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* Corresponding aut

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EJSO 43 (2017) 210e217 www.ejso.com

Enhanced recovery after surgery for gastric cancer and an assessment of preoperative carbohydrate loading

R. Makuuchi a, N. Sugisawa b, S. Kaji a, M. Hikage a, M. Tokunaga a, Y. Tanizawa a, E. Bando a, T. Kawamura a, M. Terashima a,*

aDivision of Gastric Surgery, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-Cho, Sunto-Gun,

Shizuoka, 411-8777, Japan bDepartment of Surgery, Tohoku University Graduate School of Medicine, 2-1, Seiryo-Machi, Aoba-Ku,

Sendai-Shi, Miyagi, 980-8575, Japan

Accepted 25 July 2016

Available online 10 August 2016

Abstract

Background: We previously reported on the feasibility of enhanced recovery after surgery (ERAS) protocol for gastric cancer with a pro- spective phase II study, but the superiority of this approach over non-ERAS perioperative management remains unclear. Preoperative car- bohydrate loading, an important element of the ERAS protocol, has been shown to reduce insulin resistance, but its effects on clinical endpoints in gastric cancer surgery remain controversial. The aim of this study was to clarify the efficacy of the ERAS protocol for gastric cancer surgery, with particular focus on preoperative carbohydrate loading. Methods: In this ERAS caseecontrol study, we enrolled 121 patients as a case group and 259 patients undergoing gastrectomy for gastric cancer with our conventional perioperative management as a control group. Matched-pair analysis was performed to balance the patients’ characteristics for comparison analysis. Results: After matching, 108 patients were included in each group. Postoperative hospital stay was significantly shorter in the ERAS group than in the control group (8 days vs. 9 days, p < 0.001), while the incidence of ClavieneDindo classification grade II or more postoperative complication was similar between the groups (11.1% vs. 15.7%, p ¼ 0.325). No significant differences were found in serum albumin level, body weight, or grip strength between the groups before surgery and at 1 week and 1 month after surgery. Conclusion: Use of the ERAS protocol for gastric cancer shortened the length of postoperative hospital stay without increasing complica- tions. Preoperative carbohydrate loading didn’t improve the postoperative nutritional status or maintain the muscle strength postoperatively. � 2016 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Keywords: Stomach neoplasms; Gastrectomy; Perioperative care; Carbohydrates; Case-control study

Introduction

The enhanced recovery after surgery (ERAS) protocol, also known as fast track surgery, involves integrated appli- cation of various medical interventions to accelerate recov- ery after surgery. It has been shown to shorten postoperative hospital stay and reduce postoperative complication in various surgeries, particularly colorectal surgery.1e5

Although randomized controlled trials have demonstrated the superiority of the ERAS protocol in gastric surgery,6e9

there was significant heterogeneity in non-ERAS

hor. Fax: þ81 55 989 5783. [email protected] (M. Terashima).

16/j.ejso.2016.07.140

sevier Ltd, BASO ~ The Association for Cancer Surgery,

management of control subjects and most trials included fewer than 50 patients in each group. Thus, the evidence supporting use of the ERAS protocol for gastric cancer sur- gery was considered insufficient.

Preoperative oral carbohydrate loading is one of the main elements of the ERAS protocol and has been demon- strated by several studies to reduce insulin resistance after surgery.10e12 However, its effects on clinical endpoints, such as the occurrence of postoperative complications and maintenance of muscle strength, remain controversial because of inconsistencies possibly due to small numbers of participants and heterogeneous groups of patients under- going surgical procedures of differing degrees of severity.

and the European Society of Surgical Oncology. All rights reserved.

211R. Makuuchi et al. / EJSO 43 (2017) 210e217

We previously reported a prospective phase II study to evaluate the feasibility of the ERAS protocol for gastric can- cer in 121 patients undergoing gastrectomy with curative intent.13 This study investigated a number of factors, namely omission of bowel preparation, preoperative oral carbohy- drate loading, shortening of the perioperative fasting period, use of epidural analgesia, and early postoperative mobiliza- tion. We concluded that the ERAS protocol can be safely used for gastric cancer surgery, with an incidence of postop- erative complications of 10.7%. Although we previously included several elements of the ERAS protocol in our con- ventional preoperative care, preoperative oral carbohydrate loading and initiation of postoperative feeding on postopera- tive day (POD) 2, 1 day earlier than our conventional care, were newly introduced to the ERAS study.

It remained unclear whether the ERAS protocol improved clinical endpoints compared with conventional perioperative management, and the validity of preoperative oral carbohydrate loading for gastric cancer surgery was uncertain. We therefore conducted a caseecontrol study with patients in the ERAS study as the case group and pa- tients undergoing gastrectomy with our conventional peri- operative care as the control group. The aim of this study was to clarify the validity of the ERAS protocol for gastric cancer surgery, with particular focus on the efficacy of pre- operative oral carbohydrate loading.

Patients and methods

Patients

The 121 patients in our ERAS investigation were enrolled in this study as the case group (the ERAS group). Between January 2011 and December 2012, 680 patients underwent gastrectomy with conventional perioperative care in Shizuoka Cancer Center, Shizuoka, Japan; of these, 259 patients who met the inclusion criteria were enrolled to form the control group. Inclusion criteria were the same as for the ERAS study, namely age 20e75 years, histological- ly confirmed adenocarcinoma of the stomach for which curative gastrectomy was expected without simultaneous resection of other organs except for the gallbladder, no involvement of the duodenum or esophagus, sufficient oral intake, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, no contraindication for epidural anesthesia, no prior chemotherapy or radio- therapy for any malignancy, and adequate organ function. Patients who had uncontrolled diabetes or who needed the administration of insulin were excluded.

The data collection and analysis were approved by the institutional review board of the Shizuoka Cancer Center.

Matching

As the number of patients undergoing laparoscopic or robotic gastrectomy had been increasing during the study

period, we performed matched-pair analysis to balance pa- tient characteristics for the comparison analysis. Each pa- tient in the ERAS group was matched with one patient in the control group on the basis of sex, age, and surgical approach (open or laparoscopic/robotic gastrectomy).

Conventional perioperative management

The protocol for the conventional perioperative manage- ment of the control group is shown in Fig. 1. Patients were al- lowed a normal diet until the day before surgery and were permitted to drink clear fluid until three hours before anes- thesia. Neither premedication for bowel preparation nor pre- medication for anesthesia was administered before surgery, and all patients walked to the operation room. An antibiotic drug (Cefazolin) was administered before the skin incision and every three hours subsequently, finishing with one infu- sion after surgery. Intraoperative fluid management was decided by the anesthesiologist, following the policy of avoiding sodium and fluid overload. A nasogastric tube was inserted before surgery and removed three hours after surgery unless there was any sign of bleeding. On postoperative day (POD) 1, patients startedwalking, and on POD2, they started drinking clear fluid. On POD 3, oral intake of a liquid diet commenced and was stepped up to a soft diet every day in three steps. Abdominal drainage tubeswere inserted in all pa- tients and removed at a time deemed appropriate by an attending surgeon. The urinary catheter was removed on POD 3 and the epidural analgesia catheter on POD4. Patients without fever and who ate more than half of their food were discharged between POD 8 and 10. Routine pharmacological thromboprophylaxis was not administered unless preopera- tive venous ultrasonography, routinely performed for all pa- tients, showed deep venous thrombosis.

ERAS protocol

The ERAS protocol has previously been described in detail.13 Briefly, patients were allowed to ingest a solid diet until the day before surgery, and to drink 500 ml of a carbohydrate-rich drink (18.0 g carbohydrate per 100 ml Arginaid water; Nestle Health Science, Japan) after dinner. On the day of surgery, another 250 ml was drunk at least 3 h before anesthesia. Patients were allowed to start drink- ing clear fluids on POD 1, 1 day earlier than under conven- tional management. Oral intake also began 1 day earlier, on POD 2, with a liquid diet, and was stepped up to a soft diet over the course of 3 days. Patients were discharged between POD 7 and 10.

Evaluation of early surgical outcomes

We defined postoperative complication as any morbidity observed within 30 days after the first discharge. The severity of complication was graded using the ClavieneDindo classi- fication.14 Patients who suffered a ClavieneDindo

Figure 1. Conventional management protocol followed for gastric cancer surgery.

212 R. Makuuchi et al. / EJSO 43 (2017) 210e217

classification grade II or higher event were defined as having a postoperative complication. We defined postoperative hos- pital death as mortality from any cause observed within 30 days after surgery, and defined hospital readmission as a re- admission within 30 days after the first discharge.

Nutritional status and muscle strength

To evaluate change in nutritional status, body weight and serum albumin level were measured preoperatively, on POD 6, and 1 month after discharge. To evaluate muscle strength, grip strength was measured in the non-dominant hand using a hand-held dynamometer preoperatively and 1 month after discharge.

Statistical analyses

Continuous variables are presented as medians (range). Statistical analyses were performed using the Fisher’s exact test, Student’s t-test, and the ManneWhitney U test. Statis- tical significance was defined as p < 0.05.

All statistical analyses were performed using R statistics version 3.2.2.

Results

Patient characteristics

After the matching process, 108 patients were included in each group. The characteristics of the patient groups

before, and after, matching are shown in Table 1. Before matching, there was no difference between the groups in any characteristics. After matching, lymph node metastasis was slightly higher in the ERAS group than in the control group, although this difference did not reach statistical sig- nificance (p ¼ 0.059). There was no difference between the groups in any other characteristics.

Surgical treatment

Surgical treatments of both groups before, and after, matching are shown in Table 2. Before matching, there were no differences between the groups in the type of gastrectomy or degree of lymph node dissection. Laparoscopic or robotic gastrectomy was more frequently performed in the ERAS group (69.4% vs 31.3%, p < 0.001), and there was no differ- ence between the groups in the incidence of residual tumors.

After matching, more patients in the ERAS group than the control group underwent total gastrectomy and D2 lymph node dissection (p ¼ 0.027 and p ¼ 0.022, respectively), and the surgical approach was similar between the groups. However, robotic gastrectomy was performed more frequently in the ERAS group than in the control group (31 of the 71 laparoscopic/robotic surgery patients in the ERAS group and 12 of the 71 patients in the control group).

Early surgical outcomes

Early surgical outcomes are shown in Table 3. Before matching, intraoperative blood loss was significantly lower

Table 1

Patient characteristics.

Unmatched comparison Matched comparison

ERAS Control p value ERAS Control p value

Number of patients 121 259 108 108

Age (years) 0.688 0.675

Median 64 63 64.5 64

Range 24e74 25e75 35e74 38e75

Sex (cases) 0.908 1

Male 78 169 71 71

Female 43 90 37 37

BMI (kg/m2) 0.48 0.562

Median 22.5 22.8 22.5 22.8

Range 16.5e29.6 15.4e32.1 16.5e29.6 15.4e30.5 ECOG performance status 1 1

0 121 259 108 108

1/2 0 0 0 0

Tumor depth 0.436 0.126

T1 (M/SM) 93 205 82 95

T2 (MP) 15 20 13 5

T3 (SS) 6 19 6 4

T4 (SE/SI) 7 15 7 4

Lymph node metastasis 0.308 0.059

N0 108 239 95 104

N1 8 7 8 1

N2 4 9 4 2

N3 1 4 1 1

Clinical stage (cases) 0.926 0.119

IA 91 202 80 95

IB 13 19 11 5

IIA 7 18 7 4

IIB 4 7 4 0

IIIA 3 5 3 1

IIIB 2 6 2 2

IIIC 1 2 1 1

IV 0 0 0 0

BMI, Body Mass Index; ECOG, Eastern Cooperating Oncology Group.

Table 2

Surgical treatments.

Unmatched comparison Matched comparison

ERAS Control p value ERAS Control p value

Type of gastrectomy (cases) 0.257 0.027

Distal gastrectomy 76 134 69 57

Pylorus preserving gastrectomy 31 82 27 44

Proximal gastrectomy 4 13 4 5

Total gastrectomy 10 30 8 2

Lymph node dissection (cases) 1 0.022

D1þ 88 188 76 91 D2 33 71 32 17

Surgical approach (cases) <0.001 1

Open 37 178 37 37

Laparoscopic/robotic 84 81 71 71

Residual tumor (cases) 0.183

0 121 254 108 106

1/2 0 5 0 2

213R. Makuuchi et al. / EJSO 43 (2017) 210e217

and operation time was significantly longer in the ERAS group than in the control group. Although postoperative complications were more frequent in the control group these were not statistically significant (10.7% vs. 18.1%, p ¼ 0.071). Anastomotic leakage occurred in one patient

in the ERAS group and in two patients in the control group, while pneumonia occurred in six patients in the control group, but did not occur in the ERAS group. Postoperative hospital stay was significantly shorter in the ERAS group than in the control group (8 days vs. 9 days, p < 0.001),

Table 3

Early surgical outcomes.

Unmatched comparison Matched comparison

ERAS Control p value ERAS Control p value

Blood loss (ml) <0.001 0.279

Median 30 134 35 59

Range 0e728 0e852 0e728 0e654

Operation time (min) <0.001 <0.001

Median 290 225 289.5 245.5

Range 109e486 105e400 109e486 105e400 Postoperative complication (cases) 13 47 0.071 12 17 0.325

Postoperative hospital death (cases) 0 0 1 0 0 1

Length of postoperative hospital stay (day) <0.001 <0.001

Median 8 9 8 9

Range 6e30 7e91 6e30 7e91

Hospital readmission (cases) 0 7 0.103 0 1 1

214 R. Makuuchi et al. / EJSO 43 (2017) 210e217

and seven patients in the control group, but none in the ERAS group, were readmitted within 30 days after first discharge. Two patients experienced bowel obstruction and one underwent reoperation 40 days after first discharge, while one patient had an intraabdominal abscess and needed a drainage tube inserted. Three patients experienced distal gastric emptying and another esophageal reflux. Re- operation within 30 days after first discharge was per- formed on four patients, all from the control group. Three of these had bowel obstructions while another experienced intraabdominal bleeding. There was no mortality in either group.

After matching, results show that operation time was significantly longer in the ERAS group (289.5 min vs 245.5 min, p < 0.001), although the incidence of postoper- ative complications was similar between the groups (11.1% vs 15.7%, p ¼ 0.325). There were no postoperative hospital deaths in either group, and postoperative hospital stay was significantly shorter in the ERAS group than in the control group (8 days vs. 9 days, p < 0.001). One patient in the control group was readmitted within 30 days after first discharge.

Nutritional status and muscle strength

After matching, there was no statistically significant dif- ference between the two groups in median serum albumin level (Fig. 2A), body weight (Fig. 2B), or grip strength (Fig. 2C) at any of the measurement time points.

Discussion

This caseecontrol study resulted in two important find- ings. First, the ERAS protocol shortened the length of post- operative hospital stay without increasing postoperative complications. Second, preoperative carbohydrate loading neither improved postoperative nutritional status nor main- tained muscle strength postoperatively.

The median postoperative hospital stays for the ERAS and the control groups were 8 and 9 days, respec- tively. Although the difference between them was only 1 day, this was statistically significant. Several other studies have also shown that the ERAS protocol short- ened postoperative hospital stay, mainly because of faster recovery after surgery, which resulted in a shorter duration of flatus and less postoperative pain. In this study, patients in the ERAS group began oral feeding earlier than those in the control group and were dis- charged 1 day earlier, the main reason for their short- ened stay.

Early postoperative oral feeding has been shown to accelerate recovery after various types of surgery. However, this approach was not adopted in upper gastrointestinal sur- gery for a long time because of concerns that early food intake could cause anastomotic leakage due to direct stim- ulation of anastomotic sites and elevation of intraluminal pressure. Recently, patients in Japan and Korea have gener- ally been allowed to start oral feeding between POD 3 and POD 5.15 Additionally, one randomized controlled trial re- ported on the safety of early oral feeding at POD 2 after gastrectomy.16 We initiated oral feeding at POD 3 as part of our conventional management in 2010, advanced by 1 day to POD 2 in our ERAS protocol. One case of anasto- motic leakage was observed in the ERAS group; however, there was no statistical difference between the two groups, indicating that oral feeding at POD 2 was safe. Indeed, an earlier initiation of oral feeding allowed earlier discharge.17

In this study, there was no significant difference between the groups in rate of postoperative complications. In previ- ous RCTs, the effect of the ERAS protocol on postoperative complications has been controversial.6e9,18 However, most perioperative management for control groups in previous RCTs has been outdated, involving processes such as pre- operative fasting, preoperative bowel preparation, and the initiation of oral intake after flatus, procedures no longer practiced by most hospitals in Japan and Korea. Thus, it is difficult to accept the results in those studies. Feng

2PG1PG

time after surgery time after surgery time after surgery

Before surgery 1 week 1 month Before surgery 1 week 1 month Before surgery 1 month

Grip strengthSerum albumin level Body weight (kg)

(kg) (g/dl)

ERAS

Control

ERAS

Control

ERAS

Control

A B C

Figure 2. Nutritional status and muscle strength preoperatively and postoperatively. A. Comparison of serum albumin level between the two groups preop-

eratively and at 6 days and 1 month postoperatively (ERAS: 4.4, 3.5, and 4.2 g/dl and control: 4.4, 3.5, and 4.3 g/dl, respectively). B. Comparison of body

weight between the two groups preoperatively and at 6 days and 1 month postoperatively (ERAS: 58.7, 56.3, and 54.7 kg and control: 60.4, 58.0, and 55.8 kg,

respectively). C. Comparison of grip strength between the two groups preoperatively and 1 month postoperatively (ERAS: 30.3, and 29.8 kg and control: 30.0

and 29.2 kg, respectively).

215R. Makuuchi et al. / EJSO 43 (2017) 210e217

et al.6 reported an RCT on 119 patients who underwent radial total gastrectomy for gastric cancer and in which fast-track surgery reduced the rate of postoperative compli- cations from 28.33% to 10.17%. However, for reasons that are unclear, the rate of postoperative complications in their control group was much higher than in ours, so we cannot rule out that possibility that other factors affected the re- sults. In other RCTs, no significant difference was demon- strated between ERAS and control groups in incidence of postoperative complications. Those studies, however, had small sample sizes, with fewer than 50 cases in each group. For example, Beamish et al.19 reported a significantly lower incidence of complications in the ERAS group when they integrated six high-quality studies. In this study, no statisti- cally significant difference was observed between groups in rate of complications (11.1% and 15.7% in the ERAS and the control groups, respectively) and we thus concluded that the ERAS protocol does not reduce postoperative com- plications compared with mainstream perioperative man- agement in Japan and Korea. It may be difficult to reduce complications by introducing the ERAS protocol in regions where perioperative management is already similar to the ERAS protocol and the incidence of postoperative compli- cations is low.

In this study, preoperative carbohydrate loading neither improved postoperative nutritional status nor maintained muscle strength postoperatively. Preoperative carbohydrate loading, which plays a significant role in the ERAS proto- col, is mainly intended to reduce postoperative insulin resistance. Surgical stress and preoperative fasting cause in- sulin resistance, leading to hyperglycemia and possibly to increased postoperative complications,20 while insulin resistance also leads to an increase in the catabolism of skeletal muscle and results in the loss of body fat and

protein stores.21,22 Preoperative carbohydrate loading stim- ulates endogenous insulin release, which switches off the overnight fasting metabolic state and tends to reduce the extent of peripheral insulin resistance while ameliorating the surgical stress response.23 As a result, it is expected that there should be a reduction in complications and main- tenance of nutritional status and muscle strength. However, in past clinical practice, various results have been obtained regarding postoperative nutritional status. Yamada et al.15

reported that the ratio of postoperative to preoperative body weight was higher in the ERAS group than the control group after 1 week. Although a 12.5% carbohydrate drink is generally used for preoperative carbohydrate loading, in this study a 2.5% carbohydrate one was used, leading to doubts about sufficiency of carbohydrate loading. In contrast, we used a 18.0% carbohydrate beverage in our study, with a volume considered sufficiently high for preop- erative loading. The effect of carbohydrate loading on post- operative muscle strength had been reported in several studies, but no definite conclusion has been reached.5,11,12,24 In particular, because no report focused on gastric cancer surgery has been published, the effect of carbohydrate loading in gastric cancer remains unclear. In this study, nutritional status and muscle strength were almost the same in the ERAS and control groups, indicating that preoperative carbohydrate loading had little influence on muscle strength and body weight, at least in gastric can- cer surgery without invasion under modern perioperative management.

One of the limitations of this investigation was that it was a retrospective study at a single institute. Nevertheless, a sample size of over 300 patients is large enough to ensure its value. Secondly, surgical procedures differed greatly be- tween the two groups because of different enrollment times.

216 R. Makuuchi et al. / EJSO 43 (2017) 210e217

The rate of minimally invasive surgeries including laparo- scopic gastrectomy and robotic gastrectomy was much higher in the ERAS group than in the control group. Laparo- scopic gastrectomy was not approved as standard treatment for gastric cancer before the introduction of the ERAS pro- tocol, and most patients in the control group underwent open gastrectomy. Robotic gastrectomy with the DaVinci Surgi- cal System was introduced in January 2012, and more pa- tients in the ERAS group underwent robotic gastrectomy. Because laparoscopic and robotic gastrectomy have been re- ported to reduce postoperative complications,25,26 we per- formed matched-pair analysis to balance surgical approaches for the comparison analysis. However, in a retro- spective study, revision of bias in patient characteristics was not straightforward. Thirdly, the feasibility of the ERAS protocol for elderly patients and those with poor perfor- mance status remains unclear because its eligibility has been limited to younger patients with better performance status. It may be better to treat such vulnerable patients by not using a single management protocol aiming at early re- covery but with personalized careful management. Indeed, elderly patients tend to have impaired swallowing function, considered to increase the risk of postoperative pneu- monia.27,28 Thus, early oral feeding should not be performed uniformly, and programs to prevent aspiration pneumonia should be introduced for these patients.

In conclusion, our results suggest that the ERAS proto- col for gastric cancer surgery shortened the length of post- operative hospital stay without increasing complications, but that preoperative oral carbohydrate loading did not improve postoperative nutritional status or maintain muscle strength postoperatively. Although the ERAS protocol itself has some benefits for gastric cancer surgery, results suggest that preoperative carbohydrate loading may be unnecessary.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Acknowledgement

This research was supported by Practical Research for Innovative Cancer Control (#15ck0106043h0002) from the Japan Agency for Medical Research and Development, AMED.

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