Enhanced recovery after surgery in laparoscopic distal gastrectomy: Protocol for a prospective single-arm clinical trial.

BACKGROUND: The enhanced recovery after surgery (ERAS) programme is feasible and effective in reducing the length of hospital stay, overall complication rates and medical costs when applied to cases involving colonic and rectal resections. However, a recent prospective, randomised, open, parallel-controlled trial (Chinese Laparoscopic Gastrointestinal Surgery Study-01 trial), initiated by our team, indicated that under conventional peri-operative management, the reduction of the post-operative hospital stay of laparoscopic distal gastrectomy (LDG) is quite limited compared with open gastrectomy. Thus, if we could provide valuable clinical evidence for demonstrating the efficacy of the ERAS programme for gastric cancer patients undergoing LDG, it would significantly enhance the peri-operative management of gastrectomy and benefit the patients.
METHODS: In this prospective single-arm trial, patients who are 18-75 years of age with gastric adenocarcinoma diagnosed with cT1-4aN0-3M0 and expected to undergo curative resection through LDG, are considered eligible for this study. All participants underwent LDG with peri-operative management under the ERAS programme. The primary outcome measures included the post-operative hospital stays and rehabilitative rate of the post-operative day 4. The secondary outcome measures are morbidity and mortality (time frame: 30 days), post-operative recovery index (time frame: 30 days), post-operative pain intensity (time frame: 3 days) and the medical costs from surgery to discharge.
CONCLUSION: With reasonable and scientific designing, the trial may be a great help to further discuss the benefit of ERAS programme and thus improving the peri-operative management of patients with gastrectomy.

INTRODUCTION

Gastric cancer is the third-most common cause of death due to cancer worldwide,[1] and surgical resection remains the cornerstone of current therapy. Laparoscopic gastrectomy has gained significant popularity over recent decades,[2] predominantly because it not only reduces stress in patients but also accelerates rehabilitation and results in a better quality of life (QLQ) compared to the use of open gastrectomy in the treatment of gastric cancer.[3] However, a recent prospective, randomised, open, parallel-controlled trial (Chinese Laparoscopic Gastrointestinal Surgery Study [CLASS]-01 Trial), initiated by our team, reported that the median post-operative hospital stay was 9.0 days for laparoscopic distal gastrectomy (LDG) and 10.0 days for open surgery.[4] The study indicated that under conventional peri-operative management (CONV), the reduction of the post-operative hospital stay of LDG is quite limited compared with open surgery.

First reported by Kehlet and Wilmore, in 1997, enhanced recovery after surgery (ERAS) or fast-track surgery aims to reduce the surgical stress response and facilitate recovery after surgery.[5] The ERAS programme accelerates the patient recovery rates by implementing optimised peri-operative measures using evidence-based adjustments, which include pre-operative education, pre-operative carbohydrate loading, an omission of bowel preparation, modified anaesthetic management, optimised pain control and post-operative fast-track management (early initiation of oral feeding and mobilisation).[678] Thus far, ERAS has achieved promising results in the disciplines of gynaecology,[9] urology,[10] orthopaedic surgery[11] and vascular surgery,[12] among others. As for gastrointestinal surgery, ERAS has also been successfully applied in rectal and colonic surgery and pancreaticoduodenectomies,[13141516] which shows that the implementation of a multi-model-enhanced recovery pathway is an effective means of reducing the length of hospital stays, overall complication rates and medical costs. Beginning in 2007, Jiang et al. were the first to pioneer the use of ERAS for gastric cancer surgery.[17] Furthermore, consensus guidelines for enhanced recovery after gastrectomy were published in 2014 and thus provided a solid framework for its application in this discipline.[6]

Moreover, the retrospective data (have not been published yet) from the CLASS group, showing that when compared to a CONV group, the ERAS group had a faster recovery with a notably shorter length of post-operative hospital stay (7.6 days vs. 14.8 days; P < 0.001), time to first flatus (2.0 vs. 3.8 days, P < 0.001), first ambulation (1.4 vs. 2.4 days, P < 0.001), semi-liquid oral diet recovery (3.9 vs. 6.3 days, P < 0.001) and drainage tube removal (3.2 vs. 6.9 days, P < 0.001). In addition, the ERAS group had less severe complications than that of the CONV group (P < 0.001). Similarly, Chen et al. verified that combining LDG with the ERAS protocol can result in a variety of advantages, such as the reduction of post-operative stress and the acceleration of post-operative rehabilitation in patients with gastric cancer.[18] Encouragingly, a series of studies have consistently shown promising results regarding the feasibility of ERAS in gastrectomy.[19202122] However, some of these previous studies recruited only a limited group of patients and involved retrospective investigations, thus making it difficult for us to assess the feasibility and efficacy of this technique adequately.[181920] Besides, some studies found that ERAS was associated with a higher incidence of some post-operative complications, such as nausea, vomiting and ileus, suggesting that the ERAS programme may multiply the risk of some complications after gastrectomy.[2122] Furthermore, carbohydrate loading of ERAS programme enhances intestinal movement, which may cause adverse effects at the anastomotic site.[23] Consequently, there are concerns that early oral feeding after LDG might increase the incidence of anastomotic leakage and thus leading to delayed rehabilitation for gastric cancer patients undergoing LDG.[24]

Therefore, the precise role of ERAS for gastric cancer patients undergoing LDG needs further verification and more high-quality, large-scale, prospective clinical trials are urgently required to evaluate this programme entirely. The aim of the proposed study is, therefore, to investigate whether the ERAS programme may provide further improvements in rehabilitation for gastric cancer patients undergoing LDG.

METHODS AND ANALYSIS

Study design

The study is designed as a single-centre, prospective, single-arm trial. It was conducted in a manner, as shown in Figure 1. Data were supervised by an independent data and safety monitoring committee organised by the Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong, China.

Figure 1

Study flow diagram

Participants

All consecutive patients scheduled for elective LDG in the General Department of Nanfang Hospital, Southern Medical University, Guangzhou, China, from November 2016, were identified as potential participants and were further screened by a designated investigator according to the specific criteria [Table 1]. After being screened, the potential participants were introduced to the study by an investigator and then signed written informed consent before their inclusion in the study. After that, a copy of the signed consent was given to the participant whereas the original was confidentially kept in the hospital. Then, candidates were successfully recruited.

Table 1

Inclusion, exclusion and withdrawal criteria

Inclusion criteria	Exclusion criteria	Withdrawal criteria
18 years < age <75 years	Severe mental disease	Total gastrectomy
Primary gastric adenocarcinoma confirmed pathologically by endoscopic biopsy	Previous upper abdominal surgery (except laparoscopic cholecystectomy)	Combined organ resection
Expected radical resection by laparoscopic distal gastrectomy	Previous gastrectomy, endoscopic mucosal resection or endoscopic submucosal dissection	Inability to endure surgery or anesthesia because of a changing illness state
Without severe organ dysfunction	Malignant disease within the last 5 years	Patient request to withdraw
Performance status of 0 or 1 on ECOG scale	Emergency surgery due to complications (bleeding, obstruction or perforation) caused by gastric cancer	Conversion to open surgery
ASA score class I or II	Requiring simultaneous surgery for other diseases	Distant metastasis
Informed consent		Bleeding volume over 400 ml or the need for transfusion intraoperatively
Grade cT1-4a, N0-3, M0 at preoperative evaluation according to the AJCC Cancer Staging Manual Seventh Edition

AJCC: American Joint Committee on Cancer, ECOG: Eastern Cooperative Oncology Group, ASA: American Society of Anesthesiologists

Interventions

All participants had undergone LDG with peri-operative management under the ERAS programme [Table 2].

Table 2

The Enhanced Recovery After Surgery (ERAS) program

	Post-operative day
	-1	0	1	2	3	4
Preoperative counseling and education	Preoperative counseling and education about the ERAS program will be held in the ward after admission by a specific team.
Preoperative preparation	No mechanical bowel preparation. Breathing training and atomizing. Nutritional supplement for 5–7 days (NRS >3).
Oral intake	Normal oral diet until midnight. Intake of 1000 ml of 10% carbohydrate drink 10 h before surgery	Intake of 1000 ml 10% carbohydrate drink 2 hours before the induction of anesthesia. Sips of water when awake post operation.	Oral intake of a little water	Full liquid diet	Semi-liquid diet	Daily increase, then to soft diet
Surgery		Laparoscopic surgery and incision <7 cm
Antithrombotic prophylaxis and thermostasis		Intermittent pneumatic compression, infusion warmer and warming blanket	Gradient compression socks
Anesthesia and analgesics		Nonsteroidal anti-inflammatory drug before the induction of anesthesia, general intravenous anesthesia and surgical site infiltration	Nonsteroidal anti-inflammatory drugs for 3 days after operation and adjunctive analgesia with oxycodone.
Urinary catheter and NGT		Placed after anesthesia	Removed within 6 h of operation
Mobilization care	6MWT	Exercise in bed	Ambulation (500–1000 m)	Walk up and down the corridor of the ward with assistance (1000–1500 m)	Daily increase (>1500 m)	6MWT
Drainage		Drainage tube placed in abdomen	Removed within 72 h of operation
Examination			Laboratory examination*		Laboratory examination*, abdominal ultrasonography and upper gastrointestinal radiography	Check based on discharge criteria

NRS: Nutritional Risk Screening; NGT: Nasogastric Tube; 6 MWT: 6 Minute Walk Test; *Laboratory examinations: C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and white blood cells (WBC), neutrophil percentage (NE%)

First, they were assessed and educated by the multidisciplinary teamwork (MDT) which consists of surgeons, anaesthetists and nurses. The content of assessment includes the Eastern Cooperative Oncology Group scores, Nutritional Risk Screening (NRS) scores, QLQ (measured with the European Organisation for Research and treatment of cancer QLQ questionnaire-stomach module) and the 6 min Walk Test. The contents of ERAS management education include the definition of ERAS, the benefit of ERAS programme, dietary instruction, respiratory training, guidance on inhalation, exercise rehabilitation and peri-operative psychological intervention. Then, the nutritional supplement was supplied 5–7 days for patients whose NRS scores ≥3. Fasting time was shortened by allowing the patients taking a regular oral diet until midnight and by instructing patients taking 1000 mL of 10% of carbohydrate drink 10 h before surgery and taking 1000 mL of 10% of carbohydrate drink 2 h before the induction of anaesthesia (patients without diabetes). Correspondingly, fluid therapy is restricted intraoperatively. Notably, there is no mechanical bowel preparation perioperatively.

Intra-operatively, we have provided intermittent pneumatic compression, an infusion warmer and a warming blanket to keep intra-operative core temperature at 37°C ± 0.5°C (temperature recorded every 30 min). Meanwhile, a urinary catheter and nasogastric tube (NGT) was placed after anaesthesia. Multimodal analgesia consists of non-steroidal anti-inflammatory drugs (combined with a proton-pump inhibitor) before the induction of anaesthesia, along with general intravenous anaesthesia and surgical site infiltration. Laparoscopic-assisted surgery or total laparoscopic surgery is permitted to carry out distal gastrectomy, and the length of incision is required to be <7 cm. No >1 drainage tube can be placed in the abdomen. Postoperatively, preventive nonsteroidal anti-inflammatory drug and proton-pump inhibitor therapy and the prevention of post-operative nausea and vomiting continued until at least post-operative day (POD) 3. The NGT and the urinary catheter are removed at within 6 h after surgery. Furthermore, electrocardiographic monitoring is removed within POD 1, and the drainage tube is removed within POD 3. As for the oral intake, sips of water are encouraged when patients awaken post-operation. Oral intake of little water is allowed at POD 1. A full-liquid diet at POD 2 and a semi-liquid diet at POD 3 are standard. At POD 4, a soft diet is encouraged if patients are tolerant. Meanwhile, the MDT instructed the patients to exercise in bed and ambulate 500–1000 m at POD 1, 1000–1500 m at POD 2 and >1500 m at POD 3 (increased daily), respectively. Abdominal ultrasonography and upper gastrointestinal radiography are routinely examined at POD 3. At POD 4, doctors have checked whether patients can be discharged based on specific discharge criteria.

OUTCOME MEASUREMENTS

Primary outcome measures

The primary outcome measures are post-operative hospital stays (defined as the number of days between the date of discharge and the date of surgery) and rehabilitative rate of POD 4. The recovery criteria are as follows: recovery to an oral diet intake >20 kcal/kg body weight; no intravenous infusion therapy; pain relief (visual analogue scale [VAS] score <3, measured using a horizontal 0–10-point VAS, with 0 representing no incision pain and 10 representing incision pain as severe as it could be); ambulation without assistance; no complications and no discomfort such as fever, abdominal pain, nausea or vomiting.

Secondary outcome measures

The secondary outcome measures include morbidity and mortality (time frame: 30 days), post-operative recovery index (time frame: 30 days), post-operative pain intensity (time frame: 3 days), post-operative inflammatory immune response (time frame: 7 days) and the medical costs from surgery to discharge. The morbidity and mortality are assessed 30 days after the operation and classified according to the Clavien-Dindo classification and Accordion Classification, including incision complications (infection, effusion, cracks and healing), peritoneal effusion or abscess, abdominal bleeding, gastrointestinal bleeding, intestinal obstruction, intestinal paralysis, anastomotic stenosis, anastomotic fistula, intestinal fistula, lymphatic leakage, pancreatic fistula, gastroparesis, pancreatitis, pneumonia, urinary system infection, renal failure, liver failure and cardio-cerebrovascular events (including thrombosis and embolism). The post-operative recovery index (time to first ambulation, flatus, liquid diet and soft diet) was assessed daily in the hospital (even 30 days after operation) and determined by the patient self-reporting. Pain intensity was measured using a horizontal 0–10-point VAS. The inflammatory immune response was based on laboratory examinations (C-reactive protein, interleukin-6, tumour necrosis factor-α, white blood cells and neutrophil percentage.

STATISTICAL METHODS

Sample size calculation

Based on the results of previous research reports (in which the post-operative hospital stay was 9 days), ERAS plus LDG should reduce the length of post-operative hospital stays to 6 days. We estimate that in a superiority trial with an α level of 0.05 and a statistical power of 80%, the required single sample size is 98, as determined by the Power Analysis and Sample Size.

Statistical analysis

Statistical analysis was performed using SPSS version 22.0 (SPSS Inc., Chicago, IL, USA). A non-inferiority validation was used to investigate the efficacy and indicators of safety, whereas other data were tested for differences using specific tests. A two-sided P < 0.05 was considered statistically significant. Descriptive statistics were used for baseline characteristics. For categorical variables, including the primary outcome, a Chi-square test or Fisher's exact test was applied. For continuous variables, the Student's t-test or the Mann–Whitney U-test was applied. We do not plan to perform the interim analyses. Any outcomes of analysis were implemented according to the intention-to-treat population and per protocol population.

Safety and reporting of serious adverse events

Any adverse events (AEs) (AEs, defined according to the Common Terminology Criteria for AEs [CTCAE] version 4.0 (National Institutes of Health, National Cancer Institute).[25] and the Accordion Severity Grading System [TASGS]).[26] would be assessed in time. Severity was graded according to the CTCAE and TASGS whereas causality was ranked as none, unlikely, possibly, probably and associated with the intervention. All serious AEs (SAEs defined according to TASGS and CTCAE) would be presented to the chief investigator (CI) within 24 h of being detected. If the CI considers an SAE to be unexpected and associated with the study intervention, he/she will convey this to the Medical Ethics Committee (MEC) within 72 h of being informed, and a detailed medical report will be completed within 15 days. The study's steering committee, which is formed by the authors of the protocol and the Department of General Surgery, Nanfang Hospital, supervises the progress and safety of the research. This committee will also investigate the morbidity and AEs at least three times after the enrollment of 25%, 50% and 75% of the participants. If the incidence of SAE related to the intervention exceeds more than 3% (n = 3) of the sample size, the enrolment is suspended immediately until trial's safety can be assessed by the MEC.

DISCUSSION

The ERAS programme has been successfully applied in several medical fields, including colorectal surgery,[13] gynaecology,[9] urology[10] and orthopaedic surgery.[11] However, as for gastric surgery, ERAS remains in its infancy. Consequently, the role of ERAS programme for gastric cancer patients undergoing LDG remains controversial and requires more robust evidence from well-designed clinical trials.

To begin with, it should be noticed that the ERAS programme includes a series of peri-operative measures and involves system optimisation. Thus, a MDT, including surgeons, anaesthesiologists, nutritionists, ward nurses and operating room nurses, is required to collaborate systematically and comprehensively to apply the ERAS programme. The MDT emphasises the integration and innovation of modern surgical technology and it realises the interdisciplinary cooperation. Only with good teamwork can researchers evaluate the implementation of each measure to explore the optimised ERAS clinical pathway fully.

Then, in the process of applying the ERAS programme to LDG, the ERAS MDT should emphasise the importance of humanistic care and incorporate it into the ERAS clinical path. The ERAS programme embodies the relationships between doctor–patient and doctor–doctor and reflects the concern of humanity. The humanistic care of the ERAS programme can alleviate the anxiety of patients to a certain extent, thereby relieving their stress and improving their satisfaction with the hospital. Moreover, the humanistic care of the ERAS programme can be embodied in every link. The pre-operative counselling and education, the cooperation of intraoperative anaesthesia and surgery, post-operative rehabilitation guidance, analgesia and psychological comfort, timely follow-up and guidance after discharge, all can reflect the humanistic care.

As for the design of this trial, we have two points to discuss. First, the results of the recent prospective, randomised, open, parallel-controlled trial (CLASS-01 trial) initialled by our team showed that the post-operative hospital stays were 9.0 days for LDG under CONV.[4] Thus, we designed this trial as a single-arm trial, whose results were compared with the results of the CLASS-01 trial. Such a practice will balance the persuasion and the cost of medical resources of the trial. The second point is about the primary outcomes. Consistent with other research project,[27] the primary outcome measure of this trial was post-operative hospital stays. Defined as the number of days between the date of surgery and the date of discharge, post-operative hospital stays are influenced by many factors, including variance in discharge standards and non-medical factors (such as culture and patient preference). Consequently, there is often some delay in actual hospital discharge, even if the patient meets discharge criteria. For example, Maessen et al. reported a median of 2 days delay in hospital discharge after patients were informed that they could be discharged after colonic surgery.[28] Consistent with this, a further study by Jeong et al. found that 50% of patients stayed 1–3 extra days after fulfilling the discharge criteria. Surprisingly, however, delaying hospital discharge did not reduce the readmission rate (P = 0.574).[29] Consequently, these authors proposed that the efficacy of the ERAS programme for post-operative recovery need to be evaluated more objectively rather than using the length of hospital stay alone. Therefore, in our current trial, we used the rehabilitative rate of POD 4 as another primary outcome measure. Only with clear recovery criteria can we provide a more accurate comparison of results, and therefore, convincing evidence regarding the efficacy of any interventions.[29]

CONCLUSION

In conclusion, with reasonable and scientific designing, the trial may be a great help to further discuss the benefit of ERAS programme and thus improving the peri-operative management of patients with gastrectomy.

Ethics and dissemination

The independent medical ethical committee of Nanfang Hospital has approved this trial protocol (v 1.0 2016-4-1) on 30 September 2016, with the approval number: NFEC-2016-132. All the procedures of this study are under the oversight of the Chinese Ministry of Health.

Financial support and sponsorship

The trial is supported by the Guangdong Provincial Science and Technology Key Project (No. 2014A020215014) and the Key Clinical Specialty Discipline Construction Program(No.2012.121).

Sponsorship

Special Funds for the Cultivation of Guangdong College Students' Scientific and Technological Innovation 2018(pdjha0094).

Conflicts of interest

There are no conflicts of interest.