Asian Cardiovasc Thorac Ann 2005;13:330-336
© 2005 Asia Publishing EXchange Ltd
Surgery for Non-Small Cell Carcinoma in Geriatric Patients: 15-Year Experience
Horia Sirbu, MD,
Waldemar Schreiner, MD,
Harald Dalichau, PhD,
Thomas Busch, PhD
Department of Thoracic and Cardiovascular Surgery, University of Göttingen, Göttingen, Germany
For reprint information contact: Horia Sirbu, MD Tel: 49 241 808 9221 Fax: 49 241 808 2454 Email: hsirbu{at}ukaachen.de, Department of Thoracic and Cardiovascular Surgery, University of Aachen, Pauwelsstr. 30, Aachen D-52074, Germany.
 |
ABSTRACT
|
|---|
The purpose of this study was to determine the clinical patterns, short- and long-term survival in elderly patients after surgery for non-small cell lung carcinoma. The 273 patients aged over 70 years who underwent curative resection from 1986 to 2001 were retrospectively assessed. Mean age was 73.2 ± 3.1 years, (11% were > 80 years). The mean follow-up was 31 months. Standard procedures were used: 151 lobectomies, 49 bilateral lobectomies, 42 pneumonectomies, 9 sleeve resections, and 22 wedge resections. The 30-day mortality was 5.4%. Multivariate analysis showed that extended procedures, male sex, and age were predictors of mortality. Overall survival rates at 5, 10, and 15 years were 35.6%, 10.5%, and 2.5%, respectively. Advanced disease stage, low forced expiratory volume in 1 second, and previous cardiac disease were independent predictors that adversely influenced survival. Geriatric patients with non-small cell lung carcinoma can undergo resection safely with acceptable long-term survival. Lobectomy is the procedure of choice, extended resections should only be carried out in highly selected patients. Careful attention to preoperative clinical staging is important as the elderly beyond the early stage of disease fare poorly. Surgery is justified for the treatment of stage I–II lung cancer.
|
INTRODUCTION
|
|---|
The population of Western countries is ageing and the proportion of patients older than 70 years continues to increase. The average life expectancy at age 70 is 13.1 years, and that at age 80 is 8.2 years.1–2 Lung cancer continues to be the most common cause of cancer death in both men and women; the 5-year survival has significantly increased from 12% in the 1970s to 15% in the 1990s, while the estimated number of deaths from lung cancer remains relatively stable at 157,200 patients per year in the USA.3 Therefore, lung cancer therapy in the elderly accounts for increasing medical costs, and although surgery offers the best chance of cure in patients with localized disease, radiotherapy is the most commonly used treatment option in non-small cell lung carcinoma (NSCLC).4 Thus, age appears to be a major factor influencing treatment choices. Higher operative risks, shortened life expectancy, and possible sequelae leading to an impaired quality of life are some of the reasons why surgery is often denied in this group of individuals.4 However, there is little information on analysis of these outcomes in large series of elderly patients undergoing pulmonary resection for intended cure of lung cancer. The purpose of this study was to investigate the clinical characteristics, determinants of outcome, early mortality, and long-term survival in elderly patients undergoing surgery for NSCLC.
|
PATIENTS AND METHODS
|
|---|
Between January 1986 and December 2001, 1,573 patients with proven NSCLC underwent various pulmonary resections together with ipsilateral hilar and mediastinal lymph node dissection for NSCLC at the Department of Thoracic and Cardiovascular Surgery, University of Göttingen. Among these, 273 (17.3%) patients were aged 70 years or older. We reviewed the hospital records of all patients with intended curative surgery for NSCLC. Information included age, sex, clinical diagnosis, associated conditions, preoperative staging, and postoperative TNM stage. Complications and postoperative outcome were also recorded.
Functional assessment was similar in all patients. It included medical history, physical examination, basic blood tests, electrocardiogram (EKG), and standard pulmonary function data. Pulmonary function was assessed by spirometry and preoperative blood gas determinations. Minimal requirements for performing lobectomy or pneumonectomy were normoxia at rest, an expected postoperative forced expiratory volume in 1 second (FEV1) > 15 mL·kg–1 on preoperative spirometry, and a predicted number of lung lobes removed. A perfusion lung scan was performed in borderline patients with impaired pulmonary function who might be candidates for a standard resection. A pO2 < 65 mm Hg or a pCO2 > 45 mm Hg were considered contraindications to surgical resection. All patients with symptoms or previous history of cardiovascular disease, or with EKG abnormalities, consulted a cardiologist. Additional investigations included exercise stress testing, echocardiography, and/or coronary angiography. Preoperative staging was performed in all patients with chest radiography, computed tomography (CT) scans of the chest, bronchoscopy, abdominal and pelvic ultrasonography, radionuclide bone scan, and CT-scan of the brain. When the mediastinal CT scan led to the suspicion of advanced N2 or N3 disease, an additional mediastinoscopy was performed. NCSLC was diagnosed histologically, staged according to the New International Staging System for Lung Cancer, and re-staged after 1997 according to the revisions of the International System.5 Details of the type and method of surgery and the subsequent treatment were carefully reviewed for each patient.
Pneumonectomy, lobectomy, and bilateral lobectomy, followed by systematic extensive lymphadenectomy, were performed as standard operations. Our surgical policy favored lobectomies over limited resections, and whenever possible we tried to avoid pneumonectomy, especially in elderly patients. Bronchial stump protection was carried out only after right pneumonectomies, using a pedicled pericardial fat pad. Routine systematic dissection of all hilar and mediastinal lymph nodes was performed in every case. Every dissected node was examined by a pathologist and diagnosed as microscopically positive or negative during and after the operation. In general, patients were followed-up at 3-month intervals for the first 2 years, at 6-month intervals in the 3rd year, and annually thereafter. The postoperative evaluation included a physical examination, chest radiography, and tumor markers. Moreover, each year, CT chest and abdominal scans and a radionuclide bone scan were performed. When symptoms or signs of recurrence were detected, further examinations were carried out. Minor as well as major complications were taken into account for the analyses in this study. Minor complications included all events thought to have no significant impact on the patient’s postoperative course such as air leak persisting for 7 to 14 days, atrial fibrillation, atelectasis, retained secretions successfully managed by aspiration bronchoscopy, and pleural effusion. Major complications included bronchopleural fistula, prolonged air leak > 14 days, repeat thoracotomy for bleeding, respiratory insufficiency necessitating prolonged ventilator support, adult respiratory distress syndrome, myocardial infarction, and chylothorax. Operative mortality included the true 30-day mortality as well as other deaths occurring during the initial postoperative hospital stay.
Clinical variables were collected and stored using a computerized database. The survival probabilities were calculated by the Kaplan-Meier method, and differences in survival were determined by log-rank analysis. Survival rates are presented with their 95% confidence intervals in brackets. Frequencies were compared with the chi-squared test when appropriate. Means are given as ± standard deviation. Univariate logistic regression was performed and a likelihood ratio test was used to identify the significant risk factors for postoperative complications and disease recurrence. A multivariable analysis of several independent prognostic factors was carried out using the Cox proportional hazards regression model. Zero time was the date of surgery, and the terminal event was death attributable to cancer, non-cancer, or unknown causes. Forward stepwise procedures and likelihood ratio tests were used to select the variables with the greatest prognostic value. A value of p less than 0.05 was considered to indicate statistical significance. Statistical analysis was performed using Statistical Analysis System software (SAS Institute, Cary, NC, USA).
|
RESULTS
|
|---|
The mean age of the 273 patients 
70 years old was 73.2 ± 3.1 years (maximum, 88 years), and 31 (11%) were 80 years old. There were 170 (62%) men and 103 (38) women (ratio 5:3). The number of operative procedures per year increased significantly during the study period (r2 = 0.9, p = 0.02). Of the 273 patients, 115 were current smokers, 120 former smokers, and 38 non-smokers. Co-existing arteriosclerotic cardiovascular disease in 109 (40%) patients involved the coronary arteries (n = 72), peripheral arteries (n = 26), and the carotids (n = 11). In addition, 106 (39%) patients had arterial hypertension, and 28 (10%) were diabetic. Ninety-six patients (35%) were asymptomatic and 41 (15%) complained of recent body weight loss (4.5 ± 3 kg). Chronic obstructive pulmonary disease was diagnosed in 141 (52%) patients. Spirometric values are shown in Table 1
. There was previous history of neoplastic disease in 42 patients (15%); all were free of these neoplasms at the time of operation for NSCLC. Pathological features are presented in Table 2. The distribution of histology by sex showed significant differences with a higher incidence of squamous cell carcinoma (54% vs. 31%), and a lower incidence of adenocarcinoma (21% vs. 44%) in men vs. women ( p = 0.002). The last difference was explained in part by the significantly higher incidence of bronchoalveolar carcinoma in females (18% vs. 3%). On postoperative pathological staging, 156 (57%) patients had stage I disease: 62 (23%) were in stage IA and 94 (34%) were in stage IB. There were 61 (22%) in stage II: 28 (10%) in stage IIA and 33 (12%) in stage IIB. Thirty-three patients had stage III disease: 28 (10%) in stage IIIA and 5 (2%) in stage IIIB. Only 3 patients were in stage IV, and 20 were not given a stage by reason of multicentricity (n = 13) and/or the presence of peritumoral satellite lung nodules (n = 7).
The type of surgery, operative mortality, early and long-term results are listed in Table 3. Most patients had a standard procedure, while 36 (13%) underwent extended operations for tumors involving the chest wall (n = 25), mediastinum (n = 7) and pericardium (n = 4). On the basis of removal of all macroscopic carcinoma, disease-free resection margins, and highest mediastinal node free of tumor, 90% (246) of the procedures were considered to be complete (R0). Resection was considered incomplete when the final pathology report identified microscopic residual cancer at the bronchial margin or in the highest mediastinal node (R1, n = 23, 8%), or when macroscopic tumor was left in place (R2, n = 4, 1%). Operative mortality was stable over the study period. Operative mortality according to various variables is shown in Table 3. The mortality in patients who underwent extended surgery was higher than those who had a standard operation ( p = 0.02). Mortality rates associated with extended procedures were: mediastinum and superior vena cava, 19.6%; chest wall, 6%; main bronchus (sleeve), 3.2%.
Multivariate analysis showed that extended procedures ( p = 0.0001), male sex ( p = 0.0001), low FEV1 ( p = 0.02), and age ( p = 0.02) were independent predictors of early mortality. The early and long-term results according to patient age are summarized in Table 4. Octogenarians underwent significantly less extensive resections ( p = 0.001) and fewer pneumonectomies ( p = 0.01) and bilobectomies ( p = 0.01) than septuagenarians.
Postoperative complications occurred in 131 (48%) patients, leading to a mean postoperative stay of 22 ± 18 days. There were 15 (5.5%) hospital deaths (Table 5). The leading cause of mortality and/or morbidity was pulmonary complications. One or more major pulmonary complications occurred in 34 patients and included sputum retention (n = 23), postoperative pneumonia (n = 8), and adult respiratory distress syndrome (n = 3). To allow ventilatory assistance and/or repeated bronchial suction, 10 patients required a tracheotomy postoperatively. Fatal pulmonary complications occurred in 7 (2.6%) patients. Minor respiratory complications occurred in 20 (7.3%) patients. Multivariate analysis identified extended surgery ( p = 0.0004), low FEV1 ( p = 0.0001), and low forced vital capacity ( p = 0.005) as independent predictors of major pulmonary complications.
Major cardiovascular complications occurred in 7 (2.6%) patients (Table 5
) and were fatal in 6 (2.2%). The incidence of minor cardiovascular complications was significantly higher after pneumonectomy than after lobectomy and lesser resections (35.6% vs. 20.8%, p = 0.005). Multivariate analysis identified preoperative EKG abnormalities ( p = 0.003), pneumonectomy ( p = 0.01), and age ( p = 0.01) as independent predictors of cardiovascular complications. Other fatal or non-fatal surgical complications are listed in Table 5. There was a significantly higher incidence of bronchial fistula after a right pneumonectomy than after a left pneumonectomy (5/15 vs. 1/27; p = 0.02). Three patients had a late bronchopleural fistula, which was associated with local recurrence in 2 cases, and one had a fistula following postoperative radiotherapy. Multivariate analysis demonstrated that extended procedures ( p = 0.0001), and right-sided resections ( p = 0.02) were independent predictors of these complications. Other complications were transient renal failure (n = 5) and chylothorax (n = 2).
Follow-up data were available for all 258 operative survivors. Overall survival rates were 35.6% (29.5% to 41.7%), 10.5% (6.1% to 14.9%), and 2.5% (0% to 5%) at 5, 10 and 15 years, respectively, and median survival time was 31 months (range, 1–174 months). Survival curves according to disease stage are shown in Figure 1. In stage IIIA patients, 5-year survival was 5.6% (0% to 11.2%) in cases of macroscopic N2 disease, but 19.5% (8.2% to 30.2%) in cases of T3N0-1 disease. According to histology, 5-year survival rates for squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and other types were 36.5%, 29.8%, 31.2%, and 34.2%, respectively, without any significant difference. Multivariate analysis showed that advanced disease stage ( p = 0.00012), low FEV1 ( p = 0.003), previous cardiac disease ( p = 0.01), and hypertension ( p = 0.03) were independent predictors that influenced survival. Overall survival was not influenced by age, symptoms at presentation, history of previous malignant disease, year of operation, or histology.
View larger version (17K):
[in this window]
[in a new window]
|
Figure 1. Pathologic stage-related overall survival in elderly patients who underwent complete resection of non-small cell lung cancer.
|
|
On August 1, 2003, 98 patients were alive; 85 of them were free of disease and 13 had metastases. The other 160 operative survivors died during follow-up; 112 (70%) deaths were cancer-related. Recurrences were diagnosed in 80 (31%) patients. The median disease-free interval in these patients was 11 months (mean, 15 ± 16 months). Disease stage was the only parameter that independently correlated with recurrence ( p = 0.0001). For stage I patients, the recurrence rate was 36.4% after atypical limited resection, and 22.6% after a standard lobectomy ( p = 0.007). Eight (3.1%) patients developed a second primary NSCLC within a median interval of 29 months (mean, 41 ± 35 months).
|
DISCUSSION
|
|---|
How old is too old and where is the line to be drawn in the surgical treatment of NSCLC? Although it is generally thought that cancer has less aggressive biological behavior in elderly patients, thus justifying the use of more conservative treatment modalities, there is no evidence to support this view in lung carcinoma.5 In accordance with other studies, 40% of our patients were asymptomatic, indicating that their tumors might be more localized and resectable at the time of diagnosis.6–7 Considering the risk/benefit ratio of surgery, recent studies have shown that both operative risk and long-term results entirely justify lung cancer resection in elderly patients, provided they are properly selected.7–13 More recently, the age limit for surgery has been pushed up to 80 years.14–16 If chronological age is no longer a firm limitation on surgery, some concerns remain about selection of candidates and the type of procedure used.
One of the most important findings in this study was the low overall operative mortality rate (5.4%), especially in the octogenarian subgroup (4.7%). Our overall 30-day mortality rate is similar to that in other reports.4,7,9,12,14,16–18 The mortality rate in octogenarians is lower than the 8.1% mortality rate in this age group observed by the North American Lung Cancer Study Group.18 However, it is higher than the current rate associated with NSCLC resection in the general population.19 Our multivariate analysis showed that operative risk increases with age but decreases with lung-sparing operations. Indeed, extended resection was identified as an independent predictor of operative mortality, as previously noted.4 Pneumonectomy was found to be associated with mortality exceeding 20%.20 In this study, patients aged > 80 years had fewer pneumonectomies, and this is the likely explanation for the maintenance of hospital mortality at an acceptable level. As the loss of pulmonary function is greater after a right pneumonectomy, we tried to avoid this procedure in the elderly.20 Postoperative bronchopleural fistulas are more common after right pneumonectomy, and associated with higher morbidity and 30-day mortality.9,18,20 Our multivariate analysis identified right-sided lung resection as an independent predictor of overall surgical complications.
The leading cause of mortality and morbidity in our series was pulmonary complications, which may explain the relatively long postoperative stay. Major cardiorespiratory complications are common in elderly patients.7–13 Multivariate analysis identified preoperative low FEV1 and low forced vital capacity as independent predictors of major pulmonary complications, thus more appropriate patient selection can be assumed to reduce complications. Additional stress testing and measurement of maximal oxygen consumption can be useful in identifying patients at risk.14,10 Cardiovascular complications are also seen frequently during the postoperative period.14,10 Gebitekin and colleagues11 reported a high incidence (19.3%) of cardiovascular complications in the elderly. In agreement with other reports, multivariate analysis in our study identified preoperative EKG abnormalities, pneumonectomy, and age as independent predictors of cardiovascular complications.10,20 For over 10 years, we have given special attention to the management of elderly patients at weekly formal multidisciplinary conferences consisting of pulmonologists, thoracic surgeons, and medical and radiation oncologists. Careful assessment of preoperative cardiovascular and pulmonary fitness is performed by formal liaisons between members of this interdisciplinary team before recommendations for surgery are given.
Our finding that long-term survival was not influenced by patient age agrees with previous reports.7–18 Prognosis was strongly affected by the stage of the disease. The proportion of stage I cases in series of older patients is higher than in those dealing with all age groups.7–13 Our survival data also justifies surgery for patients with clinical stage I–II lung cancer. There is a general tendency to deny surgery to elderly patients with higher-stage tumors, but we found acceptable long-term survival in advanced stage IIIA when the patients had no macroscopically N2 disease and a radical (R0) resection could be carried out. The benefits of resection in elderly patients should not be considered only in terms of overall survival; good postoperative quality of life should be a secondary but important objective. As our data are retrospective and span more than one decade, quality of life was difficult to assess precisely without the standardized questionnaires in use today.14 As a proxy variable, the incidences of late complications and sequelae, which are considered important components of patient well being, were low in this series. Although postoperative adjuvant therapies may also adversely affect quality of life, due to the retrospective nature of the study, it was difficult to collect data from all who received postoperative therapy. Similarly, more than one decade of cause of death data were difficult to obtain retrospectively, and all of our survival analyses were limited to overall survival. Nevertheless, it was concluded that elderly patients should not be denied surgery solely on the basis of age. Where the line should be drawn depends on clinical staging, extent of resection, pulmonary function, and comorbidity.
|
ACKNOWLEDGMENTS
|
|---|
We thank Robert Kwiecien and Ralf Hilgers from the Institute for Biostatistics, University of Aachen, Germany, for their generous and excellent statistical assistance.
|
REFERENCES
|
|---|
- Breyer RH, Zippe C, Pharr WF, Jensik RJ, Kittle CF, Faber LP. Thoracotomy in patients over age seventy years: ten-year experience. J Thorac Cardiovasc Surg 1981;81:187–93.[Abstract]
- Smith TJ, Penberthy L, Desch CE, Whittemore M, Newschaffer C, Hillner BE, et al. Differences in initial treatment patterns and outcomes of lung cancer in the elderly. Lung Cancer 1995;13:235–52.[Medline]
- Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5–26.[Abstract/Free Full Text]
- Thomas P, Piraux M, Jacques LF, Gregoire J, Bedard P, Deslauriers J. Clinical patterns and trends of outcome of elderly patients with bronchogenic carcinoma. Eur J Cardiothorac Surg 1998;13:266–74.
- Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:1710–7.[Abstract/Free Full Text]
- Weinmann M, Jeremic B, Toomes H, Friedel G, Bamberg M. Treatment of lung cancer in the elderly. Part I: non-small cell lung cancer. Lung Cancer 2003;39:233–53.[Medline]
- Massard G, Moog R, Wihlm JM, Kessler R, Dabbagh A, Lesage A, et al. Bronchogenic cancer in the elderly: operative risk and long-term prognosis. Thorac Cardiovasc Surg 1996;44:40–5.[Medline]
- Ishida T, Yokoyama H, Kaneko S, Sugio K, Sugimachi K. Long-term results of operation for non-small cell lung cancer in the elderly. Ann Thorac Surg 1990;50:919–22.[Abstract]
- Roxburgh JC, Thompson J, Goldstraw P. Hospital mortality and long-term survival after pulmonary resection in the elderly. Ann Thorac Surg 1991;51:800–3.[Abstract]
- Thomas P, Sielezneff I, Ragni J, Giudicelli R, Fuentes P. Is lung cancer resection justified in patients aged over 70 years? Eur J Cardiothorac Surg 1993;7:246–51.[Abstract]
- Gebitekin C, Gupta NK, Martin PG, Saunders NR, Walker DR. Long-term results in the elderly following pulmonary resection for non-small cell lung carcinoma. Eur J Cardiothorac Surg 1993;7:653–6.[Abstract]
- Santambrogio L, Nosotti M, Bellaviti N, Mezzetti M. Prospective study of surgical treatment of lung cancer in the elderly patient. J Gerontol A Biol Sci Med Sci 1996;51:M267–9.[Abstract]
- Morandi U, Stefani A, Golinelli M, Ruggiero C, Brandi L, Chiapponi A, et al. Results of surgical resection in patients over the age of 70 years with non small-cell lung cancer. Eur J Cardiothorac Surg 1997;11:432–9.[Abstract]
- Brock MV, Kim MP, Hooker CM, Alberg AJ, Jordan MM, Roig CM, et al. Pulmonary resection in octogenarians with stage I nonsmall cell lung cancer: a 22-year experience. Ann Thorac Surg 2004;77:271–7.[Abstract/Free Full Text]
- Naunheim KS, Kesler KA, D’Orazio SA, Fiore AC, Judd DR. Lung cancer surgery in the octogenarian. Eur J Cardiothorac Surg 1994;8:453–6.[Abstract]
- Pagni S, Federico JA, Ponn RB. Pulmonary resection for lung cancer in octogenarians. Ann Thorac Surg 1997;63:785–9.[Abstract/Free Full Text]
- Osaki T, Shirakusa T, Kodate M, Nakanishi R, Mitsudomi T, Ueda H. Surgical treatment of lung cancer in the octogenarian. Ann Thorac Surg 1994;57:188–93.[Abstract]
- Ginsberg RJ, Hill LD, Eagan RT, Thomas P, Mountain CF, Deslauriers J, et al. Modern thirty-day operative mortality for surgical resections in lung cancer. J Thorac Cardiovasc Surg 1983;86:654–8.[Abstract]
- Deslauriers J, Ginsberg RJ, Piantadosi S, Fournier B. Prospective assessment of 30-day operative morbidity for surgical resections in lung cancer. Chest 1994;106(6 Suppl):329S–30S.[Abstract/Free Full Text]
- Au J, el-Oakley R, Cameron EW. Pneumonectomy for bronchogenic carcinoma in the elderly. Eur J Cardiothorac Surg 1994;8:247–50.[Abstract]
This article has been cited by other articles:
|
|
|
|
 
M. F. Berry, J. Hanna, B. C. Tong, W. R. Burfeind Jr, D. H. Harpole, T. A. D'Amico, and M. W. Onaitis
Risk factors for morbidity after lobectomy for lung cancer in elderly patients.
Ann. Thorac. Surg.,
October 1, 2009;
88(4):
1093 - 1099.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. G. Pallis, C. Gridelli, J. P. van Meerbeeck, L. Greillier, U. Wedding, D. Lacombe, J. Welch, C. P. Belani, and M. Aapro
EORTC Elderly Task Force and Lung Cancer Group and International Society for Geriatric Oncology (SIOG) experts' opinion for the treatment of non-small-cell lung cancer in an elderly population
Ann. Onc.,
August 28, 2009;
(2009)
mdp360v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. A. Whitson, S. S. Groth, S. J. Duval, S. J. Swanson, and M. A. Maddaus
Surgery for Early-Stage Non-Small Cell Lung Cancer: A Systematic Review of the Video-Assisted Thoracoscopic Surgery Versus Thoracotomy Approaches to Lobectomy
Ann. Thorac. Surg.,
December 1, 2008;
86(6):
2008 - 2018.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. K. Owonikoko, C. C. Ragin, C. P. Belani, A. B. Oton, W. E. Gooding, E. Taioli, and S. S. Ramalingam
Lung Cancer in Elderly Patients: An Analysis of the Surveillance, Epidemiology, and End Results Database
J. Clin. Oncol.,
December 10, 2007;
25(35):
5570 - 5577.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
INTRODUCTION
