Extended Esophagectomy in Elderly Patients with Esophageal Cancer: Minor Effect of Age Alone in Determining the Postoperative Course and Survival

Comorbidity was determined by the American Society of Anesthesiologists (ASA) physical status classification. ASA is a readily available and widely accepted way to stratify surgical patients according to their perioperative risk and varies between ASA class 1 (very good condition) and ASA class 5 (moribund patient).23 ASA class was assigned by the anesthesiologist after completing a structured review of physical status just before esophagectomy.

Patients were considered for curative esophagectomy after a complete preoperative workup, which included physical examination, standard laboratory tests, digestive endoscopy, histopathological examination of biopsy samples, and detailed preoperative risk assessments. Staging of the tumors was performed by endoscopic ultrasound with fine-needle aspiration and computed tomography (CT) of the chest, abdomen, and cervical region. In all patients newly diagnosed with T3–4 or N1 esophageal cancer, a ¹⁸F-fluoro-2-deoxy-d-glucose positron emission tomography (PET) scan was performed. In case of anatomical difficulties on PET assessment, a PET/CT fusion scan was performed. Before surgery, all patients were discussed in multidisciplinary meetings.

An extended esophageal resection was performed in all patients. This procedure consisted of a subtotal esophageal resection through a left thoracolaparotomy with intrathoracic anastomoses for the distal and gastroesophageal cancers or through a right thoraco-mid laparotomy with cervical anastomoses for the higher intrathoracic tumors. Both were combined with a two-field lymphadenectomy of nodes at the celiac trunk, upper border of the pancreas, para-aortic region, and mediastinal nodes.

All resected specimens and lymph nodes were examined according to standard procedures. Tumor stage and grade were classified according to the 6th edition of the tumor, node, and metastasis system and the residual tumor (R) classification of the International Union Against Cancer and the American Joint Committee on Cancer.24,25 Adenocarcinomas observed on hematoxylin and eosin–stained samples were confirmed in all cases by keratin staining (immunohistochemical analysis).

Postoperative mortality was defined as any death within the same hospital admission and all deaths within the first 90 days after surgery. A separate calculation was made of only 90-day mortality (without in-hospital deaths after 90 days) to compare these figures with the data in literature. Major complications were divided into pulmonary complications: respiratory insufficiency (prolonged need for mechanical ventilation), acute respiratory distress syndrome (acute and persistent lung inflammation with increased vascular permeability and severe hypoxemia), pneumonia (infiltrate on x-ray, sepsis, and positive sputum culture, including bronchoalveolar lavage), atelectasis (collapse of lung lobe on x-ray with hypoxemia for which intensive physiotherapy or bronchoscopy was needed), pleural effusion (fluid seen on x-ray for which drainage was necessary because of hypoxemia), empyema (positive culture or positive fluid) and pulmonary embolism (diagnosed by CT); cardiac complications; arrhythmia (diagnosed on electrocardiogram) and myocardial infarction (diagnosed on electrocardiogram and positive laboratory tests); and other major complications; rebleeding (bleeding requiring transfusion or reoperation), subphrenic abscess and/or intra-abdominal abscess (CT, drainage, and positive culture), systemic inflammatory response syndrome (SIRS; deregulated host with inflammatory response with absent infection: temperature >38.5 or <35°C, heart rate > 90 beats/min, respiratory rate > 20 breaths/min or PaCO₂ < 32 mm Hg and white blood cells > 12,000 cells/mm³), sepsis (the clinical signs of SIRS, but with culture-proven infection or an infection identified by visual inspection), anastomotic leakage (CT with enteral contrast and amylase in the pleural fluid), chylothorax (chyle defined by measuring triglycerides), renal failure (increasing creatinine and oliguria for which renal replacement therapy was necessary), liver failure (increasing bilirubin, liver enzymes, lactate, and prothrombin time), and deep venous thrombosis (of the distal or proximal lower extremity) and ileus (absence of peristalsis with gastric retention and no defecation, confirmed with abdominal X-ray). Minor complications were defined as wound infections (positive wound culture with pus), wound dehiscence (spontaneous opening of the fascia) and urinary tract infections (sepsis, urinary leucocytes, and 10⁵ bacteria/ml in urine). Infectious complications were subdivided into septic complications (sepsis) and intra-abdominal or subphrenic abscess eventually with anastomotic leakage, empyema, pneumonia, severe wound infections, and urinary tract infections. The use of antibiotics and inotropes was scored during the postoperative period. The operation room time, intensive care unit (ICU) length of stay, and hospital length of stay were measured for comparison.

All medical follow-up data were collected prospectively in a patient research database. Patients were seen in the outpatient department every 3 months for the first postoperative year, every 6 months for the next year, and then annually for 10 years. Data of deceased patients were collected by consulting the general practitioners and the Comprehensive Cancer Center, North Netherlands. Follow-up was measured in months from the time of operation until death (survival time) or end of follow-up with a minimum of 2 years.

Recurrent disease was defined as locoregional recurrence or distant metastases in the follow-up period, determined by any cytologic or histologic proof, unequivocal radiologic suspicion (CT, magnetic resonance imaging, PET, bone scan, and ultrasound), and/or obvious clinical manifestations.

The follow-up was ascertained in February 2009 and was complete for all included patients.

For calculations, “elderly” was defined as a patient ≥70 years of age, as generally used in the literature.8,10,11,16‐22 Therefore, we discriminated between group I, <70 years, and group II, ≥70 years, independently of other factors.

Variables were reflected as frequencies with means and/or median with percentages. Continuous variables were compared by the t-test, and the χ² test was used for comparison of categorical variables. Survival and recurrence rates were calculated by the Kaplan-Meier method and the log rank test. Survival calculations included postoperative mortality, except for the cancer-specific survival. Prognostic factors for survival were calculated with Cox regression univariate and multivariate analyses. Univariate and multivariate logistic and linear regression analysis were used for calculating if advanced age was influencing the occurrence of comorbidity and complications; the group of complications (cardiac, pulmonary, and infectious complications) were calculated as well as individual complications. Multivariate analysis was performed by incorporating factors as covariates with a P value of ≤0.1 on univariate analysis.

The study population consisted of 234 consecutive patients, 196 men (84%) and 38 women (16%). The mean age at operation was 63 years, with a range of 28 to 82 years. Group I (<70 years of age) consisted of 170 patients (73%) and group II (≥70 years of age) of 64 patients (27%). Patients and tumor characteristics are summarized in Table 1. Surgical characteristics such as year of surgery (P = 0.4) and type of resection (P = 0.9) were similar in both groups. Stage of disease was not statistically different in both groups (P = 0.148), although more advanced disease seemed to occur in the younger patients (Table 1).

Comorbidity was not significantly different in both groups: 65 patients (38%) with comorbidity in group I versus 32 patients (50%) in group II (P = 0.104). ASA class did not differ between the two groups (P = 0.136).

Postoperative mortality (defined as within 90 days of surgery and within-hospital admission) was 6.2% (15 patients), 8 patients (5%) in group I versus 7 patients (11%) in group II (P = 0.09). The 90-day mortality alone was 4.7% (11 patients), with 5 patients (3%) in group I and 6 patients (9%) in group II (P = 0.08). Of the 15 patients who died after surgery, 10 (67%) had more than one comorbidity (P = 0.041). Four patients had a history of myocardial infarction and hypertension; one patient had diabetes with myocardial infarction; two patients had diabetes with hypertension; one patient had chronic obstructive pulmonary disease with transient ischemic attack; and two patients had a transient ischemic attack with hypertension. Only cardiovascular comorbidity in the elderly subgroup (n = 24; 38%) had a negative effect on postoperative mortality (P = 0.043).

Ninety-nine patients (58%) in group I and 44 patients (69%) in group II developed postoperative complications, which was not statistically different between both groups (P = 0.142). Pulmonary complications occurred in 72 patients (42%) in group I versus 36 patients (56%; P = 0.06) in group II, respectively (Table 2). Respiratory insufficiency was the most frequent complication and occurred more in the elderly patients (25 vs. 41%; P = 0.017). Other major pulmonary complications, atelectasis (14% vs. 28%; P = 0.009) and pleural effusion (15 vs. 27%; P = 0.036), occurred more frequently in group II. Cardiac complications, primarily consisting of arrhythmias, occurred in 27 patients (16%) versus 24 patients (38%) in group II (P = 0.001). Pneumonia was the most common infectious complication in 43 patients (18%), 16% in group I and 23% in group II (P = 0.221). There were no differences between infectious and noninfectious complications between the two groups (P = 0.5). Four abscesses developed in the elderly group (6%).

The postoperative use of antibiotics and inotropes did not differ statistically between both age groups (P = 0.4 and P = 0.13).

In logistic regression analysis, age ≥70 years was not a prognostic factor for development of postoperative complications (odds ratio [OR], 1.578; 95% confidence interval [95% CI], 0.857 to 2.904; P = 0.143). For cardiac complications (OR, 3.178; 95% CI, 1.655 to 6.100; P = 0.001) and pulmonary complications (OR, 1.750; 95% CI, 0.980 to 3.126; P = 0.05) as a group, age ≥70 years was a prognostic factor (Table 3).

There was a higher rate of complications in the patients with comorbidity; 69 (71%) of the 97 patients who had comorbidity developed one or multiple postoperative complications (P = 0.008). However, of the 143 patients who had complications, only 69 (48%) had preoperative fixed comorbidity. In logistic regression analysis, comorbidity was a prognostic factor for developing postoperative complications (OR, 2.098; 95% CI, 1.207 to 3.647; P = 0.009)

The operation time, with a median of 6 hours, was not different in both groups (95% CI, −0.72 to 0.28; P = 0.384). The median ICU stay was 3 days, with a range of 1–64 days. In group II, the ICU stay was significantly longer, with a median of 7 days (range, 1–64 days) versus group I, with a median of 3 days (range, 1–56 days) (95% CI, −9.95 to −1.86; P = 0.005). Reoperation was needed in 29 patients as a result of complications, including anastomotic leakage, postoperative bleeding, subphrenic abscess, and obstructive ileus based on torsion at the jejunostomy site. The median hospital stay was 22 days, with 21 days in group I and 26 days in group II (95% CI, −11.03 to 0.17; P = 0.06).

Stage of disease had no impact on survival between the two groups (stage I, P = 0.298; stage II; P = 0.834; stage III; P = 0.184; stage IVa; P = 2.09).

None of the individual complications had a statistically significant impact on survival. Overall, complications had no influence on long-term survival, including postoperative mortality (P = 0.174), and mortality (P = 0.655).

Recurrent disease occurred in 126 patients (54%): 99 patients (58%) in group I and 27 (42%) in group II (P = 0.028). Time to development of recurrent disease did not differ between the groups (P = 0.223).

For all 234 patients, including patients with postoperative mortality, the 1-year survival was 74% and the 5-year survival was 33%. There was no difference in survival between the two groups (P = 0.535), with a 1-year survival of 76% in group I versus 70% in group II (P = 0.282) and a 5-year survival of 33% in group I versus 33% in group II (P = 0.676) (Fig. 1).

Age classification of <70 and ≥70 years did not have any prognostic value for survival (OR, 1.117; 95% CI, 0.787 to 1.584; P = 0.535). Also, increasing age as continuous variable did not have a prognostic value for worse survival (OR, 1.005; 95% CI, 0.990 to 1.021; P = 0.514).

Cancer-related 5-year survival in patients without postoperative mortality (n = 219) and cancer-related cause of death was 35% and did not differ between the groups (35 vs. 37%, P = 0.874).

Survival curves of comorbidity versus age showed no difference between the two groups (P = 0.135). In group I and II separately, there was no statistical difference in survival of patients with and without comorbidity (Fig. 2a, b), although there was a trend for worse survival in elderly patients with comorbidity (P = 0.087) (Fig. 2b).

The presence of comorbidity was an independent prognostic factor for long-term survival (OR, 1.679; 95% CI, 1.219 to 2.314; P = 0.002). The Kaplan-Meier curve showed significantly better survival for patients without comorbidity in the long term (P = 0.001) (Fig. 3).