radiotherapy Concurrent with radiotherapy
13 (35.1) 15 (40.5) 4 (10.8)
Lung cancer Age (y) Median Range Gender Male Female Stage IA IIB IIIA IIIB IV Location Upper lobe Lower lobe Histology Adenocarcinoma Squamous cell carcinoma Small cell carcinoma Prescription dose (Gy) Median Range⁄ Radiation type IMRT/protons Chemotherapy Induction prior to radiotherapy Concurrent with radiotherapy
n
32 (86) 5 (14) 50.4 Gy (or Co-60 GE) 50.4 Gy 24/13 24 (65) 37 (100)
65 51–85 7 6 1 3 6 2 1
(7.7) (23.1) (46.2) (15.4) (7.7)
10 3 7 (54) 3 (23) 3 (23) 70 Gy (or Co-60 GE) 61.2–74 Gy 10/ 3 1(8) 11 (85)
Abbreviations: GE = Gastro-esophageal, Co-60 GE = cobalt-60 gray equivalents. Percentages are presented in parenthesis. ⁄Two patients with small cell lung cancer received 45 Gy using 1.5 Gy twice daily fractionation.
the asymptomatic versus the symptomatic group found that symptomatic patients had a higher ratio than asymptomatic patients (p < 0.006). A sensitivity analysis was performed to determine the level of the ratio of end RT eNO to pre RT eNO that can best predict symptomatic and asymptomatic patients. The threshold level of 1.4 classified between symptomatic and asymptomatic patients. The area under the ROC curve for this analysis is 1 (p < 0.001). The eNO ratio (end versus before) was tested as a classifier to
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Exhaled nitric oxide predicts radiation pneumonitis Table 2 Dosimetric parameters for asymptomatic and symptomatic cases. Parameter
Asymptomatic (n = 43)
Symptomatic (n = 7)
p⁄
MLD V5 V10 V20 V30
9.5 (3.0–20.9) 39.3 (11.9–64.5) 28.4 (8.5–45.6) 18.7 (4.6–35.2) 8.2 (1.3–30.6)
7.3 (4.4–12.0) 30.4 (17.6–56.1) 25.0 (15.3–39.9) 14.5 (11.8–24.5) 6.4 (2.3–12.2)
0.68 0.94 0.93 0.55 0.81
Abbreviations: MLD = mean lung dose; V5 = percentage of lung receiving P5 Gy; V10 = percentage of lung receiving P10 Gy; V20 = percentage of lung receiving P20 Gy; V30 = percentage of lung receiving P30 Gy. Data presented as median with range in parentheses. ⁄p-values calculated using the Wilcoxon rank sum test with p 6 0.05 or less were considered statistically significant.
Table 3 Pneumonitis grade by common toxicity criteria version 4. Toxicity grade Esophageal cancer (n = 37) 0 1 2 3 Lung cancer (n = 13) 0 1 2 3
n 21 (57) 11 (30) 4 (11) 1 (2) 4 7 2 0
(31) (54) (15) (0)
Percentages are presented in parenthesis.
Fig. 1. Frequency distribution of exhaled nitric oxide ratio. (a) A histogram is shown of the ratio of exhaled nitric oxide concentrations at the completion of treatment versus that obtained before radiotherapy (RT) from 50 cases. The symptomatic cases are shown in solid black and the asymptomatic in hashed lines. Symptomatic cases were those with CTCAEv4.0 Grade 2 or higher pneumonitis. (b) A histogram of the ratio of exhaled nitric oxide concentration obtained at the first follow-up visit (23–57 days after RT) versus that obtained before RT from 50 cases.
predict symptomatic patients, and this resulted in a very small average error rate (4%). Discussion In this prospective study, we show that eNO concentration measurements, which are rapid, inexpensive, and point-of-service, predict symptomatic RP. All symptomatic patients had no clinically significant indication of pneumonitis at the end of RT other than an elevated eNO ratio. The elevation in eNO was predictive and occurred weeks to months before peak symptoms developed in each case. This prediction does not necessarily change radiotherapy since the prediction is related to measurements at the end of radiation. Rather, an elevated eNO ratio may indicate that an intervention could be administered to an asymptomatic patient. The patients in this study received differing treatments (timedose-fractionation, dose intensity of chemoradiation, sequence, chemotherapeutics, treatment technique, dose distribution) for two distinct malignancies which may affect the risk of pneumonitis for an individual patient. In addition, this study has a relatively small number of patients. A validation study is needed to further assess NOR in predicting pneumonitis.
Fig. 2. Exhaled nitric oxide versus time to peak symptoms. Scatter plot of time from the end of radiotherapy to peak symptoms versus exhaled NO ratio. The time to peak symptoms was inversely correlated with eNO ratio (p = 0.02). For each of these symptomatic cases peak symptoms were defined during a clinical encounter such as hospitalization for dyspnea.
The present study has shown that all symptomatic cases had an elevated eNO ratio with a pneumonitis incidence of 14%. In the retrospective study of 122 pediatric patients receiving 15 Gy (Hodgkin’s disease) to 70 Gy (sarcoma) for a range of thoracic malignancies, the 1-year cumulative incidence of symptomatic RP was 8.2% with symptomatic cases found even in those receiving 15 Gy to the unilateral lung [8]. The rate of symptomatic pneumonitis was low (14%). This is in the range 13–37% reported in a data review by Rodrigues et al. [9]. In a study of 139 esophageal cancer patients [4], we found a pneumonitis rate of 58% owing to higher lung dose with MLD of 12.3 versus 9.6 Gy in the present study. This difference
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and sputum results were recorded. Every patient in this study with pulmonary symptoms were scored as RP since there was no overwhelming evidence of another cause. A viral infection could have occurred in some patients to cause an elevated NO. Medications can affect NO levels, including steroids and bronchodilators. Medications were recorded at each visit and the time of last administration was recorded. In asthma, airway caliber affects NO, where a larger diameter yields higher NO plateau [51–53]. Post-stenotic obstruction could have reduced NO levels in some patients by reducing output, while adjacent inflammation could have increased NO levels. Current smoking chronically reduces eNO and acutely reduces eNO within 1–2 h of smoking [53,54]. The ratio of NO was chosen instead of absolute values because a change in variation of NO in individuals over time could likely be demonstrated with a smaller study. Each individual acts as their own control, establishing their pretreatment baseline. In asthma patients, medications were titrated based on an individual’s NO level of time before a threshold NO level for the diagnosis of asthma was established since the later required many data points because of the significant overlap of asthma and healthy individuals. eNO is a non-invasive, rapid, point-of-service test to assess airway inflammation. In this study, the test was easy for the patients to perform and was reproducible. The sensitivity and specificity of the ratio of eNO at End RT/ pre-RT could not be fully assessed owing to the limited number of symptomatic cases in the accrual to date. The number of symptomatic cases is small but the classifier chooses subjects at random and attempts to classify with even fewer cases, which makes the findings more robust. The present study was limited by the number of NO measurements made. In an ongoing lung cancer patient cohort, weekly assessments are being made to allow earlier detection of the increase in eNO to aid in total dose determination and delivery of potential therapeutic agents for RP during radiation delivery. Conclusion Fig. 3. Toxicity analysis using exhaled nitric oxide (eNO). (a) Plot of toxicity outcome by eNO ratio and MLD. The dashed line (ratio eNO = 1.4) separates those with Grade 2 or higher toxicity from the asymptomatic cases. (b) Plot of toxicity outcome by eNO ratio and V20. The same line delineates a high risk region for those with Grade 2 or higher radiation pneumonitis toxicity. The two volumetric parameters (MLD & V20) alone or combined had poor predictive power.
in MLD is explained by the use of three-dimensional RT planning and wider planning margins without image guidance in the study of 139 esophageal cancer patients. Amifostine [46] and inhaled beclomethasone [47] may reduce the incidence of RP in locally advanced lung cancer patients receiving thoracic RT. However, the perceived risk of reduced cancer control and medication side effects have resulted in reluctance to prophylactically treat all patients undergoing thoracic RT with these medications. This study identified a group of patients, at the end of RT, at high risk of developing subsequent symptomatic pneumonitis. Now that a high risk group can be identified using eNO, studies are needed to identify methods to mitigate the development of RP in high risk patients. Several patient factors potentially affected NO levels in this study, particularly in the lung cancer patient group. Patients with asthma are known to have elevated NO levels and were excluded from this study. Two lung cancer patients had a diagnosis of chronic obstructive pulmonary disease (COPD), and NO has been reported to be high in exacerbations compared with stable patients [48]. One report suggested that NO falls after inhaled steroids in stable COPD [49]. Viral infections also have been shown to transiently elevate NO [50]. The questionnaire and medical record were used to aid in determining the cause of cough and dyspnea,
In this prospective study, an elevation in eNO at the end of RT predicted subsequent symptomatic RP. All symptomatic patients had a ratio of end of RT eNO to baseline eNO higher than asymptomatic patients. No asymptomatic patient had a ratio greater than 1.4 and vice versa. The interval to the occurrence of peak symptoms was inversely related to the increase in eNO. Serial eNO measurements may aid in identifying a group of patients at high risk of developing symptomatic RP. Conflict of interest statement None declared. Acknowledgments We extend our gratitude to the thoracic radiation oncology faculty, thoracic surgeons, and gastrointestinal medical oncologists at M. D. Anderson whose patients were the focus of this study. The authors thank Dr. Mersiha Hadziahmetovic who performed the initial calibration and clinical acceptance testing of the NO breath analyzer. The authors also thank Mr. Jan Pagilagan who served as the data coordinator for this study and Ms. Toni Williams who provided administrative support. We most sincerely thank the National Institutes of Health (NIH) and the National Cancer Institute (NCI) who provided support for this project through NIH/NCI Grant R21CA141833. Dr. Martinez was supported by a post-doctoral training grant, NCI Grant R25T-CA90301. Additional funding for this study was provided from The University of Texas M. D. Anderson Cancer Center’s Physician Scientist Program.
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