Efficacy and safety of using an enteral immunonutrition formula in the enhanced recovery after surgery protocol for Chinese patients with gastrointestinal cancers undergoing surgery: A randomized, open-label, multicenter trial (healing trial)

To the Editor: Nutrition optimization is a key component of the enhanced recovery after surgery (ERAS) protocol for patients undergoing gastrointestinal surgery, aiming to improve surgical outcomes through perioperative intervention.[1] According to the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines, malnourished patients undergoing major cancer surgery should be treated with a specific enteral nutrition formula enriched with arginine and omega-3 fatty acids, either perioperatively or at least postoperatively. This approach has been shown to reduce postoperative infectious complications, promote wound healing, and shorten hospital stays.[2,3] This study aimed to assess the efficacy and safety of an immunonutritional formula (INF), Oral Impact (Nestle Health Science, Taizhou, China) in the ERAS protocol for Chinese patients with gastrointestinal cancer (healing trials). INF, containing arginine, n-3 fatty acids, and nucleotides, has been used overseas for years but was unavailable in China until recently. For comparison, the enteral nutrition formula widely used in China, TPF-T (Fresenius Kabi, Wuxi, China) was selected as the control. The key nutrients in the two formulas are provided in Supplementary Table 1, https://links.lww.com/CM9/C496. The trial was conducted in accordance with the ethical principles of the Declaration of Helsinki and registered at ClinicalTrials.gov (NCT03665714). The study protocol was approved by the respective hospital ethics committee of each institution (No. HS2018043). Written informed consent was obtained from all patients before the study. This study was conducted from October 2018 to September 2020 across five centers in China. Patients who underwent elective curative surgery for gastrointestinal cancer were recruited for this study. The inclusion criteria and exclusion criteria of patients are shown in Supplementary Materials, https://links.lww.com/CM9/C496. The detailed feeding protocols are provided in Supplementary Figure 1, https://links.lww.com/CM9/C496. Patients received the assigned formulas either orally or via a feeding tube from the preoperative day (PRD) 5 to PRD 1 and from postoperative day (POD) 1 to POD 7 [Supplementary Figure 1, https://links.lww.com/CM9/C496]. Patients were assessed at several time points during the treatment period: PRD 5 (baseline), PRD 1, S0 (day of operation), POD 1, and POD 7 (+1). After the initial 7 days postoperatively, the patients entered a follow-up period, and the study was completed on POD 30. The detailed methods are shown in Supplementary Materials, https://links.lww.com/CM9/C496. A total of 308 patients were enrolled in the study. Of these, 20.8% (64 patients) dropped out, leaving 244 patients who completed the study. After exclusion, 202 patients were included in the per- protocol set (PPS) for analysis [100 in the sintervention group and 102 in the control group; Supplementary Figure 2, https://links.lww.com/CM9/C496]. The baseline and key clinical characteristics of the patients were well-balanced between the groups [Supplementary Table 2, https://links.lww.com/CM9/C496]. In brief, 38.6% (78/202) of patients had stomach tumors, while 61.4% (124/202) had colon or rectal tumors. Among them, 175 patients (86.6%) underwent laparoscopic surgery, and only 27 (13.4%) underwent open laparotomy. The primary efficacy variable in this study was the change in serum prealbumin level from baseline to POD 7. The 95% confidence interval (CI) lower limit for this change was –0.185 mg/dL, which exceeded the non-inferiority margin of –3.0 mg/dL. Thus, non-inferiority was established (P = 0.098). On POD 7, the average prealbumin level in the intervention group was 18.0 (± 5.0) mg/dL, compared to 16.7 (± 4.6) mg/dL in the control group. A statistically significant intergroup difference was observed on POD 7 [Figure 1A; F = 4.0, P = 0.045].Figure 1: Serum prealbumin levels (A) and BWL (B) in postoperative patients grouped by enteral nutrition formulas on postoperative day 7. BWL: Body weight loss; POD: Postoperative day.Moreover, a subgroup analysis was conducted based on surgery type (laparotomic vs. laparoscopic surgery). Among patients undergoing laparoscopic surgery, the change in prealbumin levels from baseline to POD 7 was significantly greater in the intervention group than in the control group (95% CI: 0.269–2.697; P = 0.017). This finding met the criteria for superiority, as the lower bound of the one-sided 95% CI was >0. However, no similar findings were observed in a subgroup analysis of patients who underwent laparotomic surgery. The body weights of patients in both the intervention and control groups decreased on POD 7 compared with baseline. However, the body weight loss was significantly lower in the intervention group than in the control group (body weight: −1.6 kg vs. −2.4 kg, F = 7.04, P = 0.009) [Figure 1B]. In the intervention group, on POD 30, ten patients (10%, 10/100) had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0, 80 (80%, 80/100) had an ECOG PS score of 1, and three (3%, 3/100) had an ECOG PS score of 2; those with missing data (seven cases) were excluded from this analysis. The ECOG PS score profile of the intervention group on POD 30 was similar to that of the control group. The proportion of patients with an ECOG PS score ≤2 was comparable between the two groups, with no significant difference observed (χ2 = 8316.50, P = 0.673). Overall, product-related adverse event occurred in 33 (21.9%, 33/151) individuals in the intervention group and in 34 (21.9%, 34/155) in the control group. Gastrointestinal-related events were the most frequently reported (7.8%, 24/306), which was anticipated for this patient population. Both products were well-tolerated and demonstrated favorable safety profiles. This study compared the effects of the two formulas in the ERAS protocol on the nutritional status and functional capacity of Chinese patients with gastrointestinal cancer (GIC) who underwent surgery. We found that serum prealbumin levels in patients treated with enteral INF were significantly higher on POD 7 than in those treated with traditional TPF-T. Moreover, INF significantly reduced postoperative body weight loss compared to TPF-T. INF contains three key ingredients: arginine, nucleotides, and n-3 fatty acids, which might act synergistically to more effectively control the inflammatory response, enhance immune function, and improve nutritional status.[5] This study also examined the validity and clinical utility of the ESPEN guidelines in Chinese surgical patients. The results showed that the INF formula, when administered perioperatively within the ERAS protocol, was generally well-tolerated and safe, with good patient compliance comparable to that of TPF-T. Furthermore, our findings demonstrate that INF is superior to TPF-T in improving the nutritional status and protecting body weight perioperatively. These findings highlight the safety and effectiveness of INF in the Chinese population with GIC and suggest its potential as a more effective nutritional intervention option within the context of the ERAS protocol for patients with GIC. This study has several limitations that should be considered when interpreting the results. First, owing to ethical considerations, we did not include a standard nutrition group to examine the differences in immunological indices between patients receiving a standard nutrition formula and those receiving a formula for cancer patients. Additionally, the study design was open-labelled, which could introduce bias. Physicians were aware of the group allocation, which may have influenced the interpretation and judgment of the ECOG scoring. Nevertheless, this is the first head-to-head study to compare the efficacy and safety of foods for special medical purpose (FSMP) and enteral nutrition formulas in the medicine category in China. Patients with GIC included in this study received the formulas for 5 days preoperatively and 7 days postoperatively, adhering closely to real-world clinical practice. Consequently, the findings of this study are highly applicable and generalizable. Our data supports the safety and feasibility of adequate preoperative and early postoperative nutritional delivery. In conclusion, INF significantly increased serum prealbumin levels prevented dramatic weight loss, and maintained functional capacity in Chinese patients when compared to traditional TPF-T. These findings suggest that INF can aid patients in recovering from surgical stress and support subsequent adjuvant therapy. Acknowledgments We are grateful to all patients and their families and all members of the study group. Conflicts of interest This study was sponsored by the Nestlé Health Sciences (China) Co., Ltd.