Abstract
Aim
This study was performed to evaluate the oncological impact of surgical site infection (SSI) and pneumonia on long‐term outcomes after esophagectomy.
Methods
The Japan Society for Surgical Infection conducted a multicenter retrospective cohort study involving 407 patients with curative stage I/II/III esophageal cancer at 11 centers from April 2013 to March 2015. We investigated the association of SSI and postoperative pneumonia with oncological outcomes in terms of relapse‐free survival (RFS) and overall survival (OS).
Results
Ninety (22.1%), 65 (16.0%), and 22 (5.4%) patients had SSI, pneumonia, and both SSI and pneumonia, respectively. The univariate analysis demonstrated that SSI and pneumonia were associated with worse RFS and OS. In the multivariate analysis, however, only SSI had a significant negative impact on RFS (HR, 1.63; 95% confidence interval, 1.12–2.36; P = 0.010) and OS (HR, 2.06; 95% confidence interval, 1.41–3.01; P < 0.001). The presence of both SSI and pneumonia and the presence of severe SSI had profound negative oncological impacts. Diabetes mellitus and an American Society of Anesthesiologists score of III were independent predictive factors for both SSI and pneumonia. The subgroup analysis showed that three‐field lymph node dissection and neoadjuvant therapy canceled out the negative oncological impact of SSI on RFS.
Conclusion
Our study demonstrated that SSI, rather than pneumonia, after esophagectomy was associated with impaired oncological outcomes. Further progress in the development of strategies for SSI prevention may improve the quality of care and oncological outcomes in patients undergoing curative esophagectomy.
Keywords: esophageal cancer, pneumonia, surgical site infection, survival
Our study demonstrated that SSI, rather than pneumonia, after esophagectomy was associated with impaired oncological outcomes. Further progress in the development of strategies for SSI prevention may improve the quality of care and oncological outcomes in patients undergoing curative esophagectomy.
1. INTRODUCTION
Esophageal cancer is one of the most common causes of cancer‐related death worldwide, being ranked the fifth and eighth most common cause in men and women, respectively. 1 Recent advances in surgical techniques and perioperative management have improved the short‐term outcomes of esophageal cancer surgeries; however, esophagectomy remains one of the most invasive procedures and has been shown to be associated with significant morbidity (41.9%–59.0%) and mortality (3.4%–8.9%) in large cohort studies. 2 , 3 Among the various morbidities, surgical site infection (SSI) is the most frequent surgical complication and can result in increased medical costs, a prolonged hospital stay, and deterioration of the patient's quality of life. 4 The incidence of overall SSIs in esophageal surgery is reportedly higher than that in other gastroenterological surgeries, which accounted for 17.5% in recent Japanese nationwide surveillance data (204 763 cases of gastroenterological surgery) and is decreasing annually. 5 Anastomotic leakage (AL), which is categorized as an organ/space SSI, is a major postoperative infection (PI) after esophagectomy and accounts for 3% to 30% of all PIs. 3 , 6 Notably, the incidence of AL remained unchanged even after the introduction and dissemination of minimally invasive esophagectomy (MIE). 3 , 7 In addition to the above‐mentioned drawbacks of PI, prior studies have demonstrated increased recurrence and worse survival in patients who develop PI, and particularly in those who develop AL, among patients undergoing esophageal cancer surgeries. 8 , 9 However, other studies have suggested no oncological influence of AL after esophagectomy. 6 , 10 Various factors, such as the severity of the disease, insufficient reliability of the study design, and variation of perioperative management during the patient inclusion period could be reasons for these inconsistent results.
Pneumonia is a major PI after esophagectomy. Its incidence rate ranges from 14% to 33%, 11 , 12 and it is the main cause of postoperative in‐hospital death. 13 Kinugasa et al 12 first suggested a potential negative oncological impact of postoperative pneumonia, and other studies have since reported consistent results. 14 , 15 In contrast, several studies demonstrated that PI, including pneumonia, did not affect oncological survival. 16 , 17
To obtain definitive conclusions regarding the above‐mentioned controversies, we investigated the oncological impact of SSI and pneumonia after esophageal cancer surgery using multicenter retrospective cohort data compiled by the Japan Society for Surgical Infection.
2. MATERIALS AND METHODS
2.1. Patients and eligibility
The Clinical Trial Committee of the Japan Society for Surgical Infection conducted this retrospective cohort study investigating the influence of SSI or/and pneumonia on the oncological prognosis in patients with esophageal cancer who underwent esophagectomy. Eleven centers participated in this study: eight university hospitals, two general hospitals, and one cancer center hospital.
The data of consecutive patients who underwent esophagectomy for treatment of esophageal cancer from 1 April 2013 to 31 March 2015 were extracted from the medical records in each center. The inclusion criteria were (1) histologically proven pathological stage I/II/III esophageal cancer and (2) curative primary tumor resection performed by open esophagectomy or MIE. Patients with more than one active cancer, missing or insufficient survival data, or a short follow‐up period of <6 ydmo were excluded because these factors could interfere with investigation of the direct association between PI and oncological survival. Data were collected for the following variables of interest: patient and tumor demographics, blood test results just prior to surgery (within 2 wk before surgery), and surgical procedures and outcomes. The prognostic nutritional index (PNI) was calculated with the following equation: ((10 × serum albumin (g/dL)) + (0.005 × total lymphocyte count)).
This study protocol was approved by the Ethics Committee of Nippon Medical School Tama Nagayama Hospital (Approval No. 694), and the study was conducted in accordance with the Declaration of Helsinki. The requirement for written informed consent from patients was waived because this study was retrospective.
2.2. Definitions of SSI and pneumonia
The incidences of SSI and pneumonia occurring with 30 postoperative days were recorded. SSI was defined according to the Centers for Disease Control and Prevention. 18 SSI comprised superficial SSI, deep SSI, and organ/space SSI. 18 AL was diagnosed based on the computed tomography, esophagography, or esophagoscopy findings and/or the characteristics of the anastomotic drainage fluid. AL was categorized as organ/space SSI. Pneumonia was defined as new lung infiltrates with clinical evidence of an infectious origin, including new‐onset fever, purulent sputum, leukocytosis, and a decline in oxygenation. 2 The severity of SSI and pneumonia was categorized using the Clavien–Dindo (CD) system. 19 The primary hypothesis of this study was that the occurrence of SSI could be a prognostic factor for patients with esophageal cancer. To investigate this hypothesis, we divided the patients into two groups for analysis: patients who developed SSI (SSI group) and those who did not (No‐SSI group). The secondary hypothesis was that the occurrences of pneumonia and overlapping SSI and pneumonia could also be prognostic factors.
2.3. Survival data
Relapse‐free survival (RFS) was calculated as the duration between surgery and diagnosis of relapse. If a patient died without a diagnosis of relapse, the patient's data were censored as of the time of death. Overall survival (OS) was calculated as the duration between surgery and death of any cause, including causes other than esophageal cancer.
2.4. Data analysis and statistics
All statistical analyses were performed using BellCurve for Excel (Social Survey Research Information Co., Tokyo, Japan). Quantitative results are expressed as median with interquartile range (IQR). Differences between the groups were examined for statistical significance by Student's t‐test with Yates correction. The χ 2 test and Fisher's exact test were used to compare discrete variables. Survival curves were plotted using the Kaplan–Meier method, and the curves were compared using the log‐rank test. Bonferroni's correction was applied to control for multiple comparisons. To identify the risk factors for SSI and pneumonia, multivariate logistic regression was applied using dichotomized variables that had been identified as statistically significant in the univariate analysis. A univariate analysis and a multivariate analysis comprising variables with a P‐value of < 0.05 in the univariate analysis for Cox proportional hazards models were used to examine the association between the selected variables and RFS or OS.
3. RESULTS
3.1. Characteristics of the study cohort
A total of 407 patients with pStage I/II/II esophageal cancer who underwent esophagectomy from April 2013 to March 2015 at 11 centers were ultimately included in this cohort study. The tumor stage was based on the Japanese Classification of Esophageal Cancer, 11th Edition. 20 The 407 patients were divided into the No‐SSI group [n = 317 (77.9%)] and SSI group [n = 90 (22.1%)]. The clinicopathological characteristics of all patients are shown in Table 1. Their median age was 69 years (IQR, 62–73 years), and most patients were male (88.2%). MIE was performed in 77.0% of the patients. Forty‐one percent of the patients received neoadjuvant therapy. The median follow‐up period was 58.2 mo (IQR, 17.7–76.7 mo). In the comparison between the No‐SSI and SSI groups, the SSI group had a significantly higher prevalence of men (P = 0.041) and patients with an American Society of Anesthesiologists (ASA) score of III (P = 0.024), diabetes mellitus (P = 0.021), cardiovascular disease (P = 0.003), neoadjuvant therapy (P = 0.029), or postoperative pneumonia (P = 0.021). Values of preoperative blood tests including hemoglobin, albumin, and PNI had no significant differences between the two groups. The postoperative hospital stay was significantly longer in the SSI group than in the No‐SSI group (P < 0.001).
TABLE 1.
Clinicopathological characteristics
| Variables | All (n = 407) | No‐SSI (n = 317) | SSI (n = 90) | P value |
|---|---|---|---|---|
| Age (years) a | 69 (62–73) | 69 (62–73) | 70 (64–74) | 0.166 |
| Sex (male: female) | 359 (88.2): 48 (11.8) | 274 (86.4): 43 (13.6) | 85 (94.4): 5 (5.6) | 0.041 |
| Body mass index (kg/m2) a | 21.5 (19.2–23.7) | 21.5 (19.1–23.5) | 21.8 (19.8–24.0) | 0.078 |
| Location (cervical: thoracic: abdominal) (%) | 10 (2.5): 357 (87.7): 40 (9.8) | 7 (22.1): 282 (89.0): 28 (8.8) | 3 (3.3): 75 (83.3): 12 (13.3) | 0.309 |
| ASA score (I, II / III) (%) | 318 (92.7): 25 (7.3) | 249 (94.7) / 14 (5.3) | 69 (86.3) / 11 (13.8) | 0.024 |
| Diabetes mellites (yes: no) (%) | 54 (13.3): 353 (86.7) | 35 (11.0) / 282 (89.0) | 19 (21.1) / 71 (78.9) | 0.021 |
| Cerebrovascular disease (yes: no) (%) | 34 (8.4): 373 (91.6) | 29 (9.1): 288 (90.9) | 5 (5.6): 85 (94.4) | 0.388 |
| Cardiovascular disease (yes: no) (%) | 61 (15.0): 345 (85.0) | 38 (12.0): 278 (88.0) | 23 (25.6): 67 (74.4) | 0.003 |
| Pulmonary disease (yes: no) (%) | 24 (5.9): 383 (94.1) | 18 (5.7) / 299 (94.3) | 6 (6.7) / 84 (93.3) | 0.800 |
| Smoking (yes: no) (%) | 260 (50.6): 140 (49.4) | 202 (63.7) / 109 (36.3) | 58 (64.4) / 31 (34.4) | 1.000 |
| Surgical approach (open: MIE) (%) | 96 (23.0): 311 (77.0) | 77 (24.3): 240 (75.7) | 19 (21.1): 71 (78.9) | 0.576 |
| Operation time (min) a | 482 (384–581) | 486 (372–590) | 469 (409–540) | 0.543 |
| Blood loss (ml) a | 250 (102–471) | 250 (101–470) | 236 (113–507) | 0.755 |
| Blood transfusion (yes: no) (%) | 68 (16.9): 335 (83.1) | 49 (15.7): 264 (84.3) | 19 (21.1): 71 (78.9) | 0.263 |
| Lymph node dissection (two / three field) b (%) | 76 (22.2): 266 (77.8) | 61 (23.0) / 204 (77.0) | 15 (19.5) / 62 (80.5) | 0.640 |
| Neoadjuvant therapy (yes: no) (%) | 168 (41.3): 239 (58.7) | 121 (38.8): 191 (61.2) | 47 (52.2): 43 (47.8) | 0.029 |
| Pathological stage (I, II / III) b (%) | 256 (62.9): 151 (37.1) | 192 (60.6) / 125 (39.4) | 64 (71.1) / 26 (28.9) | 0.083 |
| Hemoglobin (g/dl) a | 12.7 (11.4–13.8) | 12.6 (11.2–13.7) | 13.0 (11.7–13.8) | 0.099 |
| Albumin (g/dl) a | 4.0 (3.8–4.3) | 4.0 (3.8–4.3) | 4.0 (3.7–4.3) | 0.202 |
| PNI | 48.7 (44.9–51.9) | 49.1 (45.5–52.0) | 46.8 (43.8–50.8) | 0.125 |
| SCC (ng/dl) a | 1.1 (0.8–1.7) | 1.1 (0.8–1.7) | 1.3 (0.8–2.0) | 0.515 |
| CYFRA (ng/dl) a | 1.8 (1.2–2.8) | 1.7 (1.2–2.8) | 2.1 (1.4–2.9) | 0.521 |
| Postoperative pneumonia (yes: no) | 65 (16.0): 342 (84.0) | 43 (13.6): 274 (86.4) | 21 (24.1): 66 (75.9) | 0.021 |
| Postoperative hospital stay (d) | 24 (17–41) | 22 (16–30) | 45 (34–65) | <0.001 |
Abbreviations: ASA, American Society of Anesthesiologists; CYFRA, cytokeratin 19 fragment; MIE, minimally invasive esophagectomy; PNI, prognostic nutritional index; SCC, squamous cell carcinoma; SSI, surgical site infection.
Median (interquartile range).
Japanese Classification of Esophageal Cancer, 11th edition.
Table 2 shows the details of the postoperative complications. Among the different types of SSI, organ/space SSI (including AL) was the most common (19.2%), followed by deep SSI (10.6%) and superficial SSI (6.6%). Pneumonia accounted for 16.0% of postoperative complications, and overlapping SSI and pneumonia accounted for 5.4%.
TABLE 2.
Details of postoperative complications
| Types of complication | Incidence |
|---|---|
| SSI | 90 (22.1) |
| Superficial SSI | 27 (6.6) |
| Deep SSI | 43 (10.6) |
| Organ/space SSI | 78 (19.2) |
| Anastomotic leakage | 70 (17.2) |
| Pneumonia | 65 (16.0) |
| SSI and pneumonia (overlapped) | 22 (5.4) |
| Severity of all complications a | |
| Clavien–Dindo grading | |
| ≧II | 173 (45.2) |
| ≧III | 125 (32.6) |
Note: Data are presented as n (%).
Abbreviation: SSI, surgical site infection.
Including both infectious and noninfectious complications.
3.2. Risk factors for SSI and pneumonia
The results of the multivariate logistic analyses for SSI and pneumonia are shown in Table 3. Among the variables with statistical significance in the univariate analysis and subsequently entered into the multivariate analyses, the presence of diabetes mellitus and an ASA score of III were identified as independent predictive factors for both SSI (diabetes mellitus: odds ratio [OR], 2.20; 95% confidence interval [CI], 1.11–4.36 and ASA score of III: OR, 2.49; 95% CI, 1.03–6.03) and pneumonia (diabetes mellitus: OR, 2.59; 95% CI, 1.25–5.37 and ASA score of III: OR, 3.38; 95% CI, 1.40–8.20).
TABLE 3.
Multivariate logistic regression analysis for surgical site infection and pneumonia
| Variables | Odds ratio | 95% Confidence interval | P value |
|---|---|---|---|
| Surgical site infection | |||
| Sex | |||
| Male vs female | 2.75 | 1.00–7.58 | 0.051 |
| Diabetes mellitus | |||
| Yes vs no | 2.20 | 1.11–4.36 | 0.024 |
| Cardiovascular disease | |||
| Yes vs no | 1.13 | 0.79–1.63 | 0.506 |
| ASA score | |||
| III vs I/II | 2.49 | 1.03–6.03 | 0.043 |
| Neoadjuvant therapy | |||
| Yes vs no | 1.59 | 0.95–2.68 | 0.081 |
| Pneumonia | |||
| Diabetes mellitus | |||
| Yes vs no | 2.59 | 1.25–5.37 | 0.010 |
| Albumin (per 1 g/dL increase) | 0.62 | 0.32–1.18 | 0.146 |
| Surgical approach | |||
| Open vs MIE | 1.42 | 075–2.68 | 0.280 |
| ASA score | |||
| III vs I/II | 3.38 | 1.40–8.20 | 0.007 |
| Blood transfusion | |||
| Yes vs no | 1.66 | 0.84–3.26 | 0.143 |
Abbreviations: ASA, American Society of Anesthesiologists; MIE, minimally invasive esophagectomy.
3.3. Survival impact of SSI and pneumonia
During the follow‐up period, 194 patients (47.7%) died totally. Primary cancer deaths, other cancer deaths, other disease deaths, and deaths of unknown reason accounted for 111 (27.3%), 4 (1.0%), 46 (11.3%), and 33 (8.1%), respectively. The Kaplan–Meier curves for RFS and OS in patients with or without SSI are shown in Figure 1A,B. The 5‐y RFS rate in the No‐SSI and SSI groups was 54.4% and 40.7%, respectively, and the OS rate was 60.0% and 40.2%, respectively. The SSI group had significantly worse RFS and OS than the No‐SSI group (P = 0.014 and P < 0.001, respectively). The Kaplan–Meier curves for RFS and OS in patients with or without pneumonia are shown in Figure S2A,B. The pneumonia group had significantly worse RFS and OS than the No‐pneumonia group (P = 0.012 and P = 0.003, respectively). In the multivariate Cox proportional hazards models, three‐field lymph node dissection, neoadjuvant therapy, pStage III cancer, albumin concentration, and SSI were significantly associated with RFS (hazard ratios [HR]: 0.589, 0.640, 2.412, 0.574, and 1.628; 95% CI: 0.413–0.841, 0.457–0.897, 1.738–3.366, 0.403–0.819, and 1.121–2.364; P values: 0.004, 0.010, <0.001, 0.002, and 0.010, respectively) after adjusting for each patient characteristic. An ASA score of III, pStage III cancer, albumin concentration, and SSI were significantly associated with OS (HRs: 2.547, 2.784, 0.499, and 2.057; 95% CIs: 1.435–4.519, 1.946–3.881, 0.338–0.735, and 1.409–3.005; P values: 0.0014, <0.001, <0.001, and <0.001, respectively). In contrast, pneumonia was not associated with either RFS or OS in the multivariate analyses (Table 4).
FIGURE 1.
Kaplan–Meier curves for (A) relapse‐free survival and (B) overall survival according to the presence or absence of surgical site infection. SSI, surgical site infection
TABLE 4.
Univariate and multivariate Cox proportional hazard models for relapse‐free survival and overall survival
| Variables | Relapse‐free survival | Overall survival | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Univariate | Multivariate | Univariate | Multivariate | |||||||||
| Hazard ratio | 95% CI | P value | Hazard ratio | 95% CI | P value | Hazard ratio | 95% CI | P value | Hazard ratio | 95% CI | P value | |
| Age (≥75 vs <75) | 1.343 | 0.974–1.852 | 0.072 | 1.618 | 1.171–2.235 | 0.004 | 1.364 | 0.908–2.047 | 0.135 | |||
| Sex (male vs female) | 1.433 | 0.894–2.298 | 0.135 | 1.515 | 0.921–2.492 | 0.102 | ||||||
| Body mass index (≤21.5 vs >21.5 kg/m2) a | 1.172 | 0.892‐1.539 | 0.255 | 1.215 | 0.916–1.610 | 0.177 | ||||||
| ASA score (III vs I/II) | 2.209 | 1.367–3.568 | 0.001 | 1.682 | 0.981–2.882 | 0.059 | 2.784 | 1.718–4.510 | <0.001 | 2.547 | 1.435–4.519 | 0.0014 |
| Diabetes mellitus | 1.192 | 0.805–1.764 | 0.382 | 1.323 | 0.892–1.964 | 0.164 | ||||||
| Cerebrovascular disease | 1.064 | 0.663–1.705 | 0.798 | 0.894 | 0.536–1.491 | 0.667 | ||||||
| Cardiovascular disease | 0.995 | 0.773–1.280 | 0.966 | 1.014 | 0.783–1.313 | 0.915 | ||||||
| Pulmonary disease | 1.465 | 0.879–2.442 | 0.143 | 1.514 | 0.893–2.566 | 0.124 | ||||||
| Smoking | 0.981 | 0.735–1.310 | 0.896 | 1.070 | 0.791–1.448 | 0.661 | ||||||
| Surgical approach (open vs MIE) | 1.013 | 0.734–1.393 | 0.938 | 1.147 | 0.835–1.577 | 0.396 | ||||||
| Operation time (≥482 vs <482 min) a | 1.127 | 0.858–1.480 | 0.391 | 0.966 | 0.729–1.281 | 0.811 | ||||||
| Blood loss (≥250 vs <250 ml) a | 1.067 | 0.812–1.401 | 0.643 | 1.011 | 0.763–1.340 | 0.939 | ||||||
| Blood transfusion | 1.395 | 0.996–1.953 | 0.053 | 1.397 | 0.985–1.980 | 0.061 | ||||||
| Lymph node dissection (three vs two field) | 0.648 | 0.467–0.899 | 0.010 | 0.589 | 0.413–0.841 | 0.004 | 0.749 | 0.534–1.051 | 0.095 | |||
| Neoadjuvant therapy | 0.683 | 0.512–0.909 | 0.009 | 0.640 | 0.457–0.897 | 0.010 | 0.775 | 0.578–1.038 | 0.088 | |||
| Pathological stage (III vs I/II) b | 2.902 | 2.203–3.823 | <0.001 | 2.412 | 1.738–3.366 | <0.001 | 2.613 | 1.967–3.469 | <0.001 | 2.748 | 1.946–3.881 | <0.001 |
| Hemoglobin (g/dl) | 0.882 | 0.775–1.003 | 0.055 | 0.904 | 0.834–0.981 | 0.015 | 0.976 | 0.882–1.081 | 0.647 | |||
| Albumin (g/dl) | 0.533 | 0.394–0.719 | <0.001 | 0.574 | 0.403–0.819 | 0.002 | 0.497 | 0.368–0.671 | <0.001 | 0.499 | 0.338–0.735 | <0.001 |
| SCC (>2.5 vs ≤2.5 ng/dl) c | 1.433 | 0.708‐2.897 | 0.317 | 1.947 | 1.304–2.908 | 0.011 | 1.214 | 0.756–1.950 | 0.421 | |||
| CYFRA (>3.5 vs ≤3.5 ng/dL ng/dl) c | 1.162 | 0.710–1.902 | 0.550 | 1.019 | 0.608–1.708 | 0.942 | ||||||
| SSI | 1.476 | 1.081–2.015 | 0.014 | 1.628 | 1.121–2.364 | 0.010 | 1.775 | 1.294–2.434 | <0.001 | 2.057 | 1.409–3.005 | <0.001 |
| Pneumonia | 1.579 | 1.121–2.225 | 0.009 | 1.170 | 0.797–1.718 | 0.423 | 1.674 | 1.185–2.366 | 0.004 | 1.036 | 0.679–1.582 | 0.868 |
Abbreviations: ASA, American Society of Anesthesiologists; CI, confidence intervak; CYFRA, cytokeratin 19 fragment; MIE, minimally invasive esophagectomy; SCC, squamous cell carcinoma; SSI, surgical site infection.
Median values were used for the cutoffs.
Japanese Classification of Esophageal Cancer, 11th edition.
Reference values were used for the cutoffs.
3.4. Sole survival impact of SSI and pneumonia
To investigate the sole survival impact of SSI and pneumonia, the patients were classified into four groups: No‐SSI and No‐pneumonia (n = 274), SSI only (n = 68), pneumonia only (n = 43), and SSI plus pneumonia (n = 22). In the RFS analyses, although no comparisons between the groups reached statistical significance, the SSI plus pneumonia group tended to have worse RFS than the No‐SSI and No‐pneumonia group (P = 0.062) (Figure 2A). In the OS analyses, the SSI only group and the SSI plus pneumonia group had significantly worse OS than the No‐SSI and No‐pneumonia group (P = 0.018 and P = 0.002, respectively) (Figure 2B). In both analyses, the presence of pneumonia alone had no survival impact.
FIGURE 2.
Kaplan–Meier curves for (A) relapse‐free survival and (B) overall survival to evaluate sole oncological impact of surgical site infection and pneumonia. *P < 0.05 by Bonferroni's correction. SSI, surgical site infection
3.5. Survival impact of severity of SSI
To investigate the survival impact of SSI severity, the patients were divided into two groups: CD grade ≥III SSI (n = 63) and CD grade <III SSI (n = 23). All individual superficial and deep SSI were categorized as Clavien–Dindo (CD) grade I or II. In contrast, 80.7% (63/78) patients of organ/space SSI, of which anastomotic leakage constitutes the majority (89.7%), were categorized as CD ≥III. Four patients with missing data regarding the details of SSI were excluded. RFS and OS were significantly worse in the patients with CD grade ≥III than <III SSI (P = 0.017 and P = 0.015, respectively) (Figure 3A,B).
FIGURE 3.
Kaplan–Meier curves for (A) relapse‐free survival and (B) overall survival according to the severity of surgical site infection. CD, Clavien–Dindo; SSI, surgical site infection
3.6. Subgroup analysis
The patients were classified into selected subgroups, and the impact of SSI on RFS is shown in Figure 4. Age of <75 years, male sex, low body mass index, MIE, ASA score of III, two‐field lymph node dissection, no neoadjuvant therapy, and pStage ≤II cancer were associated with a statistically significant negative impact of SSI on RFS. In other words, three‐field lymph node dissection and neoadjuvant therapy canceled out the negative oncological impact of SSI on RFS. The Kaplan–Meier curves for RFS in patients with pStage ≤II and III cancer according to the presence or absence of SSI are shown in Figure S1A,B.
FIGURE 4.
Subgroup analysis for relapse‐free survival. ASA, American Society of Anesthesiologists; BMI, body mass index; DM, diabetes mellitus; MIE, minimally invasive esophagectomy
4. DISCUSSION
In this multi‐institutional retrospective study comprising 402 patients with stage I/II/III esophageal cancer, we found that the presence of SSI, rather than postoperative pneumonia, had a negative impact on both RFS and OS after curative surgery. Furthermore, the combination of SSI and pneumonia and the presence of severe SSI had profound negative oncological impacts. Diabetes mellitus and an ASA score of III were independent predictive factors for both SSI and pneumonia.
Recently, the most updated data of short‐term outcomes after gastroenterological surgery in Japan using the National Clinical Database (NCD) between 2011 and 2019 was published. 21 The real‐world data in Japan demonstrated that the rate of major postoperative complications (i.e. Clavien–Dindo grade ≧III) after esophagectomy is slightly increasing toward 2019 (22.8% in 2019), and the rate of 30‐day mortality is decreasing gradually (0.9% in 2019). Although the rate of major postoperative complications, 32.6%, was relatively higher in our study, but the mortality, 0.9%, is equivalent compared with the NCD data. SSI is among the most common postoperative complications after gastroenterological surgeries, and its incidence rate ranges from 4.0% to 24.0%, depending on the series. 22 For esophageal surgery, the national survey data in 2016 showed an SSI incidence rate of 19.4%, 5 and a retrospective study conducted by the Japan Society for Surgical Infection revealed a PI incidence rate of 20.1%. 5 , 22 These rates are very similar to the SSI frequency of 22.1% in the present study.
Recently, several international guidelines including Japan for the prevention of SSI were published and updated, 4 which implies that the importance of recognizing, preventing, and managing SSIs has received increased attention. We believe that it is more important to consider SSI as a whole in a comprehensive manner than to consider anastomotic leakage alone, in terms of many aspects such as medical economics and patients' quality of life. Therefore, we included all SSIs other than anastomotic leakage in this study.
Not only poor short‐term outcomes, such as a longer hospital stay, decreased quality of life, and increased medical costs, but also poor long‐term outcomes of SSI have been reported after various gastroenterological cancer surgeries. 23 , 24 However, the impact of PI on the long‐term outcomes of patients with esophageal cancer who have undergone esophagectomy remains controversial. A recent meta‐analysis of 11 368 patients by Booka et al 8 demonstrated that post‐esophagectomy PIs, such as pulmonary complications and AL, were associated with decreased long‐term survival. However, 6 of the 13 studies that were included in the OS analysis of all complications showed no significant oncological impact. 8 The subanalysis from the JCOG9907 trial showed that the OS of patients with AL was almost equivalent to that of patients without AL. 11 A study of 1063 patients from a single high‐volume center by Kamarajah et al 6 demonstrated that AL leads to prolonged critical care and a longer hospital stay, but that it does not compromise long‐term outcomes and is unlikely to have a detrimental oncological impact. One plausible reason for the heterogeneity between studies is the long patient inclusion period in previous studies, which affects the difference in treatment efficacy in neoadjuvant settings 25 and for patients with metastasis because of the dramatic improvements in chemotherapeutic drugs, molecular‐targeted agents, and immune‐checkpoint inhibitors over time. 26 Our patient inclusion period was only 2 years, which might have decreased the confounding effect of treatment improvement with time.
One of the characteristics of esophageal cancer surgery that distinguishes it from other types of cancer surgery is the more frequent occurrence of pneumonia, which is not categorized as an SSI, 13 and the particular pathophysiology of PI after esophagectomy may thus make it difficult to obtain consistent results. Therefore, we clearly discriminated PI as either SSI or pneumonia and analyzed the two conditions separately in this study. To the best of our knowledge, no other studies to date have evaluated the oncological impact of SSI itself after esophagectomy. However, SSI includes wide‐ranging disease types and severities, and this variation could confound the results. To evaluate the magnitude of the oncological impact associated with SSI severity, we divided the patients into those with or without major SSI (CD grade ≥ III) and found significantly worse RFS and OS in patients with major SSI. Bundred et al 27 performed a detailed investigation of the oncological impact of postoperative complications after esophagectomy depending on the severity. The authors found that CD grade I complications had no survival impact, but that an increasing severity of complications was associated with decreased OS. 27 However, assessment of the oncological impact depending on the respective type of SSI was relatively difficult in our study because many patients with SSI also had concurrent pneumonia, and exclusion of these patients decreased the respective sample sizes of patients with SSI alone and pneumonia alone. Hence, a future large‐scale study is warranted to address this issue.
Although pneumonia was not identified as an independent prognostic factor for both RFS and OS in our study cohort, other studies have revealed significant associations; thus, the impact of pneumonia remains uncertain. A recent study by Tanaka et al 28 focused on how the timing of pneumonia occurrence affects the oncological impact and showed that acute‐phase pneumonia (occurring within 7 days after esophagectomy) was an independent prognostic factor, whereas subacute pneumonia was not. As a possible explanation, the authors considered that pneumonia in the acute but not subacute phase is associated with an exaggerated systemic inflammatory response that may help shed cancer cells or residual minimal cancer cells to survive and escape the immune response; this would lead to the induction of tumor implantation and growth. 28 In this study, the clear mechanism of the significant negative oncological impact of SSI, not of pneumonia, in the multivariate analyses is uncertain. However, plausible reasons were as follows. First, the diagnosis of pneumonia is actually difficult, and the definition of pneumonia might differ among institutions, which could lead to the overdiagnosis for borderline pulmonary lesions, such as atelectasis. Second, information regarding the onset time of pneumonia was not available in this study cohort. Subacute onset pneumonia, which has less negative oncological impact, as mentioned above, 28 may account for a certain number of pneumonia patients. Third, anastomotic leakage is the most frequent and important SSI and sometimes requires invasive surgical repair or, if unsuccessful, esophageal diversion, which prolongs hospitalization and delays oral hydration and nutrition. It is worthy of consideration as a mechanism that sustained compromise of nutrition by anastomotic leakage can weaken immune function and make the host more susceptible to cancer recurrence more than pneumonia.
Our data of univariate analysis showed that neoadjuvant therapy was associated with a high susceptibility for SSI, not pneumonia. Among the types of SSIs, only superficial SSI had no significant difference, but others such as deep, organ/space SSIs, and anastomotic leakage were significantly higher in patients with neoadjuvant therapy compared with patients without it, but the clear mechanism is uncertain. Recently, sarcopenia, which is characterized as skeletal muscle loss, has a strong negative impact on the short‐ and long‐term in cancer surgery. 29 Motoori et al 30 demonstrated that skeletal muscle loss induced by neoadjuvant chemotherapy is a significant risk factor for PI in patients with esophageal cancer. Focusing on sarcopenia during neoadjuvant therapy could be an effective intervention for the SSI prevention.
The negative oncological impact of SSI shown in this study prompts many mechanistic speculations and clinically significant suggestions for improvement of treatment results. A well‐known explanation is delayed or abandoned postoperative adjuvant chemotherapy in patients with SSI. Tsujimoto et al 31 reported that the number of treatment cycles and relative dose intensity of adjuvant chemotherapy in patients with gastric cancer were significantly lower in patients with than without PI and that only PI was significantly associated with discontinuation of adjuvant chemotherapy. However, this theory is not necessarily applicable to esophageal cancer surgery, for which neoadjuvant therapy was recently standardized (41% of all patients in our study cohort underwent neoadjuvant therapy). Notably, our subgroup analysis showed that application of neoadjuvant therapy canceled out the significant negative impact of SSI on RFS (Figure 4). Kano et al 32 performed an in‐depth analysis of patients with esophageal cancer and found that the response to neoadjuvant chemotherapy determines the magnitude of the negative oncological impact of PI. Additionally, a more advanced pathological stage resulted in a weaker negative impact of SSI on RFS. This is consistent with a study by Booka et al 33 demonstrating that the significant negative impact of pneumonia on OS in patients with Stage I cancer disappeared in those with Stage II/III/IV cancer. This could be explained by the fact that most patients with advanced‐stage cancer have more severe immunological deterioration than patients with early‐stage cancer, drowning out the negative effect of SSI on antitumor immunity.
Because SSI was independently predictive of both RFS and OS, it follows that reducing the likelihood of SSI may improve survival. Diabetes mellitus and an ASA score of III were independently associated with SSI in our study, but the complete elimination of these factors is hardly possible. During the past decade, high compliance with systemic approaches, or bundles, has been demonstrated to reduce the risk of SSI. 34 Importantly, it has been estimated that ~50% of SSIs can be prevented by implementation of evidence‐based preventative strategies. 35 Recent studies have focused on preoperative steroid administration, 36 prehabilitation, 37 and enhanced recovery after surgery programs 38 to improve short‐term outcomes after esophagectomy. Our study emphasizes the importance of seeking effective prospective interventions with the aim of avoiding SSI, which can deteriorate patients' overall prognosis.
Our study was limited by its retrospective nature; therefore, there might have been unmeasurable confounding factors that could have influenced the study results. Other major postoperative complications, such as chylothorax and recurrent nerve palsy, were not investigated in our study because these non‐PIs were outside our target. Additionally, detailed information regarding the regimens and dose intensity of neoadjuvant therapy was not available. Factors that can be associated with PI occurrence, such as prophylactic antibiotics, perioperative steroid use, and nutritional management were not collected in detail on all patients. However, basic perioperative management policies at each institution did not differ significantly, which is shown in Figure S3. Specifically, cefazoline was used in nine institutions for prophylactic antibiotics among 11 institutions included in this study. Enteral nutrients were administrated in 10 institutions and enterostomy was created intraoperatively in nine institutions. Pneumonia is generally categorized as a remote infection, which occurs in areas not directly subjected to surgical manipulation; such infections include antimicrobial‐associated enteritis, urinary tract infection, and catheter‐related bloodstream infections other than pneumonia. Patients with remote infections other than pneumonia accounted for only 4.68% (19 patients) in this cohort, and these patients were not analyzed because our focus was on the clinical importance of pneumonia.
In conclusion, our study demonstrated that SSI, rather than pneumonia, after esophagectomy was associated with impaired oncological outcomes. Further progress in the development of strategies for SSI prevention may improve the quality of care and oncological outcomes in patients undergoing curative esophagectomy.
AUTHOR CONTRIBUTIONS
Conception/design (Matsuda A, Maruyama H, Akagi S, Inoue T, Uemura K, Kobayashi M, Shiomi H, Watanabe M); data acquisition (all authors); data interpretation (all authors); critical revision (all authors); final approval (all authors).
FUNDING INFORMATIONS
This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.
CONFLICT OF INTEREST
Y. Kitagawa received designated donations from Chugai Pharmaceutical Co., Ltd.; TAIHO Pharmaceutical Co., Ltd.; ASAHI KASEI Pharma Corporation; Otsuka Pharmaceutical Factory Inc.; ONO Pharmaceutical Co., Ltd.; SHIONOGI & Co., Ltd.; Nippon Covidien Inc.; AstraZeneca K.K.; Ethicon Inc.; Bristol‐Myers Squibb K.K.; Olympus Corporation; MSD K.K.; Smith & Nephew K.K.; KAKEN Pharmaceutical Co., Ltd.; ASKA Pharmaceutical Co., Ltd.; Miyarisan Pharmaceutical Co., Ltd.; Yakult Honsha Co., Ltd.; TSUMURA & Co.; DAINIPPON SUMITOMO Pharma Co., Ltd.; EA Pharma Co., Ltd.; Eisai Co., Ltd.; MEDICON Inc.; Kyowa Hakko Kirin Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; Toyama Chemical Co., Ltd.; Asellas Pharma Inc.; TEIJIN Pharma Limited; and Nihon Pharmaceutical Co., Ltd. His institution has endowed chairs of Chugai Pharmaceutical Co., Ltd. and TAIHO Pharmaceutical Co., Ltd. H. Tsujimoto and Y. Kitagawa are an editorial board member and a chief editor of the Annals of Gastroenterological Surgery, respectively. They were not involved in the editorial responsibilities or decision to accept this article for publication.
ETHICS STATEMENTS
Approval of Research Protocol: The protocol for this study was approved by the Ethics Committee of Nippon Medical School Tama Nagayama Hospital (Approval No. 694).
Informed Consent: N/A.
Registry and Registration Number: N/A.
Animal Studies: N/A.
Supporting information
Figure S1.
Figure S2.
Figure S3.
ACKNOWLEDGMENTS
The authors extend their deep appreciation to Prof. Shinya Kusachi, immediate past president of the Japan Society for Surgical Infection, and Prof. Kazuo Tanemoto, director of the Clinical Trial Committee of the Japan Society for Surgical Infection, for their considerable cooperation. The authors also thank Angela Morben, DVM, ELS, from Edanz (https://jp.edanz.com/ac), for editing a draft of this article.
Matsuda A, Maruyama H, Akagi S, Inoue T, Uemura K, Kobayashi M, et al. Survival impact of surgical site infection in esophageal cancer surgery: A multicenter retrospective cohort study. Ann Gastroenterol Surg. 2023;7:603–614. 10.1002/ags3.12656
[Correction added on 19 January 2023, after first online publication: The copyright line has been corrected.]
DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors without undue reservation.
REFERENCES
- 1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33. [DOI] [PubMed] [Google Scholar]
- 2. Low DE, Kuppusamy MK, Alderson D, Cecconello I, Chang AC, Darling G, et al. Benchmarking complications associated with esophagectomy. Ann Surg. 2019;269(2):291–8. [DOI] [PubMed] [Google Scholar]
- 3. Takeuchi H, Miyata H, Gotoh M, Kitagawa Y, Baba H, Kimura W, et al. A risk model for esophagectomy using data of 5354 patients included in a Japanese nationwide web‐based database. Ann Surg. 2014;260(2):259–66. [DOI] [PubMed] [Google Scholar]
- 4. Matsuda A, Yamada T, Ohta R, Sonoda H, Shinji S, Iwai T, et al. Surgical site infections in gastroenterological surgery. J Nippon Med Sch. 2022. Online ahead of print. [DOI] [PubMed] [Google Scholar]
- 5. Ministry of Health LaW . SSI division JANNIS (for the general public) annual report . 2019. https://janis.mhlw.go.jp/report/ssi.html
- 6. Kamarajah SK, Navidi M, Wahed S, Immanuel A, Hayes N, Griffin SM, et al. Anastomotic leak does not impact on long‐term outcomes in esophageal cancer patients. Ann Surg Oncol. 2020;27(7):2414–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Yoshida N, Yamamoto H, Baba H, Miyata H, Watanabe M, Toh Y, et al. Can minimally invasive esophagectomy replace open esophagectomy for esophageal cancer? Latest analysis of 24,233 esophagectomies from the Japanese National Clinical Database. Ann Surg. 2020;272(1):118–24. [DOI] [PubMed] [Google Scholar]
- 8. Booka E, Takeuchi H, Suda K, Fukuda K, Nakamura R, Wada N, et al. Meta‐analysis of the impact of postoperative complications on survival after oesophagectomy for cancer. BJS Open. 2018;2(5):276–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Saeki H, Tsutsumi S, Tajiri H, Yukaya T, Tsutsumi R, Nishimura S, et al. Prognostic significance of postoperative complications after curative resection for patients with esophageal squamous cell carcinoma. Ann Surg. 2017;265(3):527–33. [DOI] [PubMed] [Google Scholar]
- 10. Tverskov V, Wiesel O, Solomon D, Orgad R, Kashtan H. The impact of cervical anastomotic leak after esophagectomy on long‐term survival of patients with esophageal cancer. Surgery. 2022;171(5):1257–62. [DOI] [PubMed] [Google Scholar]
- 11. Kataoka K, Takeuchi H, Mizusawa J, Igaki H, Ozawa S, Abe T, et al. Prognostic impact of postoperative morbidity after esophagectomy for esophageal cancer: exploratory analysis of JCOG9907. Ann Surg. 2017;265(6):1152–7. [DOI] [PubMed] [Google Scholar]
- 12. Kinugasa S, Tachibana M, Yoshimura H, Ueda S, Fujii T, Dhar DK, et al. Postoperative pulmonary complications are associated with worse short‐ and long‐term outcomes after extended esophagectomy. J Surg Oncol. 2004;88(2):71–7. [DOI] [PubMed] [Google Scholar]
- 13. Ando N, Ozawa S, Kitagawa Y, Shinozawa Y, Kitajima M. Improvement in the results of surgical treatment of advanced squamous esophageal carcinoma during 15 consecutive years. Ann Surg. 2000;232(2):225–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Lerut T, Moons J, Coosemans W, Van Raemdonck D, De Leyn P, Decaluwe H, et al. Postoperative complications after transthoracic esophagectomy for cancer of the esophagus and gastroesophageal junction are correlated with early cancer recurrence: role of systematic grading of complications using the modified Clavien classification. Ann Surg. 2009;250(5):798–807. [DOI] [PubMed] [Google Scholar]
- 15. Rizk NP, Bach PB, Schrag D, Bains MS, Turnbull AD, Karpeh M, et al. The impact of complications on outcomes after resection for esophageal and gastroesophageal junction carcinoma. J Am Coll Surg. 2004;198(1):42–50. [DOI] [PubMed] [Google Scholar]
- 16. D'Annoville T, D'Journo XB, Trousse D, Brioude G, Dahan L, Seitz JF, et al. Respiratory complications after oesophagectomy for cancer do not affect disease‐free survival. Eur J Cardiothorac Surg. 2012;41(5):e66–73. discussion e. [DOI] [PubMed] [Google Scholar]
- 17. Lindner K, Fritz M, Haane C, Senninger N, Palmes D, Hummel R. Postoperative complications do not affect long‐term outcome in esophageal cancer patients. World J Surg. 2014;38(10):2652–61. [DOI] [PubMed] [Google Scholar]
- 18. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection, 1999. Centers for Disease Control and Prevention (CDC) hospital infection control practices advisory committee. Am J Infect Control. 1999;27(2):97–132; quiz 3‐4. discussion 96. [PubMed] [Google Scholar]
- 19. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2):205–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Japan Esophageal Society . Japanese classification of esophageal cancer, 11th edition: part I. Esophagus. 2017;14(1):1–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Marubashi S, Takahashi A, Kakeji Y, Hasegawa H, Ueno H, Eguchi S, et al. Surgical outcomes in gastroenterological surgery in Japan: report of the National Clinical Database 2011‐2019. Ann Gastroenterol Surg. 2021;5(5):639–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Niitsuma T, Kusachi S, Takesue Y, Mikamo H, Asai K, Watanabe M. Current status of postoperative infections after digestive surgery in Japan: the Japan postoperative infectious complications survey in 2015. Ann Gastroenterol Surg. 2019;3(3):276–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Artinyan A, Orcutt ST, Anaya DA, Richardson P, Chen GJ, Berger DH. Infectious postoperative complications decrease long‐term survival in patients undergoing curative surgery for colorectal cancer: a study of 12,075 patients. Ann Surg. 2015;261(3):497–505. [DOI] [PubMed] [Google Scholar]
- 24. Tsujimoto H, Ichikura T, Ono S, Sugasawa H, Hiraki S, Sakamoto N, et al. Impact of postoperative infection on long‐term survival after potentially curative resection for gastric cancer. Ann Surg Oncol. 2009;16(2):311–8. [DOI] [PubMed] [Google Scholar]
- 25. Alderson D, Cunningham D, Nankivell M, Blazeby JM, Griffin SM, Crellin A, et al. Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open‐label, randomised phase 3 trial. Lancet Oncol. 2017;18(9):1249–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, et al. Nivolumab combination therapy in advanced esophageal squamous‐cell carcinoma. N Engl J Med. 2022;386(5):449–62. [DOI] [PubMed] [Google Scholar]
- 27. Bundred JR, Hollis AC, Evans R, Hodson J, Whiting JL, Griffiths EA. Impact of postoperative complications on survival after oesophagectomy for oesophageal cancer. BJS Open. 2020;4(3):405–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Tanaka K, Yamasaki M, Kobayashi T, Yamashita K, Makino T, Saitoh T, et al. Postoperative pneumonia in the acute phase is an important prognostic factor in patients with esophageal cancer. Surgery. 2021;170(2):469–77. [DOI] [PubMed] [Google Scholar]
- 29. Jogiat UM, Sasewich H, Turner SR, Baracos V, Eurich DT, Filafilo H, et al. Sarcopenia determined by skeletal muscle index predicts overall survival, disease‐free survival, and postoperative complications in Resectable esophageal cancer: a systematic review and meta‐analysis. Ann Surg. 2022;276(5):e311–e8. [DOI] [PubMed] [Google Scholar]
- 30. Motoori M, Fujitani K, Sugimura K, Miyata H, Nakatsuka R, Nishizawa Y, et al. Skeletal muscle loss during neoadjuvant chemotherapy is an independent risk factor for postoperative infectious complications in patients with advanced esophageal cancer. Oncology. 2018;95(5):281–7. [DOI] [PubMed] [Google Scholar]
- 31. Tsujimoto H, Kouzu K, Sugasawa H, Nomura S, Ito N, Harada M, et al. Impact of postoperative infectious complications on adjuvant chemotherapy administration after gastrectomy for advanced gastric cancer. Jpn J Clin Oncol. 2021;51(3):379–86. [DOI] [PubMed] [Google Scholar]
- 32. Kano K, Aoyama T, Yoshikawa T, Maezawa Y, Nakajima T, Hayashi T, et al. The negative survival impact of infectious complications after surgery is canceled out by the response of neoadjuvant chemotherapy in patients with esophageal cancer. Ann Surg Oncol. 2018;25(7):2034–43. [DOI] [PubMed] [Google Scholar]
- 33. Booka E, Takeuchi H, Nishi T, Matsuda S, Kaburagi T, Fukuda K, et al. The impact of postoperative complications on survivals after esophagectomy for esophageal cancer. Medicine (Baltimore). 2015;94(33):e1369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Zywot A, Lau CSM, Stephen Fletcher H, Paul S. Bundles prevent surgical site infections after colorectal surgery: meta‐analysis and systematic review. J Gastrointest Surg. 2017;21(11):1915–30. [DOI] [PubMed] [Google Scholar]
- 35. Umscheid CA, Mitchell MD, Doshi JA, Agarwal R, Williams K, Brennan PJ. Estimating the proportion of healthcare‐associated infections that are reasonably preventable and the related mortality and costs. Infect Control Hosp Epidemiol. 2011;32(2):101–14. [DOI] [PubMed] [Google Scholar]
- 36. Ishiyama K, Oguma J, Kubo K, Kanematsu K, Fujii Y, Kurita D, et al. Does preoperative corticosteroid administration improve the short‐term outcome of minimally invasive esophagectomy for esophageal cancer? A propensity score‐matched analysis. Ann Surg Oncol. 2022;29(11):6886–93. [DOI] [PubMed] [Google Scholar]
- 37. Guinan EM, Dowds J, Donohoe C, Reynolds JV, Hussey J. The physiotherapist and the esophageal cancer patient: from prehabilitation to rehabilitation. Dis Esophagus. 2017;30(1):1–12. [DOI] [PubMed] [Google Scholar]
- 38. Low DE, Allum W, De Manzoni G, Ferri L, Immanuel A, Kuppusamy M, et al. Guidelines for perioperative Care in Esophagectomy: enhanced recovery after surgery (ERAS((R))) society recommendations. World J Surg. 2019;43(2):299–330. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1.
Figure S2.
Figure S3.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors without undue reservation.