Introduction
In 2018, esophageal and gastric cancers were diagnosed in over 570.000 and 1.033.000 patients, respectively, worldwide [
1]. Only a small percentage of patients present with a gastroesophageal junction (GEJ) or cardia carcinoma, defined as a tumor involving the GEJ with the epicenter within 2 cm of the cardia (true GEJ tumor) or a tumor of the gastric cardia without esophageal involvement (cardia cancer). The actual incidence of these specific cancers, however, is unknown. The Dutch Upper Gastrointestinal (GI) Cancer audit shows that in 2018, 174 patients were operated for GEJ cancer in the Netherlands, which also includes patients with cardiac tumors [
2]. Treatment of gastroesophageal junction tumors is challenging. The therapy for these cancers usually consists of neoadjuvant chemoradiotherapy or perioperative chemotherapy followed by surgery. Different surgical approaches exist: both a total gastrectomy with a Roux-Y reconstruction or an esophagectomy with gastric tube reconstruction can be performed. An esophagectomy can be executed both transhiatally and transthoracically, with either an intrathoracic or cervical anastomosis. Additionally, the operative approach can be open, minimally invasive or hybrid. There is no substantial evidence which is the preferred procedure in terms of postoperative morbidity, mortality, pathology, health-related quality of life (HR-QoL), survival or health-care costs [
3‐
6]. In addition, the results could be conflicting for the different outcome parameters: an esophagectomy might result in a better long-term survival at the cost of a worse quality of life compared to a gastrectomy or vice versa. Furthermore, not all patients value these outcome parameters the same, as for some patients, survival is more important and for others quality of life. These issues complicate surgical decision making even more.
Functional complaints after Upper GI surgery such as reflux and nausea are common, posing a challenge in maintaining QoL. Therefore, it is of great importance to examine the effects of these operations in terms of functional complaints and HR-QoL in addition to short-term morbidity and long-term survival.
Few studies compared QoL following a total gastrectomy and a transthoracic esophagectomy using different HR-QoL questionnaires [
7‐
10]. Three out of four of these studies show better HR-QoL after a total gastrectomy, with better global health, role, social functioning and less fatigue [
8], better physical functioning and less dyspnea and reflux [
9] and less gastrointestinal symptoms [
7]. The follow-up time in these studies varied from three months to 2 years. However, these studies had either a low response rate (34.5% and 52.5%) [
9,
10] or a small sample size (
N = 27 and
N = 53) [
7,
8], and patients with a distal esophageal cancer were not excluded [
8]. The aim of this study was to investigate the differences in long-term HR-QoL domains in a large series of patients with a true GEJ or cardia carcinoma undergoing a total gastrectomy with a Roux-Y reconstruction versus a transthoracic esophagectomy with gastric tube reconstruction with an intrathoracic anastomosis (Ivor Lewis) in a tertiary referral center.
Discussion
This study describes the difference in long-term quality of life in disease-free patients who underwent either a total gastrectomy or an Ivor Lewis esophagectomy for GEJ or cardia cancer. We found no significant difference in the primary endpoint HR-QoL domains ‘problems with eating,’ ‘reflux’ and ‘nausea and vomiting.’ Of the secondary HR-QoL endpoints, significantly less ‘problems with choking when swallowing’ and ‘coughing’ were found after gastrectomy. These differences were also clinically relevant. No significant differences were found in the occurrence and grade of postoperative complications. Furthermore, more lymph nodes were resected during esophagectomy with an equal number of positive lymph nodes and an equal R0 resection rate.
In the few studies on long-term HR-QoL in patients with GEJ carcinoma after esophagectomy or gastrectomy, an overall decrease in HR-QoL was observed after esophagogastric surgery, which restored within 6–12 months in disease-free patients [
10,
23‐
25]. Generally, better global health and functional outcomes such as role and social functioning are found after a total gastrectomy compared to esophagectomy [
8]. Also less fatigue, pneumonia and reflux-related symptoms are found after gastrectomy compared to esophagectomy [
8,
9]. Our results are different compared to these studies as no significant difference in global health or functioning domains was found. Furthermore, no significant difference was found in reflux or fatigue scores. The former studies were heterogenous with respect to included patients (e.g., both distal esophageal, GEJ and cardia cancer) [
8] and baseline characteristics (age, gender, comorbidity, neoadjuvant therapy, open/minimally invasive approach) [
7‐
10]. In three of these studies, no correction for confounders was performed [
7‐
9]. Furthermore, these studies had either a low response rate (34.5% and 52.5%) [
9,
10] or a small sample size (
N = 27 and
N = 53) [
7,
8]. In addition, except for the study by
Fuchs et al., follow-up was short, ranging from three to six months [
7,
8,
10]. The current study describes a large patient cohort with a true GEJ/cardia carcinoma with a high response rate and long follow-up time. In addition, correction for confounders such as differences in baseline characteristics was performed. The long follow-up time decreased the influence of surgical approach (open versus minimally invasive) and neoadjuvant therapy (chemo- or chemoradiotherapy) on HR-QoL.
No significant difference was found in postoperative complications and Clavien–Dindo classification. More specifically, no differences were observed in anastomotic leakage rates between the groups, which corresponds with the findings of
Schumacher et al. who compared a transthoracic esophagectomy (
N = 29) with a gastrectomy (
N = 67) in GEJ carcinoma [
26]. They did find a significant difference in the occurrence of atrial fibrillation between the two groups, which can be explained by the transthoracic phase of the procedure in Ivor Lewis esophagectomy. This finding corresponds to those of other recent studies. The study of
Lohani et al. found that the transthoracic approach (
N = 134) was an independent risk factor for the development of atrial fibrillation after surgery compared to transhiatal approach (
N = 58) [
27]. In our study, we did not observe such difference and the complication rate is comparable to that of other studies [
14,
28,
29]. In the present study, a minimally invasive approach was performed in 94.4% of the patients in the esophagectomy group. The open approach with right thoracotomy is well known to account for the majority of postoperative pulmonary complications (both pneumonia and pleural effusion) which drop significantly when adopting the minimally invasive approach [
30]. The similar rate reported between the gastrectomy and the esophagectomy groups in postoperative pulmonary complications as well as the comparable results in symptoms such as dyspnea could be explained by the reduced pulmonary surgical trauma.
There are limitations of this study that merit attention. Patients who did not participate in the study could have had a worse or better HR-QoL. However, a response rate of 80.2% was achieved, which is higher than the response rates published in recent studies [
9,
10]. More importantly, baseline HR-QoL data are lacking. It remains unknown whether the treatment groups differed a priori with respect to HR-QoL and how HR-QoL may have changed over time. Two ongoing studies are relevant in this respect as they include a baseline. The RENAISSANCE trial in Germany investigates the effect of chemotherapy alone versus chemotherapy followed by surgery on survival and HR-QoL in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction [
31]. The POCOP cohort study in the Netherlands is set up to obtain clinical and HR-QoL data from patients with esophageal and gastric cancer at different points over time [
32]. Furthermore, the two treatment groups differed with respect to sample size (30 vs 71) and baseline characteristics, with more patients having received chemoradiotherapy and significantly more minimally invasive procedures in the esophagectomy group. For most of these baseline characteristics, statistical correction was performed. One should keep in mind that we could not adjust for all differences, in this naturally occurring sample. Conducting a randomized clinical trial with a sufficiently large number of patients with true GEJ carcinoma is a challenge that is yet to be taken up. Moreover, given the many outcomes the number of statistical tests relative to the sample size is large. However, a stringent
p value of < 0.01 for significance was chosen to counteract this obstacle. Although we distinguished between primary and secondary outcomes, some of the results may have been found by chance. Moreover, the results of morbidity and pathology are biased by the inclusion criteria (alive and disease-free) and are therefore only applicable to the selected group of patients in this study with a long recurrence-free survival. Finally, the inclusion criterion ‘alive and disease-free’ precluded the investigation of a possible long-term survival difference between the two treatment groups. Conflicting results for HR-QoL and survival may be observed in such a study, and, additionally, individual patients may also value QoL and survival differently, making both endpoints essential subjects for future research projects. Yet, this study currently provides the most reliable long-term HR-QoL data.
In conclusion, after a follow-up of more than 1 year no significant difference was found in ‘problems with eating,’ ‘reflux’ or ‘nausea and vomiting.’ Of the less clinically relevant HR-QoL domains, ‘choking when swallowing’ and ‘coughing’ were found to be significantly less common in the gastrectomy group. No significant difference was found in postoperative complications or radicality of surgery. Based on this study, it is difficult to determine a priori which procedure for GEJ cancer is to be preferred. However, the study provides important information on long-term HR-QoL following major Upper GI surgery. Patients may be informed about the HR-QoL domains that are likely to be affected by the different surgical procedures, which in turn may support shared decision making when a choice between the two treatment options is possible. A multicenter randomized trial examining long-term HR-QoL, postoperative complications and pathology results in patients with GEJ or cardia carcinoma is the logical, much needed, next step.
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