Laparoscopic Radical Gastrectomy for Resectable Advanced Gastric Cancer Within Enhanced Recovery Programs: A Prospective Randomized Controlled Trial

Abstract

Background:

Enhanced recovery programs have become an important focus of perioperative management. A few studies have demonstrated the efficacy of an enhanced recovery after surgery (ERAS, which includes optimized pain control, restricted I.V. fluids, early initiation of postoperative oral feeding, and enforced mobilization) protocol in patients undergoing radical gastrectomy. We investigated the feasibility and safety of laparoscopic radical gastrectomy within ERAS programs.

Methods:

In this single-center prospective randomized controlled trial conducted between September 2013 and August 2014, 149 consecutive locally advanced gastric cancer patients (T2–4, any N, M0) diagnosed by the CT scanning were allocated to either ERAS group (N = 73) or conventional pathway group (N = 76). The same surgical technique was used in both groups, that is, laparoscopic gastrectomy with D2 lymphadenectomy and R0 resection. Intergroup differences were evaluated for clinical parameters and C-reactive protein for testing tissue injury.

Results:

ERAS combined with laparoscopic gastrectomy was observed in our study. Recovery parameters such as time to return to normal diet (days) 1.90 ± 0.71 versus 3.52 ± 0.81, P = .003 and time to the first defecation (days) 2.97 ± 1.23 versus 5.20 ± 1.81, P = .015 were measured. The post hospital stay (days) in ERAS and the conventional care group were 6.38 ± 2.04 and 8.62 ± 2.87, P < .001, respectively. No statistically significant intergroup differences were observed in terms of postoperative complications and C-reactive protein levels. One patient in the ERAS group was readmitted because of anastomotic leakage. No instances of deaths were reported during the 30-day follow-up period.

Conclusion:

This study demonstrates the feasibility and safety of ERAS protocol in advanced gastric cancer patients undergoing laparoscopic radical gastrectomy and was associated with shorter duration of hospital stay. (Clinicaltrials.gov Identifier No NCT02348229).

Introduction

Pioneered by Wilmore and Kehlet¹ in 1990s, Enhanced Recovery After Surgery (ERAS) approach has been applied to various surgical specialties. In particular, the approach has been extensively studied in the context of colorectal, urological, and head and neck surgery^2–4 and has gained wider acceptance due to its associated benefits of improved cardiopulmonary function, early return of bowel function, fewer complications, shorter hospital stay, and early return to normal activities.

Globally, ∼1 million new cases of gastric cancer are diagnosed every year, of which, 400,000 cases are diagnosed in China alone.^5,6 Surgical resection of gastric cancer and regional lymphadenectomy is the only curative option in these patients. Some recent studies have demonstrated the efficacy of ERAS for gastrectomy.^7,8 The components of ERAS rehabilitation include optimized pain control, restricted I.V. fluids, early initiation of postoperative oral feeding, and enforced mobilization with the aim of reducing surgical stress response.

Ever since its introduction in 1994 by Kitano et al.,⁹ laparoscopic gastrectomy (LAG) has become the standard treatment for early gastric cancer. With the recent technological advancements in surgical instrumentation, coupled with the increased surgeon experience with the technique, laparoscopic radical gastrectomy has been used even for more advanced disease in the gastric cancer population. Compared to conventional open gastrectomy, LAG shows significant advantages.¹⁰ The applicability of the ERAS approach to LAG for locally advanced resectable gastric cancer has not been investigated in detail. The aim of this study was to determine the feasibility and safety of ERAS approach in these patients by comparing the recovery parameters and surgical outcomes between the ERAS and the conventional pathway groups.

Materials and Methods

Study design

This study is a prospective, single-center, randomized controlled trial (NCT02348229). The study protocol was approved by the Ethics Committee at the First Hospital of Jilin University. Patients with operable advanced gastric cancer (T3, T4, Any N, M0 or Any T, N+ M0) receiving treatment at the Department of Gastric and Colorectal Surgery were screened for enrollment in the study.

Selection criteria

The inclusion criteria were: (1) A preoperative cancer stage of T2, T3, T4a, Any N, M0 without digestive obstruction confirmed by whole body CT scan, which could be treated with LAG; (2) age 18–75 years; (3) pathologic confirmation of gastric adenocarcinoma by endoscopic biopsy; (4) normal hematological, renal, hepatic, and cardiac parameters, ASA score ≤ III without severe systemic disease; and (5) no history of treatment with neoadjuvant chemotherapy and/or radiotherapy. Written informed consent was obtained from all participants. The following patients were excluded from the analysis: patients requiring conversion to open gastrectomy; excessive bleeding (>500 mL); and patients opting out of the study.

Patients and groups

From September 2013 to August 2014, 152 patients of the same surgeon that met the eligibility criteria were randomly assigned to one of the two study groups based on the treatment approach: LAG with ERAS rehabilitation program (ERAS group) and LAG with conventional postoperative care (conventional group) (N = 76 in both groups) (Table 1). Randomization was performed with a computerized random-number generator by a researcher not involved in patient recruitment. Baseline characteristics of the patients are presented in Table 3. One patient in the ERAS group suffered from excessive bleeding during the operation and the two other patients withdrew their consent during the course of the study (Fig. 1).

FIG. 1.

One hundred fifty-two patients of the same surgeon that met the eligibility criteria were randomly assigned to one of the two study groups with a computerized random-number generator based on the treatment approach: LAG with ERAS rehabilitation program (ERAS group) and LAG with conventional postoperative care (conventional group) (N = 76 in both groups). Three patients in the ERAS group did not receive the allocated intervention for some reasons. ERAS, Enhanced Recovery After Surgery; LAG, laparoscopic gastrectomy.

Table 1.

Perioperative Protocol by Study Group: Patients Undergoing Laparoscopic Gastrectomy with D2 Lymphadenectomy

	ERAS	Conventional postoperative care
PreOp	Preoperative education about ERAS;	No solid foods at dinner before the day of surgery; no liquids 12 hours before surgery;
	Normal meal allowed until 6 hours before surgery and carbohydrate drink until 2 hours before surgery	Routine bowel preparation; Nasogastric placement on the morning of surgery.
	No bowel preparation
	Avoid nasogastric tube placement;
	If used, tube removal on the first postoperative day
Intraoperative	Nonopioid analgesia after induction of anesthesia;	Routine use of anesthetic medicines;
	Need-based vasoactive drug administration;	Standard five-trocar laparoscopy-assisted procedure;
	Standard five-trocar laparoscopy-assisted procedure;	I/V fluids not restricted (Ringer's lactate 20 mL/kg in the first hour, followed by 10–12 mL/kg/h);
	Limited intraoperative intravenous fluids (1:2 L crystalloids/colloids);	Routine use of abdominal drainage tubes and placement of catheters.
	Minimally invasive incisions (epigastrium midline incision about 5–8 cm);
	Temperature management (aim for body temperature of 37°C);
	Intra-abdominal drains not to be used if possible;
	Intraperitoneal Ropivacaine infusion at the end of surgery.
1st PostOp day	Nasogastric catheter removed;	Keep Nil Per Os;
		Removal of urinary catheter;
	Urinary catheter removed;	Intramuscular opioid analgesics;
		Parenteral nutrition until flatus;
		I.V. fluids not restricted;
	Oral nonopioid analgesia;	Mobilization in bed.
	Oral fluids 0.5 L;
	I/V fluids (Ringer's lactate) @1 mL/kg/h;
	Active mobilization out of bed.
2nd PostOp day	Drains removed;	Patient is advised not to get out of bed until 24–48 hours after surgery.
	Stop I/V fluids if drinks >2000 mL;
	Oral diet initiated from water to carbohydrate drink to Enteral nutritional suspension, then to semifluids and normal food;
	Increased ambulation in the ward;
	Pain control maintained.
3–4th PostOp day	Stop oral nonopioid analgesia;	Remove nasogastric tube after passage of flatus;
		Oral liquids started;
	Continue as above.	Encouraged to walk in the ward.
5–6th PostOp day	Check discharge criteria.	Oral diet changed from liquids to semifluids and normal food;
		Drains removed.

ERAS, Enhanced Recovery After Surgery.

Study end points

The primary end points of the study were length of postoperative stay, time to first defecation, and time to first solid food intake after the procedure. Patients were discharged once they were fully mobile and felt comfortable with two-thirds or more oral food. Postoperative complications and serum indices were documented as secondary end points.

Sample size and statistical analysis

A power analysis determined that at least 72 patients would be required for each group with an alpha level of 0.05% and 90% power for primary end points.

Data expressed as mean ± standard deviation were analyzed by independent Student's t-test, while the categorical data were analyzed by χ² test. All statistical analyses were performed using SPSS^® version 18 software (SPSS, Inc., Chicago, IL). P < .05 was considered statistically significant.

Intervention

Patients were admitted 1–3 days before their respective dates of operation. An ERAS protocol was used in the ERAS group. The other group received conventional care.

Patients in the ERAS group were educated to ensure that they were ready to participate in the ERAS program preoperatively. They were allowed to take normal meal until 6 hours before the operation and then drink carbohydrate until 2 hours before the operation. Mechanical bowel preparation and nasogastric tube were avoided. During surgery, guidelines for the conduct of anesthesia were provided, including nonopioid analgesia after induction of anesthesia; need-based vasoactive drug administration; restriction of intravenous fluids (1:2 L crystalloids/colloids); and intraperitoneal Ropivacaine infusion. Postoperatively, the ERAS group was provided with specific instructions for nonopioid pain control, early drain removal, early oral diet, and early mobilization. Details of the two care protocols are summarized in Table 1.

Depending on the location of the primary tumor, total or distal subtotal gastrectomy was performed. There was no difference in terms of surgical procedure and types of anastomoses between the two groups, including Billroth II, and Roux-en-Y. Due to the location and the size of the tumors, there were no patients with Billroth I anastomosis in the trial. After resection, a similar supraumbilical midline incision about 5–8 cm was made for restoration of intestinal continuity and tumor retrieval in both groups. D2 lymph node dissection was done in compliance with the Guidelines of Japanese Gastric Cancer Association.^11,12

The following clinical parameters were recorded: age, sex, tumor location, type of gastrectomy and reconstruction, T stage, number of lymph nodes retrieved, duration of operation, complications, and postoperative outcomes (time to return to diet, first defecation). Blood samples were collected at 7:00 AM 1 day before and 1–5 days after operation. Serum concentrations of C-reactive protein were determined with the ELISA Kit.

Results

One hundred forty-nine consecutive patients were included in this analysis and followed up. Mean age was 61 years in the ERAS group and 63 years in the conventional group, with 2:1 male to female ratio. The clinical data of all the patients are summarized in Table 2. D2 lymphadenectomy was performed in all patients. Number of lymph nodes retrieved, duration of surgery, amount of blood loss, and type of surgery are shown in Table 3.

Table 2.

Clinical Characteristics of Subjects by Study Group

	ERAS	Conventional	P
Gender (male/female)	48/25	50/26	.996
Age (years)	61 (40–75)	63 (35–75)	.401
American Society of Anesthesiologists score	2 (2–3)	2.5 (2–3)	.075
Tumor location
Upper	9	11
Middle	23	25	.889
Lower	41	40

Table 3.

Surgical and Oncological Characteristics by Study Group

Variables	ERAS	Conventional	P
Type of anastomoses
Billroth II	56	55	.543
Roux-en-Y	17	21
Tumor stage
IB	1	2	.458
IIA	9	12
IIB	11	21
IIIA	20	14
IIIB	25	19
IIIC	7	8
Blood loss (mL)	56.50 ± 74.85	68.52 ± 85.80	.650
Operation time (min)	140.43 ± 35.47	135.65 ± 30.50	.636
Reconstruction
Billroth I	8	5	.579
Billroth II	48	50
Esophagojejunal anastomosis	17	21
Lymph nodes retrieved	23.85 ± 5.14	25.14 ± 5.67	.146

Compared to the conventional group, patients in the ERAS group showed faster recovery with noticeably shorter length of postoperative hospital stay (8.62 ± 2.87 versus 6.38 ± 2.04, P < .001). Postoperative food intake in the ERAS group was started earlier than that in the conventional group (1.90 ± 0.71 versus 3.52 ± 0.81, P = .003). There was also a significant difference in time to defecation between the ERAS and conventional group (2.97 ± 1.23 versus 5.20 ± 1.81, P = .015).

There was 1 case of ileus in the conventional group, who was treated with nasogastric aspiration and total parenteral nutrition for 10 days. One patient in the ERAS group suffered from fever and was readmitted because of the anastomotic leakage that was diagnosed by digestive tract radiography on the fifth postoperative day. He was managed by puncture drainage, nasogastric decompression, and total parenteral nutrition for 3 weeks without any subsequent complications. One patient in each group suffered from wound infection. No significant intergroup differences were observed with respect to incidence of complications (P = .573) (Table 4). No mortality was reported during the 30-day follow-up period (Table 5).

Table 4.

Postoperative Outcomes by Study Group

Variables	ERAS	Conventional	P
Time to first defecation (days)	2.97 ± 1.23	5.20 ± 1.81	.015
Time to first solid food intake (days)	1.90 ± 0.71	3.52 ± 0.81	.003
POS (days)	6.38 ± 2.04	8.62 ± 2.87	.000

Table 5.

Complications and Readmission by Study Group

Variables	ERAS	Conventional	P
Morbidity
Wound infection	1	1	.573
Postoperation bleeding	0	0
Ileus	0	1
Stenosis	0	0
Leakage	1	0
Others	0	0
Mortality	0	0	—

The C-reactive protein (CRP) levels in both groups were significantly elevated after the operation (P < .001), with the peak level observed on postoperative day 2 (Table 6). The postoperative CRP levels in the conventional group were slightly higher than those in the ERAS group; however, the difference was not statistically significant (P = .07) (Fig. 2).

FIG. 2.

The CRP levels in both groups were significantly elevated on the first day after the operation (P < .001) and peaked on second postoperative day followed by a persistent decrease in their levels. The postoperative CRP levels in the conventional group were slightly higher than those in the ERAS group; however, the difference was not statistically significant (P = .07). CRP, C-reactive protein.

Table 6.

Trends in Postoperative CRP Levels by Study Group

	PreOp	1st PostOp day	2nd PostOp day	3rd PostOp day	4th PostOp day	5th PostOp day
ERAS	1.47 ± 1.23	37.01 ± 18.04	94.72 ± 43.01	73.28 ± 3 3.53	64.84 ± 40.24	39.12 ± 31.85
Conventional	1.86 ± 0.95	48.73 ± 25.50	110.39 ± 43.95	78.61 ± 29.76	71.84 ± 28.12	47.42 ± 37.31

Discussion

Even though LAG was first performed over 20 years ago, the applicability of this technique in certain conditions continues to be debated.^13,14 Experts believe that it is very difficult to perform radical lymphadenectomy using laparoscopic approach, particularly in advanced cancer patients. Moreover, there are relatively few centers in the world where laparoscopy is routinely used for gastric resection. However, some prospective trials in Japan, Korea, and China evaluated the safety and oncological feasibility of LAG for early or advanced gastric cancer.^15–17 Some of them have provided robust evidence of the safety, feasibility, and efficacy of LAG in advanced gastric cancer, with outcomes comparable to that achieved with open gastrectomy. The advantages of LAG in terms of decreased pain, less cosmetic disfigurement, shorter length of hospital stay, less postoperative pain, and better quality of life are universally acknowledged.^18,19

The ERAS approach is a multimodal perioperative care pathway designed to achieve fast recovery after surgery, including patients education, anesthesia, goal-direct fluid therapy, prevention of nausea and ileus, minimally invasive techniques, temperature monitoring, early nutrition, and early mobilization. All the elements within protocols help to reduce stress response to surgical injury and maintain homeostasis. It can be inferred that LAG and ERAS have several commonalities in principle and approach. However, the combination of LAG and ERAS has not been evaluated for surgical safety and outcomes.

This prospective, single-center, randomized controlled trial of ERAS program was performed in association with LAG technique. With the principles of ERAS, we were able to show an improvement in accelerated return of digestive function among the patients after the laparoscopic radical gastrectomy.

The primary end points of this research were postoperative stay, time to first defecation, and time to first solid food intake. At First Hospital of Jilin University, the last 5 years mean postoperative stay for similar patients was 8.54 days, with a standard deviation of 2.94 days. According to relevant reports, the clinical difference was 1.59 days of the postoperative stay between the two groups.²⁰ In our study, the postoperative stay in the ERAS group was significantly lower than that in the conventional group (6.38 ± 2.04 versus 8.62 ± 2.87; P = .013), without increase in postoperative morbidity and mortality, which is similar with the historical data and other reports.^21,22 Currently, a few publications report improved postoperative outcomes in laparoscopic gastric surgery as a result of enhanced recovery programs.^21,22 Such publications emphasize the shorter hospital stays that result from using the ERAS protocol, which is similar to results obtained in our study.

In the ERAS group, time to first defecation was 2.97 ± 1.23 days, while in the conventional group it was 5.20 ± 1.81 days (P = .015), time to return to normal diet (days) was 1.90 ± 0.71 versus 3.52 ± 0.81 (P = .003), while no statistically significant intergroup differences were observed in terms of postoperative complication. Our result indicated that early intake of normal food and activity did not increase the incidence of postoperative complications. Based on the traditional concept that eating soon after operation might cause intestinal obstruction and anastomotic disruption, surgeons routinely order oral intake restriction to patients receiving conventional care. However, a recent prospective study has confirmed that early oral feeding after laparoscopic gastric surgery is safe and might be associated with enhanced recovery with shorter hospital stay.² Furthermore, we believe that early oral feeding, nonopioid oral analgesia, and early mobilization have an important impact on gut recovery by the activation of normal digestive reflexes, which is central to rehabilitation after gastrectomy. CRP, an acute phase protein, is a nonspecific parameter which measures the concentration in blood serum of a specific type of protein produced in the liver. It plays an important role in the immunologic defense mechanism and tends to reflect the extent of tissue injury after surgery. Recently, Silvestre et al. demonstrated that CRP was useful in distinguishing between infected and noninfected patients with a significant difference after elective colorectal surgery.²² In the present study, CRP was used as a predictive index of persistent postoperative inflammatory activity.²³ The average CRP levels in both groups increased after surgery and peaked on second postoperative day followed by a persistent decrease in their levels. The continued rise in CRP levels is usually indicative of occult infection or anastomotic leakage²⁴ and is likely to be associated with increased duration of hospital stay. In patients with wound infection (n = 2) and anastomotic site leakage (n = 1) in our study, the CRP levels were found to be increased at the start of the complication and then decreased gradually, reflecting a more complex and prolonged recovery. Based on this result, we speculate that CRP levels may be a sensitive predictor for discharge; however, this needs further verification in a larger multi-institutional study.

Conclusion

This study has demonstrated that a laparoscopic technique combined with an enhanced recovery program is feasible and safe and can result in excellent short-term outcomes in locally advanced gastric cancer. CRP appears to be a good predictor of surgical complication and duration of recovery.

Footnotes

Disclosure Statement

No competing financial interests exist.

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