Neoadjuvant treatments, comorbidity, and age
Neoadjuvant chemotherapy or chemo-radiation followed by surgery has become the standard of care in the treatment of esophageal cancer [
11,
12]. However, a recent large retrospective European multicenter study revealed a significantly higher risk of postoperative complications including AL in cardiorespiratory comorbid patients after neoadjuvant chemo-radiation, but not after neoadjuvant chemotherapy [
13,
14]. Consequently, neoadjuvant chemo-radiation should be employed with particular caution in patients with known respiratory comorbidity [
15].
Numerous comorbidities are linked to increased AL risk such as obesity, heart failure, coronary artery disease, peripheral vascular disease, hypertension, steroids, diabetes mellitus, renal insufficiency, and tobacco use [
16]. In addition, atrial fibrillation [
17] and COPD [
18] are known independent risk factors. Most comorbidities have a negative impact on microvascular perfusion, and it has been hypothesized that arteriosclerosis may play an important role in the etiology of AL [
19]. Consequently, several retrospective cohort studies have confirmed an association between AL and loco-regional post-coeliac [
20,
21] and aortic and coeliac trunk [
22] calcifications. Moreover, others have evidenced an association between AL and supra-aortic and coronary arteriosclerosis [
18], implying that general radiological arteriosclerosis scores may be useful to estimate the risk of AL [
21,
23,
24].
Besides the abovementioned factors, age may play a major role in postoperative morbidity as older patients have more comorbidities and a reduced physiological resilience [
25]. For example, older individuals have a higher probability of new-onset atrial fibrillation after esophagectomy [
26], which is a known risk factor for pneumonia and AL. In addition, in patients ≥ 75 years, the nutritional status is often impaired [
27] and the sarcopenia rate is higher [
28,
29]. However, none of the prospective cohort studies comparing younger (< 75 years) and older (≥ 75) cohorts found an association between age and postoperative morbidity or mortality [
27,
30].
In summary, several secondary illnesses and comorbidities play a pivotal role in patient outcome after esophagectomy. In order to optimize preoperative assessment of esophageal cancer patients, prediction tools using readily available characteristics have been suggested recently [
31]. Careful patient selection and thorough navigation through risks and benefits remains key for achieving optimal results.
Preoperative nutrition
Malnutrition is highly prevalent in patients with esophageal carcinoma and has been linked to a higher incidence of AL in GI-tract surgery [
32]. Consequently, nutritional support prior to surgery is associated with a reduced complication rate after esophagectomy [
33]. In this context, screening of the nutritional status in patients scheduled for esophagectomy following the ESPEN (European Society for Clinical Nutrition and Metabolism) criteria is highly recommended [
34]. Most experts agree that preoperative nutritional support is indicated if body weight loss was ≥ 10–15% over the past 6 months, and in patients with a BMI < 18.5 kg/m
2 or a serum albumin < 30 g/l [
34]. In addition, nutritionists should be involved to monitor protein and calorie intake and to assess the need for dietary supplements. In case of severe dysphagia, placement of an enteral feeding tube and preoperative nutritional support for a minimum of 7–14 days is recommended according to the ESPEN guidelines [
35,
36].
Perioperative dietary supplementation with immune-stimulating nutrients (omega-3 fatty acids, arginine, nucleotides) may reduce oxidative stress and inflammatory response. Correspondingly, perioperative immunonutrition was found to reduce postoperative morbidity in gastrointestinal cancer surgery in a systematic review of randomized controlled trials (RCTs) [
37]. However, another recent meta-analysis of RCTs with a specific focus on esophagectomy did not confirm a positive effect of immunonutrition on AL, overall morbidity, postoperative hospital stay, or immune indices such as C-reactive protein, interleukin-6, IL-8, and tumor necrosis factor-α [
38]. Therefore, immunonutrition prior to esophageal cancer surgery remains a controversial issue.
Prehabilitation
Prehabilitation is a relatively new concept that entails a variety of preoperative measures to prepare patients for surgery. Prehabilitation is part of enhanced recovery after surgery (ERAS) protocols [
39] and includes nutritional, physical, and psychological components. The physical component of prehabilitation programs entails inspiratory muscle training, aerobic exercise, and general strengthening activities. The effect of preoperative inspiratory muscle training on postoperative morbidity and AL rate remains controversial, although most research points towards a beneficial effect. The use of spirometers has been found to correlate positively with postoperative pulmonary morbidity [
40], and two RCTs and one observational study have evidenced a reduction in severe pulmonary [
41,
42] and overall complications [
43] through perioperative inspiratory muscle training. However, other randomized studies could not confirm a benefit of inspiratory muscle training [
44].
Likewise, aerobic exercises and strengthening activities during > 4 weeks prior to esophagogastric surgery had a positive impact on preoperative fitness tests, an effect that sustained for 4–8 weeks after surgery [
45]. Four RCTs on prehabilitation programs in gastroesophageal carcinoma are pending [
46‐
49]. Interestingly, an RCT comparing the effect of prehabilitation with postoperative rehabilitation after colorectal cancer surgery evidenced that a 4-week prehabilitation program was even more effective than postoperative rehabilitation [
50].