Clinical impact of diarrhea during enteral feeding after esophagectomy

Background Enteral feeding (EF) is recommended to enhance nutritional status after esophagectomy; however, diarrhea is a common complication of EF. We investigated the clinical and prognostic impact of diarrhea during EF after esophagectomy. Methods One hundred and fifty-two patients who underwent transthoracic esophagectomy were enrolled. The King's stool chart was used for stool characterization. The short- and long-term outcomes were compared between a non-diarrhea (Group N) and diarrhea group (Group D). Results A higher dysphagia score (≥ 1) was observed more frequently in Group D than in Group N (45.7% vs. 19.8%, p = 0.002). Deterioration of serum total protein, serum albumin, serum cholinesterase, and the prognostic nutritional index after esophagectomy was greater in Group D than in Group N (p = 0.003, 0.004, 0.014, and 0.001, respectively). Patients in Group D had significantly worse overall survival (OS) and recurrence-free survival (RFS) than those in Group N (median survival time (MST): OS, 21.9 vs. 30.6 months, p = 0.001; RFS, 12.4 vs. 27.7 months, p < 0.001). In stratified analysis due to age, although there was no difference in OS with or without diarrhea in young patients (MST: 24.1 months in a diarrhea group vs. 33.6 months in a non-diarrhea group, p = 0.218), patients in a diarrhea group had significantly worse OS than those in a non-diarrhea group in elderly patients (MST: 17.8 months vs. 27.9 months, p < 0.001). Conclusions Diarrhea during EF can put elderly patients at risk of postoperative malnutrition and a poor prognosis after esophagectomy. Supplementary Information The online version contains supplementary material available at 10.1007/s10147-023-02428-5.


Introduction
Global cancer statistics show that esophageal cancer is the sixth leading cause of cancer-related deaths worldwide [1].Patients with esophageal cancer have many nutritional risks.Masses often cause solid food obstruction preoperatively, and oral intake must be ceased for a certain period postoperatively to protect the anastomosis site [2].Additionally, transthoracic esophagectomy, recognized as a principal treatment for esophageal cancer [3,4], is more invasive, resulting in a systemic in ammatory response and poses a risk for postoperative complications [5].We previously reported that enhancing postoperative nutritional status in patients with preoperative malnutrition leads to a better prognosis after esophagectomy [6].Other studies have suggested that nutritional management in the early postoperative period is important to enhance cell-mediated immunity after esophagectomy [5,7,8].Enteral feeding (EF) has been recommended as supportive therapy for patients after surgery or in intensive care [2,5,7,9].EF has been shown to promote nitrogen retention, restore immune function, and accelerate wound healing [10].Postoperative EF has also been shown to reduce the risk of septic complications after esophagectomy [2].
However, the complications associated with speci c EF methods may diminish the intended bene ts.
Diarrhea is a major complication of EF [10,11].The incidence of diarrhea during EF in intensive care is reported to be 2-95% [2,[10][11][12].In addition, diarrhea has been linked to malnutrition [2,10].In intensive care, the combination of stress and malnutrition is associated with a negative energy balance, which leads to delayed wound healing, prolonged hospital stay, and higher healthcare costs [12].Furthermore, malnutrition is associated with increased morbidity and mortality during critical illness [2,12].However, the clinical signi cance of diarrhea during EF after esophagectomy remains unknown.
This study hypothesizes that diarrhea during EF after esophagectomy could be a risk factor for postoperative malnutrition and poor prognosis.Therefore, we investigated the associations between diarrhea during EF with short-and long-term outcomes.

Patients
Between January 2017 and December 2021, 178 patients with esophageal and esophagogastric junction cancer (EGJC) were retrospectively reviewed.All patients underwent esophagogastroduodenoscopy (EGD) and computed tomography (CT) from the neck to the pelvis to determine the clinical stage.The clinical and pathological stages were determined based on the Union for International Cancer Control TNM classi cation of malignant tumors, 8th edition [13].

Multidisciplinary treatment
In accordance with the esophageal cancer practice guidelines 2017 in Japan, neoadjuvant chemotherapy (NAC) was administered to patients with non-Stage I squamous cell carcinoma (SCC) [3,4].At our institution, patients with adenocarcinoma with bulky lymph node (LN) metastases underwent NAC.For SCC, the treatment regimens were a combination of cisplatin and 5-uorouracil or a combination of docetaxel, cisplatin, and 5-uorouracil for SCC and a combination of S-1 and oxaliplatin for adenocarcinoma.A right transthoracic subtotal esophagectomy with 2-or 3-eld LNs dissection was performed as a standard surgical procedure at our institution [14,15].Upper, middle, and lower mediastinal LNs and abdominal LNs were routinely dissected.The upper mediastinal region included the upper thoracic paraesophageal nodes, and left and right paratracheal nodes; the middle mediastinal region included the middle thoracic paraesophageal nodes, subcarinal nodes, and main bronchus nodes; and the lower mediastinal region included the lower thoracic paraesophageal nodes, posterior mediastinal nodes, and supradiaphragmatic nodes.In the abdominal region, bilateral paracardial nodes, lesser curvature nodes, and LNs along the left gastric artery, common hepatic artery, celiac artery, and proximal splenic artery were dissected.Except for patients with low surgical tolerance or high surgical risk, bilateral cervical LNs dissection was generally performed for advanced cancer or super cial cancer in the middle or upper thoracic esophagus.Gastric conduit reconstruction via the posterior mediastinal route was performed with hand-sewn anastomosis in the neck.The retrosternal route was selected when the risk of anastomotic leakage (AL) was considered high, such as in those who took steroids or suspected insu cient blood ow in the gastric conduit.In posterior mediastinal route reconstruction, a 12-Fr jejunostomy catheter was inserted into the proximal jejunum.Further, we inserted this into the gastric antrum in retrosternal route reconstruction.Following esophagectomy, cefazolin 1g was administered twice daily via a peripheral intravenous line for 3 days as a prophylactic antibiotic.
The Clavien-Dindo classi cation was used to assess postoperative complications such as pneumonia, AL, and surgical site infection (SSI).Further, postoperative complications of grade ≥ 2 were identi ed [16].Postoperative body weight (BW), body mass index (BMI), serum total protein, serum albumin, serum cholinesterase, prognostic nutritional index (PNI) [17], and neutrophil-to-lymphocyte ratio (NLR) were used to assess nutritional status.BW and BMI were measured before and at 1 and 3 months after surgery.Other parameters were measured in blood samples taken before and 1 month after surgery.These parameters were measured after NAC but before surgery in patients who received NAC.

Perioperative nutritional support
In April 2017, a multidisciplinary support team was established to prevent complications and improve nutritional status [18].Before treatment, dietitians assessed the oral intake and recommended oral nutritional supplements for those whose calorie intake was insu cient.An elemental diet started at 10 kcal/h on the day of surgery via a jejunostomy tube.EF speed was gradually increased to 50 ml/h based on the abdominal symptoms.After postoperative day 7, the EF agent was gradually changed from an elemental diet to a fat-containing agent.Meals were started after a video-uoroscopic and videoendoscopic examination of the swallowing function.When diarrhea occurred, reduce the EF speed rst.
We changed the EF agent or started probiotics if there was no improvement.A multidisciplinary team conference was held to discuss the required calories, nutritional status, dietary intake, EF agents, and stool condition of the patients [6,18].EF was continued in patients after hospital discharge until oral intake was satisfactory.The degree of preoperative food passage obstruction was assessed using the dysphagia score (Table 1).[19,20].In this study, diarrhea is de ned as KSC ≥ 16 for 3 days.

Follow-up
For 5 years after surgery, CT was performed every 6 months, and EGD was performed yearly.Recurrencefree survival (RFS) was calculated from the day of surgery to the day of esophageal cancer or EGJC recurrence.Overall survival (OS) was calculated from the day of surgery to the day of death.Patients were followed up until death, ve years after esophagectomy, or the study termination (December 31, 2022).Patients who were alive at the study termination, interrupted follow-up, and died due to an illness unrelated to their primary disease were recognized as censored.

Statistical analysis
All statistical analyses were performed using IBM SPSS Statistics version 26 for Windows (IBM Corp., Armonk, NY, USA).Medians and ranges were calculated, and differences were identi ed using the Mann-Whitney U test.Differences between categories were identi ed using the chi-square or Fisher's exact test.
Repeated measures ANOVA was used to analyze the association between preoperative and postoperative nutritional status.Survival curves were generated using the Kaplan-Meier survival method and the logrank test.Odds ratios (OR) and hazard ratios (HR) were calculated.Univariate and multivariate analyses were performed using logistic regression analysis for nominal variables and Cox proportional hazards regression models for survival analysis.The threshold for signi cance was set at p < 0.05.

Demographics and perioperative outcomes
Diarrhea occurred in 46 (30.3%) patients during EF, and patients were divided into a non-diarrhea (Group N, n = 106) and diarrhea group (Group D, n = 46) (Fig. 1).The clinicopathological features of each group are shown in Tables 3 and 4.There was no signi cant difference in age, sex, histology, tumor location, clinical stage, or rate of NAC administration.Patients with a higher dysphagia score (≥ 1) were signi cantly found in Group D than in Group N (45.7% vs. 19.8%,p = 0.002) (Table 3).The morbidity of postoperative complications was similar between the two groups.The median duration from surgery to diarrhea onset was 10 days (range, 4-24 days), and it took several days after starting diarrhea management to achieve stool control (median 4 days, range 0-28 days).The duration of postoperative hospital stay was signi cantly longer in Group D compared to Group N (median 29 vs. 24 days, p = 0.011) (Table 3).Stool cultures were collected from 39 patients (28 in Group D and 11 in Group N), and revealed that Enterococcus spp.and Escherichia coli were frequently cultured in both groups.Furthermore, Clostridioides di cile and Klebsiella oxytoca, known to cause antibiotics-associated colitis, were found in a few patients in Group D (Online Resource 1).

Loss of postoperative nutritional status due to diarrhea
The impact of diarrhea on postoperative nutritional status was investigated (Fig. 2).There was no signi cant difference in BW (p = 0.325) and BMI (p = 0.526) decline between the two groups before and at 1 and 3 months after surgery (Fig. 2a, b).However, compared to Group N, postoperative serum total protein (p = 0.003), serum albumin (p = 0.004), serum cholinesterase (p = 0.014), and PNI (p = 0.001) were signi cantly decreased in Group D (Fig. 2c-f).In addition, NLR values in Group N decreased from the preoperative phase to 1 month after surgery, whereas NLR values in Group D increased during the same period (p = 0.042) (Fig. 2g).

Risk factors for diarrhea during EF
Variables in Table 5 indicate potentially signi cant clinicopathological factors affecting diarrhea during EF.A higher dysphagia score (≥ 1) was associated with diarrhea in the univariate analysis.There was no statistical signi cance; nonetheless, NAC, preoperative BW, thoracotomy, and postoperative pneumonia tended to be linked to diarrhea during EF (Table 5).However, no correlation was observed between therapeutic antibiotic use and diarrhea (p = 0.255).A higher dysphagia score (≥ 1) was an independent relevant factor of diarrhea during EF in the multivariate analysis (OR 2.750; p = 0.014; 95% CI 1.231-6.144)(Table 5).

Survival analysis
The median follow-up period was 27.5 months (range 1.9-66.3months); 52 (34.2%) patients experienced recurrence.Patients in Group D had signi cantly higher rates of regional LN and distant organ recurrence than those in Group N (regional LN recurrence: 39.1% vs. 15.2%,p = 0.003; distant organ recurrence:  3c, d).However, patients in Group D-E had signi cantly worse OS and RFS than those in Group N-E (MST OS: 17.8 vs. 27.9months, p < 0.001; RFS: 11.9 vs. 26.9months, p < 0.001) (Fig. 3e, f).Finally, clinicopathological variables potentially affecting poor OS were investigated (Table 6).In younger groups, univariate analysis revealed that NAC and advanced pathological stage (≥ III) were associated with poor OS and the multivariate analysis identi ed advanced pathological stage (≥ III) (HR 3.492; p = 0.049; 95% CI 1.007-12.112)was an independent predictive factor for poor OS (Table 6).Diarrhea during EF was not associated with poor OS.

Discussion
This study demonstrated that patients with diarrhea during EF after esophagectomy had signi cantly worse OS and RFS than those without diarrhea.Multivariate analysis revealed that diarrhea during EF was an independent prognostic factor for poor OS after esophagectomy.Furthermore, nutritional status in Group D signi cantly decreased compared to Group N. Postoperative malnutrition has been reported to result in immune function de ciency and chemotherapy intolerance [5,21].Additionally, NLR increased only in Group D from the preoperative phase to 1 month after esophagectomy.The NLR has been reported as an oncological prognostic marker [22].Diarrhea during EF may induce in ammation, increasing neutrophil production and NLR elevations.Neutrophils induce chemokines and cytokines production, which enhance tumor growth, invasion, and angiogenesis [23].These results suggest that diarrhea during EF can cause postoperative in ammation and malnutrition, resulting in decreased tumor immunity and a poor prognosis.To our knowledge, this is the rst report to reveal the survival impact of diarrhea during EF after esophagectomy.
The strati ed analysis revealed that RFS in the diarrhea group was signi cantly worse than those in the non-diarrhea group both in younger and elderly groups.In addition, patients in the diarrhea group had signi cantly worse OS than those in the non-diarrhea group in the elderly group.Furthermore, multivariate analysis revealed diarrhea during EF as an independent risk factor for poor OS in the elderly.Elderly patients usually have reduced satiety and poor digestive function, resulting in long-term reduced oral intake and malnutrition [11,24].Additionally, physiological function, especially organ reserve, declines with age, and comorbidities and frailty become increasingly common as people age.The decline in organ reserve becomes apparent only after stresses such as surgery or chemotherapy [25].These ndings suggest that diarrhea may have devastating effects on postoperative quality of life, physical strength, and prognosis, especially in the elderly.
Diarrhea during EF was associated with a higher dysphagia score.There is evidence that loss of oral intake can cause digestive and absorptive capacity deterioration due to intestinal villi atrophy [24,26].
The esophageal cancer mass frequently obstructs the passage of solids before surgery, which causes atrophy of the intestinal villi and increases the risk of postoperative diarrhea.
Diarrhea can potentially disrupt microbiota.By modulating the immune function of the host, intestinal bacteria can improve the immune system defense against cancer [27].Intestinal microbiota disturbance can lead to the development of several pathologies, including malnourishment, and chronic in ammatory disorders such as in ammatory bowel disease, that have a signi cant impact on colorectal cancer pathogenesis [27,28].These ndings suggest that diarrhea during EF may be a risk factor for intestinal microbiota distribution, malnutrition, and immunological disorder, contributing to poor prognosis after esophagectomy.
This study found that there was no relationship between therapeutic antibiotic use and diarrhea.Antibiotics can negatively affect the gut microbiota, causing pathogenic bacteria, including Clostridioides di cile, to proliferate [29,30].However, few patients in this study had pathogenic bacteria that cause antibiotics-associated colitis, and resident bacteria in the intestinal tract were cultured in many patients.
These ndings suggest that diarrhea during EF was predominantly osmotic.
Diarrhea can be managed by slowing EF infusion or changing enteral nutritional supplements [31].
However, the frequency of diarrhea is often not accurately assessed and may be overlooked.Furthermore, improved stool condition took several days from the start of diarrhea management in this study.
Therefore, we formed a multidisciplinary support team and shared information on nutritional status, dietary intake, selection of EF agents, and diarrhea at the conference [6,18].
This study had some limitations.First, it was a single-institution retrospective study.However, this study reviewed consecutive patients, which reduced selection bias.Second, there was some variability because the diagnosis of diarrhea was based on the subjective records of the nurse.To reduce bias among nurses, the de nition of diarrhea was set at 3 days of continuous liquid stool.Finally, some patients were under treatment for recurrence at the conclusion of this study.Therefore, the effect of diarrhea on chemotherapy tolerance and response rate for recurrence remains unclear.Continuous follow-up and a multi-institutional prospective study should validate the current ndings in the future.
In conclusion, diarrhea during EF can induce postoperative malnutrition, which leads to a poor prognosis after esophagectomy, especially in the elderly.Therefore, precise observation of the patients' condition after esophagectomy may be essential in preventing EF-related diarrhea and a multidisciplinary support team may play an important role.

Figure 1 Study ow diagram Figure 2
Figure 1

Table 5
Independent relevant factors of clinicopathological features on diarrhea during EF

Table 6
Independent factors of clinicopathological features on poor overall survival HR, hazard ratio; CI, con dence interval; EF, enteral feeding; POM, post-operative month; PNI, Prognostic nutritional index; NLR, Neutrophil-to-lymphocyte ratio