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Efficacy of immunonutritional supplement after neoadjuvant chemotherapy in patients with esophageal cancer

Journal of Cardiothoracic Surgery volume 17, Article number: 41 (2022) Cite this article

Abstract

Background

In recent years, preoperative nutrition has received great attention, especially for patients who received surgical reconstruction of the digestive tract such as esophagectomy. Preoperative nutrition therapy was reported to accelerate the patient's postoperative recovery. In addition, immune suppression, nausea, and vomiting may lead to poor immune and nutritional status of patients with esophageal cancer who underwent neoadjuvant chemotherapy (NAC), which is not conducive to surgery. Therefore, preoperative nutritional treatment is necessary for patients with esophageal cancer who underwent NAC.

Method

Patients with esophageal cancer who received NAC at Nanjing Jinling Hospital from January 2018 to September 2020 were retrospectively identified. Patients were divided into enteral immunonutrition (EIN) group (those who received a conventional diet and immunonutrition supplement, Peptisorb, Nutricia, 500 mL/day * 7 via oral intake), and control group (those who only received a conventional diet were divided into). The primary outcomes were immune and nutritional indicators changes, including immunoglobulin M (IgM), immunoglobulin A (IgA), immunoglobulin G (IgG), and albumin (ALB), which were measured at preoperative day (PRD) 7, PRD-1, postoperative day (POD) 1 and POD-7. The secondary outcomes were postoperative complications, adverse reactions, and length of hospital stay.

Results

A total of 124 eligible patients were included in the study, with 21 patients in EIN group. After 1:2 matching, significant difference in baseline characteristics between the two groups was not observed (EIN: n = 21, Control group: n = 42). Compared with the control group, the IgA is significantly increased in the EIN group at POD-7 (p = 0.017). However, we observed that the IgM level in the control group was significantly higher than those in the EIN group at POD-7 (p = 0.007). The incidence of pneumonia and total complications in the EIN group were significantly lower than those in control group (p = 0.024, p = 0.028, respectively). There is no significant difference in ALB and adverse reactions between two groups (p = 0.303, p = 0.108, respectively).

Conclusion

Immunonutritional supplement after NAC is an effective strategy to improve the postoperative immune status of esophageal cancer patients and could reduce the incidence of infectious complication. More well-designed prospective studies are needed to verify and update our finding.

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Introduction

Esophageal cancer is one of the most common tumors and ranks sixth in mortality worldwide [1]. NAC combined with surgery is one of the common treatments for patients with locally advanced esophageal cancer [2]. For these patients, NAC may significantly enable them to obtain a better overall survival rate [3]. However, NAC may lead to a delay in surgery and an amplification of operative and postoperative complications [3, 4]. Dysphagia and weight loss in patients with esophageal cancer will lead to malnutrition. Nausea and vomiting often occur during the period of NAC, which will aggravate malnutrition of patients and is not conducive to the follow-up treatment of patients. It is reported that preoperative malnutrition will also affect the postoperative prognosis, including complications and adverse reactions [5, 6]. The interval between NAC and surgery provides the possibility to correct the deterioration of nutritional status before esophagectomy [7]. Immune-modulating substances such as arginine, omega-3 fatty acids, and antioxidants can modulate immune and inflammatory processes in major surgery and improve clinical outcomes. Arginine is a non-essential amino acid that plays a role in the synthesis of nitric oxide, which regulates gene expression and stimulates cell-mediated immunity [8].

However, there are few studies to explore the effect of immunonutrition therapy/supplement after NAC in patients with esophageal cancer. So, we conducted a retrospective study to explore the effects of preoperative immunonutritional support after NAC on postoperative immunonutritional parameters, postoperative complication, adverse reaction, and length of hospital stay in patients with esophageal cancer.

Materials and methods

Patients

Between 2018.01 and 2020.09, 1168 was diagnosed with esophageal cancer in Jinling hospital (Fig. 1). 1001 patients who didn’t receive neoadjuvant chemotherapy were excluded. Twenty-eight patients were withdrawn without esophagectomy. Of the remained 139 patients underwent esophagectomy, 15 patients were excluded due to allergic to soy or milk, unable to swallow, or individual data missing > 5%. Finally, 124 patients were eligible for the study. 103 patients in the control group and 21 patients in the EIN group were analyzed. A propensity score matching analysis was performed to reduce the effects of characteristics. Finally, 42 patients were included in the control group and 21 patients were included in the EIN group.

Fig. 1
figure 1

Flow chart of participants selection

Full size image

Study design

A retrospective study was performed between January 1, 2018, and September 1, 2020, at the Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing, China. All patients included in the study received two courses of NAC. The chemotherapy regimen was paclitaxel plus cisplatin. Patients in the EIN group received enteral immune nutrition fluids (500 mL/day, Enteral Nutritional Emulsion, ω-3 Fatty Acids, Arginine) with their regular meals consecutively for a week after NAC, and the control group received only regular meals consecutively for a week after NAC. The primary endpoints were immune and nutritional parameters, including IgM, IgA, IgG, and ALB, which were measured at PRD-7, PRD-1, POD-1, and POD-7. The secondary endpoints were, complications, adverse reactions, and length of hospital stay. Postoperative complications included anastomotic fistula, pneumonia, chylothorax, and recurrent laryngeal nerve injury. All postoperative complications were evaluated according to Clavien-Dindo criteria and grade II or more was defined as positive [9]

Meanwhile, baseline characteristics of all included patients were extracted from the hospital information system (HIS), including age, sex, body mass index (BMI), comorbidities, TNM stage, tumor site, differentiation grade, size. Tumor staging was based on the seventh edition of the International Union for Cancer Control (UICC) TNM staging system for esophageal carcinoma.

Objects of study

The inclusion criteria were as follows: (1) Patients who received NAC (2) Patients who underwent esophagectomy. Patients were excluded when: (1) Patients without esophagectomy due to: (1) Refusal; (2) Without pathologic response; (3) Severe toxic effects of chemotherapy; (2) Patients excluded due to: (1) Allergic to soy or milk; (2) Unable to swallow; (3) Individual data missing > 5%.

Statistical analyses

Continuous variables were performed as the mean with standard deviation (SD) or median with interquartile ranges (IQR). The student t-test, χ2 tests or Fisher’s exact tests were utilized to compare the difference between the two groups. We created a propensity score matched cohort by attempting to match each patient receiving enteral immune nutrition fluids with their regular meals with a patient receiving regular meals (1:2 match). The covariates included in the propensity score matching were age, sex, BMI, diabetes, hypertension, smoking, and alcohol. All statistical analyses were executed with Stata 16.0 (Stata Corp LLC, college station, USA). P < 0.05 was considered statistically significant.

Results

As showed in Fig. 1, a total of 1168 patients were screened and 1001 patients who didn’t receive neoadjuvant chemotherapy were excluded. Twenty-eight patients were withdrawn without esophagectomy. Of the remained 139 patients underwent esophagectomy, 15 patients were excluded due to allergic to soy or milk, unable to swallow, or individual data missing > 5%. Finally, 124 patients were eligible for the study. 103 patients in the control group and 21 patients in the EIN group were analyzed. After a propensity score matching, 42 patients were included in the control group and 21 patients were included in the EIN group.

The baseline characteristics of patients were presented in Table 1. Significant differences were not observed between the two groups after propensity score matching.

Table 1 Comparison of baseline characteristics between EIN group and control group
Full size table

Immune and nutritional indicator of all patients were measured at the four timepoints mentioned above shown in Table 2. Immune indicators (IgA) in the two groups have significantly differences at POD-7 (p = 0.017). However, patients in the control group have a higher level of IgM at POD-7 (p = 0.007). Nutritional indicator (ALB) in two groups has no significant difference at POD-7.

Table 2 Comparison of immune and nutritional parameters
Full size table

The secondary outcomes are listed in Table 3. The incidence of pneumonia and total complications in the EIN group were significantly lower than those in control group (p = 0.024, p = 0.028, respectively). There were no significant differences in the hospital stays and the incidence of adverse reaction between two groups.

Table 3 Comparison of surgical outcomes between two groups
Full size table

Linear regression of anastomotic leakage (AL) and nutritional indicators are showed in the Additional file 1: Table S1. Anastomotic leakage has statistical significance for ALB at POD-1 (p = 0.038), which should be discarded. Because anastomotic leakage generally does not occur on the first day after operation. There was no statistical significance in the nutritional way for ALB at POD-1 and POD-7. And anastomotic leakage has no statistical significance for IgM, IgA, IgG at POD-7.

Logistic regression of type of operation and complications are showed in the Additional file 1: Table S2. Type of operation has no statistical significance for anastomotic leakage and pneumonia.

Discussion

Esophageal cancer is a common gastrointestinal tumor in the world. There are many treatment options for advanced esophageal cancer, one of which is neoadjuvant chemotherapy (NAC) combined with esophagectomy. Multimodality treatment, which implies NAC in combination with surgery, has shown a better survival benefit than surgery alone [10,11,12]. Malnutrition is highly prevalent in patients with esophageal cancer. Due to the influence of tumor, patients with esophageal cancer often have symptoms such as dysphagia, vomiting, insufficient nutritional intake, fatigue, weight, and muscle loss. The adverse effects of NAC, such as immune suppression, nausea and vomiting, combined with the clinical symptoms of esophageal tumor itself, will adversely affect the follow-up treatment. It’s very important to integrate the early screening of malnutrition and appropriate nutritional support into the overall preoperative management of esophageal cancer patients [13,14,15,16]. According to previous studies, preoperative nutritional support can improve postoperative nutritional status and immune function [17, 18].

In our study, immunoglobulin for patients with EIN was found to outstrip those who are without EIN. IgA was significantly higher in the EIN group (p = 0.017) at POD-7. IgM in the control group is significantly higher than the EIN group (p = 0.007). Although there is fewer differences in IgG between two groups from POD-1 to POD-7, IgG is still better in the EIN group.

Immunoglobulin plays an important role in the humoral immune system. IgA is divided into serum type and secretory type; the secretory type is the main antibody in mucosal infection. Patients with esophageal cancer always suffer from eating disorders for a long time which might cause intestinal mucosal barrier dysfunction [19]. EIN may be beneficial to maintain the integrity of the structure and function of intestinal mucosal cells, and to protect the intestinal mucosal barrier [20]. IgM appears first in infection. In control group, the incidence of pneumonia is higher than the EIN group. The high incidence of pneumonia in the control group could result in the high level of IgM, compared with the EIN group. Thus, EIN may be beneficial for patients with esophageal cancer after NAC by enhancing their immune function and reducing the incidence of infectious complication and length of hospital stay. However, some researchers uphold that there are no significant differences in clinical outcomes (complications, hospital stay) between treatment and control group, that used immunonutrition before esophageal cancer surgery [21,22,23,24,25]. But Alfred Adiamah et al. [26] thought that preoperative immunonutrition could lead to an appreciable and significant reduction in postoperative infectious complications and a tendency for a shortened length of hospital stay. The conclusion is consistent with our result. But the systematic review and meta-analysis included most gastrointestinal cancers but few esophageal cancers.

Limitation

It is a retrospective single-center study that may be subject to selection bias. And this is a small-scale study which may lead to unstable results; therefore, we will continue to conduct further studies with larger samples in this area to prove significant differences between the two groups. We did not conduct Kaplan–Meier curves to compare the difference in long-term survival between groups.

Conclusion

Immunonutritional supplement after NAC is an effective strategy to improve the postoperative immune status of esophageal cancer patients and reduce the incidence of infectious complication and length of hospital stay. More well-designed prospective studies are needed to verify and update our finding.

References

  1. Fitzmaurice C, Dicker D, Pain A, et al. The global burden of cancer 2013. Ann Thorac Surg. 2015;1(4):505–27.

    Google Scholar 

  2. Lagergren J, Smyth E, Cunningham D, et al. Oesophageal cancer. Lancet. 2017;390(10110):2383–96.

    Article  Google Scholar 

  3. Babic B, Fuchs HF, Bruns CJ. Neoadjuvant chemoradiotherapy or chemotherapy for locally advanced esophageal cancer? Chirurg. 2020;91(5):379–83.

    Article  CAS  Google Scholar 

  4. Luu TD, Gaur P, Force SD, et al. Neoadjuvant chemoradiation versus chemotherapy for patients undergoing esophagectomy for esophageal cancer. Ann Thorac Surg. 2008;85(4):1217–23 (discussion 23–4).

    Article  Google Scholar 

  5. Mora RJ. Malnutrition: organic and functional consequences. World J Surg. 1999;23(6):530–5.

    Article  CAS  Google Scholar 

  6. van Bokhorst-de van der Schueren MA, van Leeuwen PA, Sauerwein HP, et al. Assessment of malnutrition parameters in head and neck cancer and their relation to postoperative complications. Head Neck. 1997;19(5):419–25.

    Article  Google Scholar 

  7. Steenhagen E. Preoperative nutritional optimization of esophageal cancer patients. J Thorac Dis. 2019;11(Suppl 5):S645–53.

    Article  Google Scholar 

  8. Ma C, Tsai H, Su W, et al. Combination of arginine, glutamine, and omega-3 fatty acid supplements for perioperative enteral nutrition in surgical patients with gastric adenocarcinoma or gastrointestinal stromal tumor (GIST): a prospective, randomized, double-blind study. J Postgrad Med. 2018;64(3):155–63.

    Article  CAS  Google Scholar 

  9. 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.

    Article  Google Scholar 

  10. Lordick F, Mariette C, Haustermans K, et al. ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl 5):v50–7.

    Article  CAS  Google Scholar 

  11. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074–84.

    Article  Google Scholar 

  12. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11–20.

    Article  CAS  Google Scholar 

  13. Arends J, Bachmann P, Baracos V, et al. ESPEN guidelines on nutrition in cancer patients. Clin Nutr. 2017;36(1):11–48.

    Article  Google Scholar 

  14. Low DE, Allum W, De Manzoni G, et al. Guidelines for perioperative care in esophagectomy: enhanced recovery after surgery (ERAS(®)) society recommendations. World J Surg. 2019;43(2):299–330.

    Article  Google Scholar 

  15. Chen MJ, Wu IC, Chen YJ, et al. Nutrition therapy in esophageal cancer-consensus statement of the Gastroenterological Society of Taiwan. Dis Esophagus. 2018;31(8):doy016.

    Article  Google Scholar 

  16. Yu Z, Li S, Liu D, et al. Society for Translational Medicine Expert Consensus on the prevention and treatment of postoperative pulmonary infection in esophageal cancer patients. J Thorac Dis. 2018;10(2):1050–7.

    Article  Google Scholar 

  17. Wang R, Cai H, Li Y, et al. Impact exerted by nutritional risk screening on clinical outcome of patients with esophageal cancer. Biomed Res Int. 2018;2018:7894084.

    PubMed  PubMed Central  Google Scholar 

  18. Kanekiyo S, Takeda S, Iida M, et al. Efficacy of perioperative immunonutrition in esophageal cancer patients undergoing esophagectomy. Nutrition. 2019;59:96–102.

    Article  Google Scholar 

  19. Li X, Cong Z, Wu W, et al. Efficacy of 4 wk of home enteral feeding supplementation after esophagectomy on immune function: a randomized controlled trial. Nutrition. 2020;77:110787.

    Article  CAS  Google Scholar 

  20. Zou XP, Chen M, Wei W, et al. Effects of enteral immunonutrition on the maintenance of gut barrier function and immune function in pigs with severe acute pancreatitis. JPEN J Parenter Enteral Nutr. 2010;34(5):554–66.

    Article  CAS  Google Scholar 

  21. Hallay J, Kovács G, Kiss Sz S, et al. Changes in the nutritional state and immune-serological parameters of esophagectomized patients fed jejunaly with glutamine-poor and glutamine-rich nutriments. Hepatogastroenterology. 2002;49(48):1555–9.

    CAS  PubMed  Google Scholar 

  22. Mudge LA, Watson DI, Smithers BM, et al. Multicentre factorial randomized clinical trial of perioperative immunonutrition versus standard nutrition for patients undergoing surgical resection of oesophageal cancer. Br J Surg. 2018;105(10):1262–72.

    Article  CAS  Google Scholar 

  23. Ryan AM, Reynolds JV, Healy L, et al. Enteral nutrition enriched with eicosapentaenoic acid (EPA) preserves lean body mass following esophageal cancer surgery: results of a double-blinded randomized controlled trial. Ann Surg. 2009;249(3):355–63.

    Article  Google Scholar 

  24. Sakurai Y, Masui T, Yoshida I, et al. Randomized clinical trial of the effects of perioperative use of immune-enhancing enteral formula on metabolic and immunological status in patients. World J Surg. 2007;31(11):2150–7 (discussion 8–9).

    Article  Google Scholar 

  25. Healy LA, Ryan A, Doyle SL, et al. Does prolonged enteral feeding with supplemental omega-3 fatty acids impact on recovery post-esophagectomy: results of a randomized double-blind trial. Ann Surg. 2017;266(5):720–8.

    Article  Google Scholar 

  26. Adiamah A, Skořepa P, Weimann A, et al. The impact of preoperative immune modulating nutrition on outcomes in patients undergoing surgery for gastrointestinal cancer: a systematic review and meta-analysis. Ann Surg. 2019;270(2):247–56.

    Article  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (81172032) and the Natural Science Foundation of Jiangsu Province (BK20181239).

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Authors and Affiliations

  1. Department of Cardiothoracic Surgery, Jinling Hospital, Southern Medical University, Guangzhou, China

    Chao Luo & Yi Shen

  2. Department of Cardiothoracic Surgery, Jinling Hospital, School of Clinical Medicine, Nanjing Medical University, Nanjing, China

    Kai Xie, Yang Xu & Yi Shen

  3. Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China

    Chi Zhang, Zhuang-Zhuang Cong, Wen-Feng Gu, Li-Wen Hu & Yi Shen

  4. Department of Cardiothoracic Surgery, Jinling Hospital, School of Medicine, Southeast University, Nanjing, China

    Yong Qiang, Xiao-Kun Li, Chao Zheng & Yi Shen

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  1. Chao Luo
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Contributions

CL made a major contribution to the design of the research and the manuscript writing; KX, Z-ZC, and CZ was responsible for collecting the data; CZ was responsible for performing the statistical analysis; all authors took part in the promotion of the results’ interpretation and critically reviewed the manuscript’s first draft. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Chao Zheng, Li-Wen Hu or Yi Shen.

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The authors declare that they have no competing interests.

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Supplementary Information

Additional file 1: Table S1.

linear regression of anastomotic leakage (AL) and nutritional indicators. Table S2. logistic regression of type of operation and complications.

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Luo, C., Xie, K., Zhang, C. et al. Efficacy of immunonutritional supplement after neoadjuvant chemotherapy in patients with esophageal cancer. J Cardiothorac Surg 17, 41 (2022). https://doi.org/10.1186/s13019-022-01786-x

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Journal of Cardiothoracic Surgery

ISSN: 1749-8090

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