- Email: [email protected]
Symptomatic Radiation Pneumonitis in Elderly Patients Receiving Thoracic Irradiation
Original Study
Symptomatic Radiation Pneumonitis in Elderly Patients Receiving Thoracic Irradiation Jordan Kharofa, Elizabeth Gore Abstract Elderly patients have decreased tolerance to radiation therapy; however, the impact of lung dose parameters in this group is not well defined. In this retrospective review of 256 patients, elderly patients were observed to have significantly higher rates of grade >3 pneumonitis compared with younger patients. The threshold for clinically acceptable pneumonitis may be lower than in younger patients. Purpose: Advanced age has been associated with increased risk of radiation pneumonitis. The purpose of this study was to examine the clinical and dosimetric predictors of radiation pneumonitis in elderly patients relative to younger patients treated with thoracic radiation therapy for lung cancer. Methods: Two hundred fifty-six consecutive patients with stage I-III small cell and non–small-cell lung cancer treated with definitive radiation with or without concurrent chemotherapy, between 2004 and 2009, were reviewed. Pneumonitis was graded by using the Common Terminology Criteria for Adverse Events version 4. Clinical parameters and dosimetric variables were assessed in univariate and multivariate analysis to evaluate predictors of grade ⱖ2 pneumonitis in patients age ⱖ70 years and age ⬍70 years. Results: There were 99 patients age ⱖ70 and 157 patients age ⬍70 years old. Pneumonitis occurred in 32 patients (grade 2 [22], grade 3 [7], grade 4 [3], grade 5 [1]). On multivariate analysis, the V5 Gy (P ⫽ .005) and age ⱖ70 years (P ⫽ .001) predicted for grade ⱖ2 pneumonitis, whereas angiotensin converting enzyme inhibitor use was associated with decreased risk (P ⫽ .02). Pneumonitis grade ⱖ3 occurred in 10% (n ⫽ 10/99) of patients age ⱖ70 years and in 1% (n ⫽ 1/157) of patients ⬍70 years (P ⫽ .001). In patients with a V20 Gy ⬎31%, the incidence of grade ⱖ3 pneumonitis was 33% (n ⫽ 4/12) in elderly patients compared with 2% (n ⫽ 1/44) in younger patients (P ⫽ .005). Conclusions: Elderly patients were observed to have an increased risk of symptomatic pneumonitis. Radiation dose parameters remain useful in this population; however, the threshold for clinically acceptable pneumonitis may be lower than in younger patients. angiotensin converting enzyme inhibitors use may mitigate radiation pneumonitis. Clinical Lung Cancer, Vol. 14, No. 3, 283-7 Published by Elsevier Inc. Keywords: Elderly, Radiation pneumonitis, Toxicity, V5 Gy
Introduction
Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI
this group is not well defined. The primary objective of this study was to quantify the incidence of symptomatic pneumonitis in elderly patients relative to younger patients and to examine the impact of dosimetric parameters in this population. Clinical factors in addition to age have been shown to influence the risk of pneumonitis. Results of studies have revealed an increased risk of pneumonitis in patients who receive concurrent chemotherapy5-7 and a decreased the risk of pneumonitis with incidental use of angiotensin converting enzyme (ACE) inhibitors.8-10 The secondary objective of this study was to examine the effect of other clinical factors on the risk of symptomatic pneumonitis.
Submitted: Jul 11, 2012; Revised: Sep 29, 2012; Accepted: Oct 8, 2012; Epub: Jan 4, 2013
Materials and Methods
Address for correspondence: Elizabeth Gore, MD, Department of Radiation Oncology, Medical College of Wisconsin, 9200 W Wisconsin Avenue, Milwaukee, WI 53226 Fax: 414-805-4369; e-mail contact: [email protected]
Patients with stage I-III (The American Joint Committee on Cancer, 6th edition) small cell and non–small-cell lung cancer (NSCLC) treated with definitive radiation with or without concurrent chemotherapy from 2004 to 2009 at Medical College of Wisconsin and the
The proportion of elderly patients with newly diagnosed lung cancer is significant. In a recent analysis of the SEER (Surveillance, Epidemiology, and End result) database, patients age ⬎70 years accounted for 47% of all lung cancers.1 Elderly patients are observed to have increased risk of pulmonary toxicity after thoracic radiation.2-4 Despite multiple reports of decreased tolerance to radiation therapy in the elderly, the impact of lung dose parameters in
1525-7304/$ - see frontmatter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.cllc.2012.10.005
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Symptomatic Pneumonitis in Elderly Patients Clement J Zablocki Veterans Affairs Medical Center were retrospectively reviewed. All the patients were treated with 3-dimensional conformal radiation therapy techniques. The patients who received palliative radiation therapy in the setting of stage IV disease and patients who received postoperative radiation therapy were excluded. Two hundred fifty-six patients met the criteria for inclusion. Treatment plans were available for review in 226 patients. In 2 additional patients, the V20 was known from the medical record. Lung volume was defined as total lung-clinical target volume. The V5 Gy, V10 Gy, V20 Gy, V30 Gy, and mean lung dose were recorded. The Vx Gy corresponds to the percentage of total lung volume receiving “x” dose of radiation. Conventional daily fractionation (1.8-2.0 Gy) was used in 227 patients with a median dose of 64 Gy (range, 56-74 Gy). Twenty-one patients were treated to 45 Gy (1.5 Gy twice a day) for small cell lung cancer. Nine patients received stereotactic body radiation therapy for stage I disease and were treated with 54 Gy in 3 fractions (n ⫽ 5) or 40 Gy in 4 fractions (n ⫽ 4). Clinical factors examined included age, disease stage, concurrent chemotherapy, histology, and ACE inhibitor use. During the study period, the patients were typically treated with carboplatin and paclitaxel for NSCLC or cisplatin and etoposide for small cell lung cancer. Due to relative homogeneity of concurrent chemotherapy regimens and the limited number of pneumonitis events, concurrent chemotherapy was coded as a binary variable. Acute pulmonary toxicity was quantified within 6 months of completion of treatment according to the Common Terminology Criteria for Adverse Events (version 4) (grade 1, asymptomatic, clinical, or diagnostic observations only, intervention not indicated; grade 2, symptomatic, medical intervention indicated, limiting instrumental activities of daily living; grade 3, severe symptoms, limiting self-care activities of daily living, oxygen indicated; grade 4, lifethreatening respiratory compromise, urgent intervention indicated; grade 5, death].
Statistical Analysis Statistical analysis was performed with MedCalc version 12.1.4 (Marlakerke, Belgium). The Fisher exact test was used to compare binary variables. Univariate and multivariate logistic regression analyses were performed to evaluate clinical and dosimetric predictors for grade ⱖ2 pneumonitis in all patients. Variables with P ⬍ .05 on univariate analysis were entered in multivariate analysis. Dosimetric parameters (V5, V10, V20, V30, mean lung dose) were entered as continuous variables. Receiver operating characteristic (ROC) curve analysis was used to identify the dosimetric parameters that best segregated grade ⱖ3 pneumonitis. The ROC analysis was only performed in patients age ⱖ70 years because only 1 event occurred in the younger cohort that was higher than grade 2.
Results Patient Demographics A cohort of patients age ⱖ70 years (n ⫽ 99) was identified and compared with patients ⬍70 years old (n ⫽ 157). The demographic information for the 2 cohorts is outlined in Table 1. Patients age ⱖ70 years were more likely to have stage I tumors (26% vs. 7%; P ⫽ .001). Patients age ⱖ70 years with stage III disease were less likely to receive concurrent chemotherapy (54% and 84%, respectively; P ⫽ .001).
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Table 1 Patient Demographics
No. Patients
Age >70 y
Age <70 y
99
157
26 (26)
11 (7)
P
NSCLC, No. (%) Stage I
.001
Stage II
9 (9)
14 (9)
1
Stage III
53 (54)
92 (59)
.001
Limited-Stage Small Cell Lung Cancer, No. (%)
11 (11)
40 (25)
.005
Stage III NSCLC Treated With Concurrent Chemotherapy, No. (%)
27 (51)
77 (84)
.001
Concurrent Chemotherapy, No. (%)
43 (43)
127 (81)
.001
34 (34)
43 (27)
.26
92
136
V5 ⬎62%
15 (16)
26 (19)
.73
V10 ⬎47%
18 (20)
41 (30)
.12
V20 ⬎27%
39 (42)
78 (57)
.06
V30 ⬎21%
68 (74)
38 (28)
.34
MLD ⬎17 Gy
31 (34)
70 (51)
.09
ACE Inhibitor Use, No. (%) a
Dosimetric Variables, No. (%) No. patient
Data in bold represent patient demographics. Abbreviations: ACE ⫽ angiotensin converting enzyme; MLD ⫽ mean lung dose; NSCLC ⫽ non–small-cell lung cancer. a Complete in 228 patients, V20 was available for 229 patients.
Toxicity Pneumonitis occurred in 32 patients (grade 2 [22 patients], grade 3 [7], grade 4 [3], grade 5 [1]). One patient age ⬍70 years experienced an event that was grade ⱖ3 compared with 10 patients age ⱖ70 years (1% and 10%, respectively; P ⫽ .001). The results of univariate and multivariate analysis of grade ⱖ2 pneumonitis in all patients are outlined in Table 2. Significant predictors for grade ⱖ2 pneumonitis in all patients on multivariate analysis include the V5 Gy (OR [odds ratio] 1.05 [95% CI, 1.01-1.09]; P ⫽ .005) and age ⱖ70 years (OR 4.52 [95% CI, 1.82-11.24]; P ⫽ .001). At each dose volume range for V5 and V20, the incidence of grade ⱖ3 pneumonitis was higher in patients ⱖ70 years old (Table 3). One pneumonitis event of grade ⱖ3 occurred in a patient ⬍70 years old with a V5 of 65%. A representative case example is provided in Figure 1. Concurrent chemotherapy, disease stage, and histology were not associated with an increased risk of grade ⱖ2 pneumonitis. In the subset of elderly patients who received concurrent chemotherapy, grade ⱖ3 pneumonitis was observed in 14% (6/43) compared with 7% (4/56) of elderly patients treated with radiation alone. The use of an ACE inhibitor was associated with a decreased risk of pneumonitis (OR 0.22 [95% CI, 0.06-0.79]; P ⫽ .02). Pneumonitis grade ⱖ2 occurred in 2% of ACE users compared with 19% of nonusers (P ⫽ .02). In the subset of patients age ⱖ70, ACE inhibitor users (n ⫽ 34) had an incidence of grade ⱖ2 pneumonitis of 12% compared with 25% in patients age ⱖ70 years who were not ACE inhibitors users (P ⫽ .18).
Jordan Kharofa, Elizabeth Gore Table 2 Univariate and Multivariate Analysis of Grade >2 Pneumonitis in All Patients Univariate Analysis OR
95% CI
Multivariate Analysis P
OR
95% CI
P
Age >70 y
3.05
1.42-6.58
.004
4.52
1.82-11.24
.001
V5
1.05
1.01-1.09
.003
1.05
1.02-1.09
.005
V10
1.05
1.00-1.08
.017
—
V20
1.06
1.00-1.13
.03
—
.24
—
1.16
1.03-1.32
.008
—
0.29
0.10-0.87
.012
V30 MLD Concurrent Chemotherapy
.76
ACE Inhibitor Stage
.17
Histology
.16
— 0.2218
0.06-0.80
.021
Data in bold represent patient and treatment characteristics. Abbreviations: ACE ⫽ angiotensin converting enzyme; MLD ⫽ mean lung dose; OR ⫽ odds ratio.
Table 3 Pneumonitis Grade >3 as a Function of Age and DVH Parametersa > Grade 3 Pneumonitis Age >70 y, % (no./total)
Age < 70 y
Pb
⬍20%
5 (1/22)
0 (0/26)
.46
20%-30%
7 (4/56)
0 (0/68)
.04
31%-41%
33 (4/12)
2 (1/44)
.01
⬍45%
5 (2/38)
0 (0/50)
.18
45%-61%
11 (4/37)
0 (0/60)
.02
⬎62%
20 (3/15)
4 (1/26)
.13
V20 Gy
V5 Gy
Abbreviation: DVH ⫽ dose-volume histogram. a V5 and V20 are available for 90/99 patients age ⱖ70 y; V5 was available in 136/158 patients age ⬍70 y; V20 was available in 138/158 patients age ⬍ 70 y. b Calculated by using the Fisher exact test for each DVH range; patients age ⱖ70 y compared with patients age ⬍70 y.
ROC Curve Analysis The results of ROC curve analysis are outlined in Table 4. ROC curve analysis of V5, V10, V20, V30, and mean lung dose was performed for patients age ⱖ70 years to assess the best predictors of grade ⱖ3 pneumonitis. In patients age ⱖ70 years, ROC curve analysis identified V20 ⬎ 31% as the best predictor for grade ⱖ3 pneumonitis (area under the curve 0.732, P ⫽ .02). A V30 ⬎24% was also a significant predictor of grade ⱖ3 pneumonitis in patients age ⱖ70 years but was not as strong as V20.
Discussion Elderly patients were observed to have increased pulmonary toxicity after thoracic irradiation in several prospective trials.2-4,11,12 A recent meta-analysis of 836 patients who underwent chemoradiation for lung cancer showed that patients age ⬎65 years who received concurrent carboplatin and paclitaxel were at highest risk of radia-
tion pneumonitis.13 In a phase III trial conducted by the North Central Cancer Treatment Group, patients with stage III NSCLC received concurrent etoposide and cisplatin, and were randomized to once or twice daily radiation therapy. Pneumonitis grade ⱖ4 was observed in 1% of patients age ⬍70 years and in 6% of patients age ⱖ70 years (P ⫽ .02).3 In a phase III trial of radiotherapy regimens in limited-stage small cell lung cancer, patients age ⱖ70 years were at increased risk of grade ⱖ4 pneumonitis compared with patients age ⬍70 years (6% and 0%, P ⫽ .008).12 Similarly, in a trial from the Japanese Clinical Oncology Group, patients age ⱖ71 years with locally advanced lung cancer were randomized to receive radiation alone or radiation with low-dose carboplatin. After accruing 46 patients, the trial was closed due to treatment-related deaths from pulmonary toxicity in 4 (8.7%) patients. The researchers cite the age of the patient population and protocol violations as potential reasons for the high rate of grade 5 pneumonitis. The trial was repeated with the inclusion of radiation quality assurance with lower rates of pulmonary toxicity. In the 200 patients age 71 years or older, there were 7 (4%) treatment-related deaths. Deaths were due to pneumonitis in 4 patients and due to fungal infections secondary to steroid treatment of pneumonitis in 2 additional patients.14 The results of our study are consistent with previously published reports of decreased lung tolerance to thoracic radiation therapy in elderly patients. Age ⱖ70 years was the most significant predictor for symptomatic pneumonitis in all patients on multivariate analysis. All but 1 pneumonitis event grade ⱖ3 occurred in patients age ⱖ70 years. Despite consistent reports of decreased tolerance to thoracic radiation in the elderly, dosimetric parameters in radiation treatment planning are not well defined in this age group. A primary objective of this study was to examine the impact of dosimetric parameters in the elderly population, with the overarching goal of defining dosimetric recommendations for treatment planning in this population. The volume of lung that receives at least 20 Gy (V20 Gy) has been previously identified by multiple investigators as a useful dosimetric parameter in patients who receive thoracic irradiation.5,15-17 Graham et al16 identified V20 Gy as a predictor of symptomatic
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Symptomatic Pneumonitis in Elderly Patients Figure 1 A 77-Year-Old Man Treated With Chemoradiation for Stage IIIA Non–Small-Cell Lung Cancer of the Left Upper Lobe. The V5 Gy was 70%, and the V20 Gy was 34%. The Patient Developed Grade 3 Pulmonary Toxicity Approximately 3 Months After Completion of Chemoradiation and Required Hospital Admission and High-Dose Steroids. (A) Baseline Pretreatment Computed Tomography (CT) of the Chest. (B) CT of the Chest 3 Months After Treatment Revealed Traction Bronchiectasis, Ground-Glass Opacities, and Infiltrates Within the Treatment Field
B
A
Table 4 Results of ROC Curve Analysis of Dosimetric Predictors of Grade >3 Pneumonitis in Patients Age >70 Y Grade >3 Pneumonitis in Patients Age >70 Best Threshold
AUC
P
V5
⬎50%
0.664
.1
V10
⬎45%
0.663
.19
V20
⬎31%
0.732
.02
V30
⬎24%
0.698
.04
MLD
⬎16 Gy
0.663
.14
Abbreviations: AUC ⫽ area under the curve; MLD ⫽ mean lung dose; ROC ⫽ receiver operating characteristic.
pneumonitis in a series of 99 patients treated for NSCLC. Pneumonitis grade ⱖ3 was observed in 5% of patients with a V20 Gy between 32% and 40%, and in 23% of patients with a V20 Gy ⬎ 40%.16 In our series, the incidence of grade ⱖ3 pneumonitis in elderly patients age ⱖ70 years was higher than the incidence reported by Graham et al.16 In elderly patients with a V20 Gy between 31% and 41%, the incidence of grade ⱖ3 pneumonitis was 33% compared with 2% of patients age ⬍70 years (P ⫽ .005). These results are consistent with clinical observations of an increased risk of pneumonitis in elderly patient cohorts. The higher incidence of pneumonitis events in the elderly patient does not appear to be random across the lung dose volume spectrum. The proportion of patients experiencing grade ⱖ3 pneumonitis was directly proportional to increases in V20 Gy. The V20 Gy remains a useful treatment parameter in the elderly population; however, the threshold for clinically acceptable pneumonitis may be lower than in younger patients. To maintain a ⬍20% inci-
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dence of grade ⱖ3 pneumonitis, a V20 Gy ⬍31% should be considered when possible in patients age ⱖ70 years. With the increasing use of intensity modulated radiation therapy in the treatment of thoracic malignancies, it will be important to consider the V5 Gy in treatment planning because more lung receives low doses of radiation. In a series of 37 patients with NSCLC treated with helical tomotherapy, an unexpectedly high number of treatment-related deaths were observed in 4 (11%) patients. Of the 4 patients who died of treatment-related pneumonitis, 3 were age ⱖ70 years. The researchers identified V5 Gy ⬎60% as the only independent risk factor for the development of grade ⱖ3 pneumonitis.18 Similarly, in a series of 223 patients treated with definitive chemoradiotherapy for NSCLC, the V5 Gy was the most significant predictor of treatment-related pneumonitis.19 The results of our study also highlight the importance of the large volume of lung that receives low doses of radiation. The V5 Gy was the only independent dosimetric predictor of grade ⱖ2 pneumonitis in all patients on multivariate analysis. In patients age ⬎70 years, grade ⱖ3 pneumonitis occurred in 20% of patients with a V5 ⬎ 62%. One pneumonitis event of grade ⱖ3 occurred in a patient age ⬍70 years, with a V5 of 65%. Taken together, the results of these studies suggest that the V5 Gy is an important dosimetric parameter to consider in treatment planning and elderly patients with a V5 ⬎ 62% appearing to have unacceptably high rates of grade ⱖ3 pneumonitis. The reasons for decreased lung tolerance to radiation therapy in the elderly population are not entirely understood. Normal changes in pulmonary function in the elderly include dilatation of alveoli, enlargement of airspaces, and loss of supporting tissue for peripheral airways. Elderly patients also have decreased pulmonary reserve and may be more susceptible to acute illnesses.20 Cardiac and or pulmonary comorbidities in this group may play an important role in the increased rates of pneumonitis observed in elderly patients. Inherent flaws in the dose-volume histogram
Jordan Kharofa, Elizabeth Gore may also contribute to the increased incidence of pneumonitis among elderly patients. The dose-volume histogram does not account for functional variability throughout the lung. Investigators have studied single photon emission computed tomography imaging for radiation therapy planning as a means of defining a more accurate “functional volume” of lung.21 The dose to areas of higher pulmonary function may be a more accurate means of predicting toxicity than dose-volume histograms in which anatomic and functional information is lost. This may be particularly important in elderly patients who often have several pulmonary comorbidities. Our results also demonstrate the potential protective effects of ACE inhibitors on the development of pneumonitis. On multivariate analysis, ACE inhibitor use was associated with a decreased risk of grade ⱖ2 pneumonitis. ACE inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models.22 Proposed mechanisms include alteration of the stromal and endothelial response to radiation injury through suppression of the renin-angiotensin system, reductions in transforming growth factor , and/or alterations in blood flow.22 Several observational studies have demonstrated a decreased risk of radiation pneumonitis among users of ACE inhibitors, however, a prospective trial has not been completed.8-10 A randomized trial that evaluates the mitigating effects of ACE inhibitors in patients age ⱖ70 years may be warranted given the increased pulmonary toxicity observed in this group. In our series, the incidence of grade ⱖ2 pneumonitis in elderly patients who used ACE inhibitors was 12% compared with 25% in elderly patients who did not use ACE inhibitors (P ⫽ .18). The results did not meet significance; however, no definitive conclusions can be drawn from these data given the small number of patients in this group (n ⫽ 34). Our study has several limitations. It is subject to the inherent flaws present in a retrospective, nonrandomized study. Variables that were not accounted for may have biased our results. The comorbidities among the elderly patient population may play an important role in the development of pneumonitis. In addition, the retrospective grading of pneumonitis events can be challenging. If symptoms in elderly patients were interpreted as higher grade, then this may have biased the results. Ideally, pulmonary toxicity should be graded prospectively.
Conclusion Elderly patients have significantly higher rates of grade ⱖ3 pneumonitis compared with younger patients. Both the V20 Gy and the V5 Gy remain useful dosimetric parameters in elderly patients. A V20 Gy ⬍31% and a V5 Gy ⬍62% is recommended in patients older than 70 years to achieve ⬍20% incidence of grade ⱖ3 pneumonitis. Further strategies are needed to decrease pneumonitis in elderly patients. ACE inhibitor use was associated with a decreased risk of pneumonitis, which is consistent with preclinical data and may warrant further evaluation in a prospective trial.
Clinical Practice Points ●
The proportion of patients of advanced age treated for lung cancer continues to increase. Elderly patients have been observed to have decreased tolerance to radiation therapy in previous prospective trials; however, the impact of lung dose parameters in this group is not well defined. In this retrospective review of 256 patients, patients aged ⱖ70 years were observed to have significantly higher rates of grade ⱖ3 pneumonitis compared with younger patients.
●
●
Radiation dose parameters were found to be useful in this population; however, the threshold for clinically acceptable pneumonitis rates may be lower than in younger patients. In addition, use of an ACE inhibitor was associated with decreased risk of pneumonitis. These findings are consistent with preclinical studies and should be prospectively evaluated as a mitigation strategy against pneumonitis in elderly patients at high risk.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Owonikoko TK, Ragin CC, Belani CP, et al. Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results Database. J Clin Oncol 2007; 25:5570-7. 2. Gridelli C, Langer C, Maione P, et al. Lung cancer in the elderly. J Clin Oncol 2007; 25:1898-907. 3. Schild SE, Stella PJ, Geyer SM, et al. The outcome of combined-modality therapy for stage III non-small-cell lung cancer in the elderly. J Clin Oncol 2003; 21:3201-6. 4. Schild SE, Mandrekar SJ, Jatoi A, et al. The value of combined-modality therapy in elderly patients with stage III nonsmall cell lung cancer. Cancer 2007; 110:363-8. 5. Asakura H, Hashimoto T, Zenda S, et al. Analysis of dose-volume histogram parameters for radiation pneumonitis after definitive concurrent chemoradiotherapy for esophageal cancer. Radiother Oncol 2010; 95:240-4. 6. Barriger RB, Fakiris AJ, Hanna N, et al. Dose-volume analysis of radiation pneumonitis in non-small-cell lung cancer patients treated with concurrent cisplatinum and etoposide with or without consolidation docetaxel. Int J Radiat Oncol Biol Phys 2010; 78:1381-6. 7. Dang J, Li G, Lu X, et al. Analysis of related factors associated with radiation pneumonitis in patients with locally advanced non-small-cell lung cancer treated with three-dimensional conformal radiotherapy. J Cancer Res Clin Oncol 2010; 136:1169-78. 8. Jenkins P, Watts J. An improved model for predicting radiation pneumonitis incorporating clinical and dosimetric variables. Int J Radiat Oncol Biol Phys 2011; 80:1023-9. 9. Jenkins P, Welsh A. Computed tomography appearance of early radiation injury to the lung: correlation with clinical and dosimetric factors. Int J Radiat Oncol Biol Phys 2011; 81:97-103. 10. Kharofa JC, Cohen EP, Tomic R, et al. Decreased risk of radiation pneumonitis with incidental concurrent use of angiotensin-converting enzyme inhibitors and thoracic radiation therapy. Int J Radiat Oncol Biol Phys 2012; 84:238-43. 11. Kean HM, Stella PJ, Hillman SL, et al. Exploring therapeutic decisions in elderly patients with non-small cell lung cancer: results and conclusions from North Central Cancer Treatment Group Study N0222. Cancer Invest 2011; 29:266-71. 12. Schild SE, Stella PJ, Brooks BJ, et al. Results of combined-modality therapy for limited-stage small cell lung carcinoma in the elderly. Cancer 2005; 103:2349-54. 13. Palma DA, Senan S, Tsujino K, et al. Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data metaanalysis. Int J Radiat Oncol Biol Phys 2012 [Epub ahead of print]. 14. Atagi S, Kawahara M, Yokoyama A, et al. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol 2012; 13:671-8. 15. Marks LB, Bentzen SM, Deasy JO, et al. Radiation dose-volume effects in the lung. Int J Radiat Oncol Biol Phys 2010; 76:S70-6. 16. Graham MV, Purdy JA, Emami B, et al. Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 1999; 45:323-9. 17. Tsujino K, Hirota S, Endo M, et al. Predictive value of dose-volume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer. Int J Radiat Oncol Biol Phys 2003; 55:110-5. 18. Song CH, Pyo H, Moon SH, et al. Treatment-related pneumonitis and acute esophagitis in non-small-cell lung cancer patients treated with chemotherapy and helical tomotherapy. Int J Radiat Oncol Biol Phys 2010; 78:651-8. 19. Wang S, Liao Z, Wei X, et al. Analysis of clinical and dosimetric factors associated with treatment-related pneumonitis (TRP) in patients with non-small-cell lung cancer (NSCLC) treated with concurrent chemotherapy and three-dimensional conformal radiotherapy (3D-CRT). Int J Radiat Oncol Biol Phys 2006; 66:1399-407. 20. Janssens JP, Pache JC, Nicod LP. Physiological changes in respiratory function associated with ageing. Eur Respir J 1999; 13:197-205. 21. Yin L, Shcherbinin S, Celler A, et al. Incorporating quantitative single photon emission computed tomography into radiation therapy treatment planning for lung cancer: impact of attenuation and scatter correction on the single photon emission computed tomography-weighted mean dose and functional lung segmentation. Int J Radiat Oncol Biol Phys 2010; 78:587-94. 22. Ghosh SN, Zhang R, Fish BL, et al. Renin-angiotensin system suppression mitigates experimental radiation pneumonitis. Int J Radiat Oncol Biol Phys 2009; 75:1528-36.
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Symptomatic Radiation Pneumonitis in Elderly Patients Receiving Thoracic Irradiation Jordan Kharofa, Elizabeth Gore Abstract Elderly patients have decreased tolerance to radiation therapy; however, the impact of lung dose parameters in this group is not well defined. In this retrospective review of 256 patients, elderly patients were observed to have significantly higher rates of grade >3 pneumonitis compared with younger patients. The threshold for clinically acceptable pneumonitis may be lower than in younger patients. Purpose: Advanced age has been associated with increased risk of radiation pneumonitis. The purpose of this study was to examine the clinical and dosimetric predictors of radiation pneumonitis in elderly patients relative to younger patients treated with thoracic radiation therapy for lung cancer. Methods: Two hundred fifty-six consecutive patients with stage I-III small cell and non–small-cell lung cancer treated with definitive radiation with or without concurrent chemotherapy, between 2004 and 2009, were reviewed. Pneumonitis was graded by using the Common Terminology Criteria for Adverse Events version 4. Clinical parameters and dosimetric variables were assessed in univariate and multivariate analysis to evaluate predictors of grade ⱖ2 pneumonitis in patients age ⱖ70 years and age ⬍70 years. Results: There were 99 patients age ⱖ70 and 157 patients age ⬍70 years old. Pneumonitis occurred in 32 patients (grade 2 [22], grade 3 [7], grade 4 [3], grade 5 [1]). On multivariate analysis, the V5 Gy (P ⫽ .005) and age ⱖ70 years (P ⫽ .001) predicted for grade ⱖ2 pneumonitis, whereas angiotensin converting enzyme inhibitor use was associated with decreased risk (P ⫽ .02). Pneumonitis grade ⱖ3 occurred in 10% (n ⫽ 10/99) of patients age ⱖ70 years and in 1% (n ⫽ 1/157) of patients ⬍70 years (P ⫽ .001). In patients with a V20 Gy ⬎31%, the incidence of grade ⱖ3 pneumonitis was 33% (n ⫽ 4/12) in elderly patients compared with 2% (n ⫽ 1/44) in younger patients (P ⫽ .005). Conclusions: Elderly patients were observed to have an increased risk of symptomatic pneumonitis. Radiation dose parameters remain useful in this population; however, the threshold for clinically acceptable pneumonitis may be lower than in younger patients. angiotensin converting enzyme inhibitors use may mitigate radiation pneumonitis. Clinical Lung Cancer, Vol. 14, No. 3, 283-7 Published by Elsevier Inc. Keywords: Elderly, Radiation pneumonitis, Toxicity, V5 Gy
Introduction
Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI
this group is not well defined. The primary objective of this study was to quantify the incidence of symptomatic pneumonitis in elderly patients relative to younger patients and to examine the impact of dosimetric parameters in this population. Clinical factors in addition to age have been shown to influence the risk of pneumonitis. Results of studies have revealed an increased risk of pneumonitis in patients who receive concurrent chemotherapy5-7 and a decreased the risk of pneumonitis with incidental use of angiotensin converting enzyme (ACE) inhibitors.8-10 The secondary objective of this study was to examine the effect of other clinical factors on the risk of symptomatic pneumonitis.
Submitted: Jul 11, 2012; Revised: Sep 29, 2012; Accepted: Oct 8, 2012; Epub: Jan 4, 2013
Materials and Methods
Address for correspondence: Elizabeth Gore, MD, Department of Radiation Oncology, Medical College of Wisconsin, 9200 W Wisconsin Avenue, Milwaukee, WI 53226 Fax: 414-805-4369; e-mail contact: [email protected]
Patients with stage I-III (The American Joint Committee on Cancer, 6th edition) small cell and non–small-cell lung cancer (NSCLC) treated with definitive radiation with or without concurrent chemotherapy from 2004 to 2009 at Medical College of Wisconsin and the
The proportion of elderly patients with newly diagnosed lung cancer is significant. In a recent analysis of the SEER (Surveillance, Epidemiology, and End result) database, patients age ⬎70 years accounted for 47% of all lung cancers.1 Elderly patients are observed to have increased risk of pulmonary toxicity after thoracic radiation.2-4 Despite multiple reports of decreased tolerance to radiation therapy in the elderly, the impact of lung dose parameters in
1525-7304/$ - see frontmatter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.cllc.2012.10.005
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Symptomatic Pneumonitis in Elderly Patients Clement J Zablocki Veterans Affairs Medical Center were retrospectively reviewed. All the patients were treated with 3-dimensional conformal radiation therapy techniques. The patients who received palliative radiation therapy in the setting of stage IV disease and patients who received postoperative radiation therapy were excluded. Two hundred fifty-six patients met the criteria for inclusion. Treatment plans were available for review in 226 patients. In 2 additional patients, the V20 was known from the medical record. Lung volume was defined as total lung-clinical target volume. The V5 Gy, V10 Gy, V20 Gy, V30 Gy, and mean lung dose were recorded. The Vx Gy corresponds to the percentage of total lung volume receiving “x” dose of radiation. Conventional daily fractionation (1.8-2.0 Gy) was used in 227 patients with a median dose of 64 Gy (range, 56-74 Gy). Twenty-one patients were treated to 45 Gy (1.5 Gy twice a day) for small cell lung cancer. Nine patients received stereotactic body radiation therapy for stage I disease and were treated with 54 Gy in 3 fractions (n ⫽ 5) or 40 Gy in 4 fractions (n ⫽ 4). Clinical factors examined included age, disease stage, concurrent chemotherapy, histology, and ACE inhibitor use. During the study period, the patients were typically treated with carboplatin and paclitaxel for NSCLC or cisplatin and etoposide for small cell lung cancer. Due to relative homogeneity of concurrent chemotherapy regimens and the limited number of pneumonitis events, concurrent chemotherapy was coded as a binary variable. Acute pulmonary toxicity was quantified within 6 months of completion of treatment according to the Common Terminology Criteria for Adverse Events (version 4) (grade 1, asymptomatic, clinical, or diagnostic observations only, intervention not indicated; grade 2, symptomatic, medical intervention indicated, limiting instrumental activities of daily living; grade 3, severe symptoms, limiting self-care activities of daily living, oxygen indicated; grade 4, lifethreatening respiratory compromise, urgent intervention indicated; grade 5, death].
Statistical Analysis Statistical analysis was performed with MedCalc version 12.1.4 (Marlakerke, Belgium). The Fisher exact test was used to compare binary variables. Univariate and multivariate logistic regression analyses were performed to evaluate clinical and dosimetric predictors for grade ⱖ2 pneumonitis in all patients. Variables with P ⬍ .05 on univariate analysis were entered in multivariate analysis. Dosimetric parameters (V5, V10, V20, V30, mean lung dose) were entered as continuous variables. Receiver operating characteristic (ROC) curve analysis was used to identify the dosimetric parameters that best segregated grade ⱖ3 pneumonitis. The ROC analysis was only performed in patients age ⱖ70 years because only 1 event occurred in the younger cohort that was higher than grade 2.
Results Patient Demographics A cohort of patients age ⱖ70 years (n ⫽ 99) was identified and compared with patients ⬍70 years old (n ⫽ 157). The demographic information for the 2 cohorts is outlined in Table 1. Patients age ⱖ70 years were more likely to have stage I tumors (26% vs. 7%; P ⫽ .001). Patients age ⱖ70 years with stage III disease were less likely to receive concurrent chemotherapy (54% and 84%, respectively; P ⫽ .001).
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Table 1 Patient Demographics
No. Patients
Age >70 y
Age <70 y
99
157
26 (26)
11 (7)
P
NSCLC, No. (%) Stage I
.001
Stage II
9 (9)
14 (9)
1
Stage III
53 (54)
92 (59)
.001
Limited-Stage Small Cell Lung Cancer, No. (%)
11 (11)
40 (25)
.005
Stage III NSCLC Treated With Concurrent Chemotherapy, No. (%)
27 (51)
77 (84)
.001
Concurrent Chemotherapy, No. (%)
43 (43)
127 (81)
.001
34 (34)
43 (27)
.26
92
136
V5 ⬎62%
15 (16)
26 (19)
.73
V10 ⬎47%
18 (20)
41 (30)
.12
V20 ⬎27%
39 (42)
78 (57)
.06
V30 ⬎21%
68 (74)
38 (28)
.34
MLD ⬎17 Gy
31 (34)
70 (51)
.09
ACE Inhibitor Use, No. (%) a
Dosimetric Variables, No. (%) No. patient
Data in bold represent patient demographics. Abbreviations: ACE ⫽ angiotensin converting enzyme; MLD ⫽ mean lung dose; NSCLC ⫽ non–small-cell lung cancer. a Complete in 228 patients, V20 was available for 229 patients.
Toxicity Pneumonitis occurred in 32 patients (grade 2 [22 patients], grade 3 [7], grade 4 [3], grade 5 [1]). One patient age ⬍70 years experienced an event that was grade ⱖ3 compared with 10 patients age ⱖ70 years (1% and 10%, respectively; P ⫽ .001). The results of univariate and multivariate analysis of grade ⱖ2 pneumonitis in all patients are outlined in Table 2. Significant predictors for grade ⱖ2 pneumonitis in all patients on multivariate analysis include the V5 Gy (OR [odds ratio] 1.05 [95% CI, 1.01-1.09]; P ⫽ .005) and age ⱖ70 years (OR 4.52 [95% CI, 1.82-11.24]; P ⫽ .001). At each dose volume range for V5 and V20, the incidence of grade ⱖ3 pneumonitis was higher in patients ⱖ70 years old (Table 3). One pneumonitis event of grade ⱖ3 occurred in a patient ⬍70 years old with a V5 of 65%. A representative case example is provided in Figure 1. Concurrent chemotherapy, disease stage, and histology were not associated with an increased risk of grade ⱖ2 pneumonitis. In the subset of elderly patients who received concurrent chemotherapy, grade ⱖ3 pneumonitis was observed in 14% (6/43) compared with 7% (4/56) of elderly patients treated with radiation alone. The use of an ACE inhibitor was associated with a decreased risk of pneumonitis (OR 0.22 [95% CI, 0.06-0.79]; P ⫽ .02). Pneumonitis grade ⱖ2 occurred in 2% of ACE users compared with 19% of nonusers (P ⫽ .02). In the subset of patients age ⱖ70, ACE inhibitor users (n ⫽ 34) had an incidence of grade ⱖ2 pneumonitis of 12% compared with 25% in patients age ⱖ70 years who were not ACE inhibitors users (P ⫽ .18).
Jordan Kharofa, Elizabeth Gore Table 2 Univariate and Multivariate Analysis of Grade >2 Pneumonitis in All Patients Univariate Analysis OR
95% CI
Multivariate Analysis P
OR
95% CI
P
Age >70 y
3.05
1.42-6.58
.004
4.52
1.82-11.24
.001
V5
1.05
1.01-1.09
.003
1.05
1.02-1.09
.005
V10
1.05
1.00-1.08
.017
—
V20
1.06
1.00-1.13
.03
—
.24
—
1.16
1.03-1.32
.008
—
0.29
0.10-0.87
.012
V30 MLD Concurrent Chemotherapy
.76
ACE Inhibitor Stage
.17
Histology
.16
— 0.2218
0.06-0.80
.021
Data in bold represent patient and treatment characteristics. Abbreviations: ACE ⫽ angiotensin converting enzyme; MLD ⫽ mean lung dose; OR ⫽ odds ratio.
Table 3 Pneumonitis Grade >3 as a Function of Age and DVH Parametersa > Grade 3 Pneumonitis Age >70 y, % (no./total)
Age < 70 y
Pb
⬍20%
5 (1/22)
0 (0/26)
.46
20%-30%
7 (4/56)
0 (0/68)
.04
31%-41%
33 (4/12)
2 (1/44)
.01
⬍45%
5 (2/38)
0 (0/50)
.18
45%-61%
11 (4/37)
0 (0/60)
.02
⬎62%
20 (3/15)
4 (1/26)
.13
V20 Gy
V5 Gy
Abbreviation: DVH ⫽ dose-volume histogram. a V5 and V20 are available for 90/99 patients age ⱖ70 y; V5 was available in 136/158 patients age ⬍70 y; V20 was available in 138/158 patients age ⬍ 70 y. b Calculated by using the Fisher exact test for each DVH range; patients age ⱖ70 y compared with patients age ⬍70 y.
ROC Curve Analysis The results of ROC curve analysis are outlined in Table 4. ROC curve analysis of V5, V10, V20, V30, and mean lung dose was performed for patients age ⱖ70 years to assess the best predictors of grade ⱖ3 pneumonitis. In patients age ⱖ70 years, ROC curve analysis identified V20 ⬎ 31% as the best predictor for grade ⱖ3 pneumonitis (area under the curve 0.732, P ⫽ .02). A V30 ⬎24% was also a significant predictor of grade ⱖ3 pneumonitis in patients age ⱖ70 years but was not as strong as V20.
Discussion Elderly patients were observed to have increased pulmonary toxicity after thoracic irradiation in several prospective trials.2-4,11,12 A recent meta-analysis of 836 patients who underwent chemoradiation for lung cancer showed that patients age ⬎65 years who received concurrent carboplatin and paclitaxel were at highest risk of radia-
tion pneumonitis.13 In a phase III trial conducted by the North Central Cancer Treatment Group, patients with stage III NSCLC received concurrent etoposide and cisplatin, and were randomized to once or twice daily radiation therapy. Pneumonitis grade ⱖ4 was observed in 1% of patients age ⬍70 years and in 6% of patients age ⱖ70 years (P ⫽ .02).3 In a phase III trial of radiotherapy regimens in limited-stage small cell lung cancer, patients age ⱖ70 years were at increased risk of grade ⱖ4 pneumonitis compared with patients age ⬍70 years (6% and 0%, P ⫽ .008).12 Similarly, in a trial from the Japanese Clinical Oncology Group, patients age ⱖ71 years with locally advanced lung cancer were randomized to receive radiation alone or radiation with low-dose carboplatin. After accruing 46 patients, the trial was closed due to treatment-related deaths from pulmonary toxicity in 4 (8.7%) patients. The researchers cite the age of the patient population and protocol violations as potential reasons for the high rate of grade 5 pneumonitis. The trial was repeated with the inclusion of radiation quality assurance with lower rates of pulmonary toxicity. In the 200 patients age 71 years or older, there were 7 (4%) treatment-related deaths. Deaths were due to pneumonitis in 4 patients and due to fungal infections secondary to steroid treatment of pneumonitis in 2 additional patients.14 The results of our study are consistent with previously published reports of decreased lung tolerance to thoracic radiation therapy in elderly patients. Age ⱖ70 years was the most significant predictor for symptomatic pneumonitis in all patients on multivariate analysis. All but 1 pneumonitis event grade ⱖ3 occurred in patients age ⱖ70 years. Despite consistent reports of decreased tolerance to thoracic radiation in the elderly, dosimetric parameters in radiation treatment planning are not well defined in this age group. A primary objective of this study was to examine the impact of dosimetric parameters in the elderly population, with the overarching goal of defining dosimetric recommendations for treatment planning in this population. The volume of lung that receives at least 20 Gy (V20 Gy) has been previously identified by multiple investigators as a useful dosimetric parameter in patients who receive thoracic irradiation.5,15-17 Graham et al16 identified V20 Gy as a predictor of symptomatic
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Symptomatic Pneumonitis in Elderly Patients Figure 1 A 77-Year-Old Man Treated With Chemoradiation for Stage IIIA Non–Small-Cell Lung Cancer of the Left Upper Lobe. The V5 Gy was 70%, and the V20 Gy was 34%. The Patient Developed Grade 3 Pulmonary Toxicity Approximately 3 Months After Completion of Chemoradiation and Required Hospital Admission and High-Dose Steroids. (A) Baseline Pretreatment Computed Tomography (CT) of the Chest. (B) CT of the Chest 3 Months After Treatment Revealed Traction Bronchiectasis, Ground-Glass Opacities, and Infiltrates Within the Treatment Field
B
A
Table 4 Results of ROC Curve Analysis of Dosimetric Predictors of Grade >3 Pneumonitis in Patients Age >70 Y Grade >3 Pneumonitis in Patients Age >70 Best Threshold
AUC
P
V5
⬎50%
0.664
.1
V10
⬎45%
0.663
.19
V20
⬎31%
0.732
.02
V30
⬎24%
0.698
.04
MLD
⬎16 Gy
0.663
.14
Abbreviations: AUC ⫽ area under the curve; MLD ⫽ mean lung dose; ROC ⫽ receiver operating characteristic.
pneumonitis in a series of 99 patients treated for NSCLC. Pneumonitis grade ⱖ3 was observed in 5% of patients with a V20 Gy between 32% and 40%, and in 23% of patients with a V20 Gy ⬎ 40%.16 In our series, the incidence of grade ⱖ3 pneumonitis in elderly patients age ⱖ70 years was higher than the incidence reported by Graham et al.16 In elderly patients with a V20 Gy between 31% and 41%, the incidence of grade ⱖ3 pneumonitis was 33% compared with 2% of patients age ⬍70 years (P ⫽ .005). These results are consistent with clinical observations of an increased risk of pneumonitis in elderly patient cohorts. The higher incidence of pneumonitis events in the elderly patient does not appear to be random across the lung dose volume spectrum. The proportion of patients experiencing grade ⱖ3 pneumonitis was directly proportional to increases in V20 Gy. The V20 Gy remains a useful treatment parameter in the elderly population; however, the threshold for clinically acceptable pneumonitis may be lower than in younger patients. To maintain a ⬍20% inci-
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dence of grade ⱖ3 pneumonitis, a V20 Gy ⬍31% should be considered when possible in patients age ⱖ70 years. With the increasing use of intensity modulated radiation therapy in the treatment of thoracic malignancies, it will be important to consider the V5 Gy in treatment planning because more lung receives low doses of radiation. In a series of 37 patients with NSCLC treated with helical tomotherapy, an unexpectedly high number of treatment-related deaths were observed in 4 (11%) patients. Of the 4 patients who died of treatment-related pneumonitis, 3 were age ⱖ70 years. The researchers identified V5 Gy ⬎60% as the only independent risk factor for the development of grade ⱖ3 pneumonitis.18 Similarly, in a series of 223 patients treated with definitive chemoradiotherapy for NSCLC, the V5 Gy was the most significant predictor of treatment-related pneumonitis.19 The results of our study also highlight the importance of the large volume of lung that receives low doses of radiation. The V5 Gy was the only independent dosimetric predictor of grade ⱖ2 pneumonitis in all patients on multivariate analysis. In patients age ⬎70 years, grade ⱖ3 pneumonitis occurred in 20% of patients with a V5 ⬎ 62%. One pneumonitis event of grade ⱖ3 occurred in a patient age ⬍70 years, with a V5 of 65%. Taken together, the results of these studies suggest that the V5 Gy is an important dosimetric parameter to consider in treatment planning and elderly patients with a V5 ⬎ 62% appearing to have unacceptably high rates of grade ⱖ3 pneumonitis. The reasons for decreased lung tolerance to radiation therapy in the elderly population are not entirely understood. Normal changes in pulmonary function in the elderly include dilatation of alveoli, enlargement of airspaces, and loss of supporting tissue for peripheral airways. Elderly patients also have decreased pulmonary reserve and may be more susceptible to acute illnesses.20 Cardiac and or pulmonary comorbidities in this group may play an important role in the increased rates of pneumonitis observed in elderly patients. Inherent flaws in the dose-volume histogram
Jordan Kharofa, Elizabeth Gore may also contribute to the increased incidence of pneumonitis among elderly patients. The dose-volume histogram does not account for functional variability throughout the lung. Investigators have studied single photon emission computed tomography imaging for radiation therapy planning as a means of defining a more accurate “functional volume” of lung.21 The dose to areas of higher pulmonary function may be a more accurate means of predicting toxicity than dose-volume histograms in which anatomic and functional information is lost. This may be particularly important in elderly patients who often have several pulmonary comorbidities. Our results also demonstrate the potential protective effects of ACE inhibitors on the development of pneumonitis. On multivariate analysis, ACE inhibitor use was associated with a decreased risk of grade ⱖ2 pneumonitis. ACE inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models.22 Proposed mechanisms include alteration of the stromal and endothelial response to radiation injury through suppression of the renin-angiotensin system, reductions in transforming growth factor , and/or alterations in blood flow.22 Several observational studies have demonstrated a decreased risk of radiation pneumonitis among users of ACE inhibitors, however, a prospective trial has not been completed.8-10 A randomized trial that evaluates the mitigating effects of ACE inhibitors in patients age ⱖ70 years may be warranted given the increased pulmonary toxicity observed in this group. In our series, the incidence of grade ⱖ2 pneumonitis in elderly patients who used ACE inhibitors was 12% compared with 25% in elderly patients who did not use ACE inhibitors (P ⫽ .18). The results did not meet significance; however, no definitive conclusions can be drawn from these data given the small number of patients in this group (n ⫽ 34). Our study has several limitations. It is subject to the inherent flaws present in a retrospective, nonrandomized study. Variables that were not accounted for may have biased our results. The comorbidities among the elderly patient population may play an important role in the development of pneumonitis. In addition, the retrospective grading of pneumonitis events can be challenging. If symptoms in elderly patients were interpreted as higher grade, then this may have biased the results. Ideally, pulmonary toxicity should be graded prospectively.
Conclusion Elderly patients have significantly higher rates of grade ⱖ3 pneumonitis compared with younger patients. Both the V20 Gy and the V5 Gy remain useful dosimetric parameters in elderly patients. A V20 Gy ⬍31% and a V5 Gy ⬍62% is recommended in patients older than 70 years to achieve ⬍20% incidence of grade ⱖ3 pneumonitis. Further strategies are needed to decrease pneumonitis in elderly patients. ACE inhibitor use was associated with a decreased risk of pneumonitis, which is consistent with preclinical data and may warrant further evaluation in a prospective trial.
Clinical Practice Points ●
The proportion of patients of advanced age treated for lung cancer continues to increase. Elderly patients have been observed to have decreased tolerance to radiation therapy in previous prospective trials; however, the impact of lung dose parameters in this group is not well defined. In this retrospective review of 256 patients, patients aged ⱖ70 years were observed to have significantly higher rates of grade ⱖ3 pneumonitis compared with younger patients.
●
●
Radiation dose parameters were found to be useful in this population; however, the threshold for clinically acceptable pneumonitis rates may be lower than in younger patients. In addition, use of an ACE inhibitor was associated with decreased risk of pneumonitis. These findings are consistent with preclinical studies and should be prospectively evaluated as a mitigation strategy against pneumonitis in elderly patients at high risk.
Disclosure The authors have stated that they have no conflicts of interest.
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