Abstract
Aim: To justify esophagectomy for elderly patients. Patients and Methods: A total of 1,002 patients with thoracic esophageal cancer who underwent esophagectomy were divided into three groups: I (≤74 years old, n=898); II (75-79 years, n=81); and III (≥80 years, n=23). Historical changes were compared between the first surgical period (1964-1989) and the second period (1990-2011). Results: The morbidity rates were 40%, 41% and 26% in the respective groups. Pulmonary complications decreased historically in groups II and III (36% to 15% and 43% to 0%, respectively). The mortality was higher in the older groups (4.8%, 8.6% and 13.0%, respectively); however, there was a marked historical decrease in groups II (18.2% to 5.1%) and III (28.6% to 6.3%). The 5-year survival improved from 5% to 35% in group II and from 0% to 17% in group III. Conclusion: The outcomes of esophagectomy for elderly patients have markedly improved, with acceptable mortality even in octogenarians.
Esophageal cancer is highly aggressive, and until recently it was usually associated with a dismal prognosis (1). Surgical resection has been the gold standard of treatment for localized esophageal cancer (2). However, this type of surgery is extremely invasive and it is also associated with high mortality and morbidity rates (3). Another clinical problem of esophageal cancer is that it tends to develop mainly in elderly men. According to a nationwide study of the Japan Esophageal Society, this type of cancer develops most frequently in men in their 60s. In elderly patients, dysfunction of critical organs such as the lungs, heart or kidneys is frequently associated with this disease. Furthermore, it is also frequently associated with senile dementia in elderly patients, and not surprisingly the patients and their families do not want aggressive treatment. The indications for surgical treatment in elderly patients with esophageal cancer therefore tend to be limited, and remain controversial (5-10).
Previously, we examined the clinical results of esophagectomy for elderly patients and reported satisfactory prognosis without any increased morbidity and mortality, even in patients aged ≥80 years (11). Due to advances in esophageal cancer surgery, marked improvement in prognosis after esophagectomy has been achieved in patients with esophageal cancer (1). However, a significant number of in-hospital deaths still occur (3). In the current study, we therefore examined the clinical results after esophagectomy for elderly patients, paying special attention to the historical changes and causes of death.
Patients and Methods
One thousand one hundred and forty-five Japanese patients underwent esophagectomy for esophageal cancer between 1964 and 2011, at the Department of Surgery and Science (Department of Surgery II), Kyushu University Hospital. After excluding 67 patients with cervical esophageal cancer and 76 with abdominal esophageal cancer, the subjects of this study consisted of 1002 patients with thoracic esophageal cancer. The patients consisted of 881 men and 121 women, with a mean age of 63.1 years (range 35-90 years). The main lesion was histologically diagnosed as squamous cell carcinoma in 971 patients, adenocarcinoma in 12, and other histological types in 19.
The patients were divided into three groups depending on their age at the time of esophagectomy: Group I included 898 patients ≤74 years old; group II included 81 patients aged 75-79 years; and group III included 23 patients aged ≥80 years. The historical changes regarding clinical outcomes were analyzed according to the period when the surgery was performed: the first period was 1964-1989, and the second period was 1990-2011.
The strategy associated with the surgical approach and perioperative management was previously reported in detail (1). Subtotal esophagectomy was performed via a cervico right thoracoabdominal approach in 733 patients and a trans-hiatal approach in 12. Distal esophagectomy was performed in the other 257 patients and the approaches were right thoracotomy, laparotomy, and intrathoracic anastomosis (modified Ivor Lewis procedure) in 229; a left thoracoabdominal approach in 21; and a trans-hiatal approach in seven. A two-stage operation, in which reconstruction was performed three weeks after esophagectomy, was adopted for elderly patients with general risk, such as diabetes, pulmonary diseases and post-gastrectomy (12).
Clinical characteristics of patients who underwent esophagectomy according to age.
The principles of esophagectomy for patients aged ≥80 years were applied as previously reported (11). Surgery was performed only for cases with performance status 0 or 1, as well as normal cardiac and pulmonary function: echocardiography revealed left ejection fraction to be ≥55% and spirography revealed ≥80% vital capacity and ≥70% forced expiratory volume in one second (FEV1). The presence of dementia was considered to be a contraindication for the operation. In patients aged 75-79 years (group II), these indications were also adopted in principle.
Pulmonary complications were defined as pneumonia (positive bacterial culture of sputum), atelectasis, or hypoxia requiring reintubation. Anastomotic leakage was diagnosed by esophagography, dye test, or saliva discharge. The in-hospital mortality was defined as those who died during their initial postoperative hospitalization.
Historical changes in clinical characteristics of patients who underwent esophagectomy.
The differences in distribution frequencies among the groups were evaluated using either Fisher's exact test or unpaired t-test. The independent factors associated with pulmonary complications were evaluated by logistic regression analysis. The survival curves were plotted according to the Kaplan–Meier method and any differences between the two curves were analyzed using the log-rank test. Differences were considered to be significant if p was <0.05. The data were analyzed using StatView software (Abacus Concepts, Berkeley, CA, USA).
Results
Clinical background. Table I shows the clinical characteristics of each group according to age. There were no significant differences in the clinical backgrounds, such as sex, tumor location, depth of invasion, and lymph node metastasis. Regarding operative factors, less invasive procedures tended to be adopted in the elderly groups (II and III): distal esophagectomy was more frequent in these groups and three-field lymphadenectomy was never performed in patients aged ≥80 years.
Historical changes in incidence of postoperative complications after esophagectomy (upper graphs; gray bars indicate the incidence of pulmonary complications) and of in-hospital death (lower graphs; gray bars indicate the incidence of 30-day mortality) according to age groups. The asterisks indicate statistically significant differences compared with the first period (*p<0.01 and **p<0.05).
Table II shows the historical changes in the patients' clinical background. The incidence of adventitial invasion and lymph node metastasis significantly decreased in the second period. Regarding the operative procedure, distal esophagectomy, three-field lymphadenectomy, and reconstruction through either posterior mediastinal or intrathoracic routes were more commonly performed in the second period.
Morbidity and mortality. Postoperative complications developed in 400 (39.9%) out of 1,002 patients. Anastomotic leakage was most frequent (260 patients, 25.9%), followed by pulmonary complications (179 patients, 17.9%). According to the patients' age, there were no significant differences in the incidence of postoperative complications. The incidences of any postoperative complications were 40.2%, 40.7% and 26.1% in groups I, II and III, respectively. Among these, pulmonary complications developed in 17.7%, 21.0% and 13.0% of patients, respectively. The upper graphs in Figure 1 show the historical changes in the morbidity of each group. The incidences of postoperative complications decreased in all groups: from 50% to 34% in group I, 55% to 36% in group II and 43% to 19% in group III. Pulmonary complications markedly decreased in all groups: In groups I and II, pulmonary complications developed in 27% and 36% of patients during the first period, and decreased to 11% and 15% during the second period, respectively. Pulmonary complications were not seen in 16 patients in group III during the second period. A multivariate analysis revealed that the period of surgery, as well as depth of invasion, was an independent factor associated with pulmonary complications; however, age was not related to these complications (Table III).
In-hospital death occurred in 53 (5.3%) out of 1,002 patients after esophagectomy. Among these, 21 patients (2.1%) died within 30 days after esophagectomy. In-hospital death tended to occur more frequently in the older groups, although the difference was not significant. In-hospital death was recognized in 43 (4.8%), seven (8.6%), and three patients (13.0%) in groups I, II and III, respectively. Thirty-day mortality occurred in 17 (4.0%), three (3.7%), and one (4.3%) patients, respectively. The lower graphs in Figure 1 indicate the historical changes. In-hospital death, especially 30-day mortality, decreased in all groups. During the second period, in-hospital death occurred in 2.0%, 5.1% and 6.3%, while 30-day mortality occurred in 0.6%, 1.7 % and 0% in groups I and II and III, respectively. Table IV shows the clinical features of 10 elderly patients in groups II and III who died in hospital. Pulmonary complications, such as pneumonia, pyothorax, and adult respiratory distress syndrome, developed in nine patients, while complications regarding the reconstruction and anastomosis occurred in 75. Respiratory failure due to pneumonia was the direct cause of hospital death in three patients who died 15, 39 and 64 days, respectively after esophagectomy. Other causes of in-hospital mortality were cerebral infarction, multiorgan failure, and pyothorax in one patient each. In three patients who underwent esophagectomy after 1998, either re-growth or recurrence of esophageal cancer resulted in in-hospital death, which occurred >100 days after esophagectomy.
Factors associated with the development of pulmonary complications according to logistic regression analysis.
Clinical factors of 10 elderly cases of in-hospital death in groups II and III.
Overall and disease-specific survival after esophagectomy according to patient age group. There were no significant differences between the groups.
Historical changes in overall survival according to patients' age groups. There were significant differences in survival between the first period (1964-1989) and the second period (1990–2011) in group I (p<0.001) and group II (p=0.003).
Prognosis after esophagectomy. Figure 2 shows the overall and disease-specific survival. Overall survival was poorer in the elderly groups, especially three years after esophagectomy, although the difference was not significant. The three-year survival rates were 42%, 37% and 30%, and the five-year survival rates were 35%, 25% and 10%, in groups I, II and III, respectively. There were no differences in the disease-specific survival.
Figure 3 shows the historical changes in overall survival after esophagectomy according to age. The survival improved in all groups. The five-year survival improved from 19% to 47% in group I and 5% to 35% in group II. In group III, all seven patients died within three years after esophagectomy during the first period, whereas the three- and five-year survival rates were 50% and 17% during the second period, respectively.
Discussion
In Japan, people tend to be living longer and treatment for cancer in elderly people is currently a major problem. Esophageal cancer tends to develop in elderly patients, in whom it is frequently associated with a comorbidity such as heart disease, brain infarction, and diabetes. Furthermore, pulmonary disease, such as chronic obstructive pulmonary disease, and liver failure are frequently associated with esophageal cancer because both cigarette smoking and alcohol consumption are risk factors (13). Synchronous or metachronous association of esophageal cancer with cancer of other organs makes therapy difficult in elderly patients. In cases of association with gastric cancer, reconstruction methods tend to be complicated by gastrectomy (14). Patients with synchronous cancer in the thoracic esophagus and head and neck often need to undergo extremely complex and invasive surgical procedures in order to resect both lesions, while previous surgery and/or irradiation of the neck region makes the treatment for esophageal cancer difficult (15). Esophageal cancer is relatively sensitive to radiation and anticancer drugs such as 5-fluorouracil and cisplatin (16). Given the high operative mortality associated with esophagectomy, many elderly patients prefer non-operative treatment of esophageal cancer, such as definitive chemoradiotherapy-alone (17). Cijs et al. reported on higher operative mortality (8.4% versus 3.8%) as well as in-hospital mortality (11.6% versus 5.4%) in patients aged ≥70 years, compared with younger patients (6). They also reported on lower disease-specific and five-year survival (27% and 34%) in older patients. Furthermore, a national study from the US which examined clinical outcomes in octogenarians undergoing esophagectomy revealed similar results. The operative mortality was higher (19.9% versus 8.8%) and the five-year survival was lower (17.6% versus 31.4%) in octogenarians than in patients aged <70 years (5). In contrast, other studies in the US (7), Europe (8, 10) and Asia (9, 18) have emphasized that patients should not be denied esophagectomy based solely on their age because acceptable mortality and substantial long-term survival can be achieved.
In the current study, the incidence of postoperative complications was not significantly different between the three groups. In particular, pulmonary complications, which may result in most critical outcomes, were found to decrease markedly in the second period, and multivariate analysis revealed that age was not an independent factor associated with the development of these complications. The marked decrease in the incidence of pulmonary complications can be attributed to several factors, including appropriate indications for surgery as a result of accurate evaluation of general condition, establishment of safer operative techniques, improved anesthesia, better intraoperative fluid management to minimize fluid administration, and advances in intensive respiratory care (19). Regarding operative methods for elderly patients, we recently performed an aggressive two-stage operation for those with some general risk, such as diabetes, pulmonary diseases and post-gastrectomy (12), and the less invasive Ivor Lewis method with distal gastrectomy has been performed in patients with comparatively early-stage carcinoma (20). As perioperative management for prevention of pneumonia, frequent suctioning of sputum by bronchoscopy, as well as physiological rehabilitation after early extubation has been recently emphasized (21). Furthermore, we recently performed preoperative dental care with brushing since the presence of pathogens in dental plaque is a risk factor associated with postoperative pneumonia in patients with esophageal cancer (22).
In the current study, in-hospital death was found to decrease in the second period and the decrease in 30-day mortality was marked in all groups. However, in-hospital deaths tended to be more frequent in the elderly groups, although the difference was not significant. Therefore, we examined the details of in-hospital death of elderly patients. As a result, most in-hospital deaths of elderly patients were associated with pulmonary complications. Direct cause of in-hospital death seen after esophagectomy was death due to either regrowth or recurrence of esophageal cancer before recovery from the postoperative complication. These tendencies are similar to those in younger patients (3). However, especially in elderly patients, it takes a long time to recover from postoperative complications. Strict surgical indications, as well as careful postoperative management, are therefore important for elderly patients.
Although the overall survival seemed to be poorer in the older groups, especially more than three years after esophagectomy, the disease-specific survival was similar between the three groups. These data reflect that death other than from cancer occurred more frequently as a natural course in elderly patients, and that surgical curability was similar between the groups. Furthermore, the prognosis after esophagectomy was markedly improved in the second period in older groups, as well as in the younger group. Similar results have been described by Shimada et al. (18). The reason for such improvement in prognosis must be owing to multiple factors, just as the decrease in pulmonary complications was.
The current study clearly indicates that clinical outcomes of esophagectomy for elderly patients have markedly improved, with acceptable mortality even in patients aged ≥80 years. However, postoperative complications may result in in-hospital mortality, especially in elderly patients. Clinical outcomes after esophagectomy are significantly related to the hospital volume (23). Most studies that have reported acceptable outcomes after esophagectomy in elderly patients were from high-volume centers (7-11, 18). Esophagectomy for elderly patients should be performed in high-volume centers, and strict surgical indications, less invasive surgery, and careful perioperative management must be achieved.
Acknowledgements
This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sport, Science and Technology of Japan.
- Received March 1, 2013.
- Revision received March 10, 2013.
- Accepted March 12, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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