Enhanced Recovery After Major Gastrectomy for Cancer

Abstract

Enhanced recovery after surgery (ERAS) protocols have gained increasing popularity over the past 10 years, and its overarching objectives are to improve perioperative morbidity and reduce postoperative length of stay. Consensus guidelines from the ERAS Society specific to major gastrectomy were published in 2014, however since that time, prospective and retrospective studies have expanded the collective evidence for both the content and efficacy of ERAS pathways for gastrectomy. This objective of this review was to summarize recent data pertinent to the preoperative, perioperative, and postoperative management of gastrectomy patients along an ERAS pathway.

Beginning in the 1990s, there has been increasing interest in multidisciplinary perioperative pathways that aim to improve patient outcomes while reducing resource utilization. Dr. Henrik Kehlet is often credited with pioneering ‘fast-track’ surgery, with a 1999 publication describing a perioperative pathway that yielded an impressive 2-day hospitalization following open sigmoidectomy.¹ Soon thereafter, enhanced recovery after surgery (ERAS) gained popularity through a designated study group within the European Society for Clinical Nutrition and Metabolism (ESPEN), which published its first consensus guideline for colorectal surgery in 2005. In 2010, the group became formalized as the ERAS Society and began disseminating organ-specific consensus recommendations.

Guidelines specific to major gastrectomy were published by the ERAS Society in 2014, as the ERAS-GC.² The ERAS-GC recommendations were comprised of gastrectomy-specific items, as well as general, organ-nonspecific items derived from pancreaticoduodenectomy guidelines. Gastrectomy-specific components included directives on preoperative nutrition, pharmaconutrition, minimally invasive versus open approach, regional analgesia, gastric decompression, drains, and postoperative nutrition. Organnonspecific recommendations included preoperative counseling, fasting, anesthesia, fluid balance, and others (Fig. 1). This article will review key components of the gastrectomy ERAS pathway and best evidence on the efficacy of ERAS for major gastrectomy.

FIG. 1.

Components of Early Recovery After Surgery, gastrectomy (ERAS-GC). MIS minimally invasive surgery

PREOPERATIVE CONSIDERATIONS

Patient Counseling

Preoperative education and counseling are critical to set expectations regarding functional recovery, postoperative pain, and nutrition. Dedicated counseling interventions, including multimedia platforms, verbal direction from a registered nurse, or written material, may result in better knowledge and less anxiety, pain, and nausea compared with routine surgeon-performed discussion.³ While prospective data specific to gastric cancer are lacking, a randomized trial of ERAS versus ERAS plus extended preoperative nurse-lead counseling showed that extended counseling resulted in shorter length of stay (LOS) and better adherence to early mobilization and diet.⁴ These results corroborate ERAS-GC recommendations for routine dedicated preoperative counseling.

Nutrition

Baseline malnutrition and micronutrient deficiency is associated with impaired immune response to physiologic stress and increased perioperative morbidity.⁵ Oral intolerance and weight loss affect a large proportion of patients with gastric cancer. While definitions of preoperative malnutrition vary, among the most commonly referenced are the ESPEN criteria: (1) body mass index (BMI)\ 18.5 kg/m², or (2) combined weight loss [10% or [5% over 3 months and reduced BMI.⁶ Specific to gastric cancer, sarcopenia, commonly quantified by psoas muscle cross-sectional area, is associated with increased LOS and complications, while poor baseline nutrition is associated with both short- and long-term survival.^7,8

Optimal management of pre-gastrectomy malnutrition remains contentious. While albumin supplementation for hypoalbuminemic patients has been shown to have no impact on perioperative mortality or morbidity via a landmark randomized trial, data from cohort studies continue to challenge this philosophy.⁹ In retrospective cohorts, malnourished patients with gastric cancer who receive nutritional support or supplemental albumin experience lower rates of wound infection following gastrectomy;^10,11 however, in the absence of prospective data and multivariable survival analysis, routine preoperative parenteral nutrition or supplemental albumin are currently not recommended. In the modern era, most patients with symptomatic locally advanced gastric cancer are recommended for neoadjuvant or perioperative chemotherapy. Data from the esophageal cancer literature suggest that enteric access can preserve nutritional status during neoadjuvant therapy, but up to one-quarter of patients may not use the enteric access appropriately.¹²

Immune modulating nutrition (IMN), also called pharmaconutrition, focuses on micronutrients that support the physiologic immune response to surgical stress. Typical components include arginine, glutamine, omega-3 fatty acids, and nucleotides. Randomized data in gastric cancer are conflicting, and the original ERAS-GC guidelines indicated insufficient evidence to support routine IMN prior to gastrectomy.² In one Japanese randomized trial of 244 patients, a 5-day preoperative IMN diet did not impact wound infection rate or overall morbidity.¹³ However, in a smaller trial of 60 patients, a 7-day preoperative IMN diet blunted the duration of postoperative systemic inflammatory response and reduced infectious morbidity.¹⁴ In a recent meta-analysis encompassing 16 randomized trials spanning a variety of gastrointestinal cancer operations, IMN was associated with lower infectious complications and LOS, but had no impact on non-infectious complications or postoperative mortality.¹⁵

Prehabilitation

While the ERAS-GC recommends smoking cessation for 1 month prior to surgery and preoperative pulmonary rehabilitation, the guidelines provided no specifics regarding supportive data or an optimal prehabilitation protocol for gastrectomy. Prehabilitation has been shown to reduce the complication rate following major abdominal surgery,¹⁶ but data specific to gastrectomy are sparse. In a matched pair study from Japan, 18 stage I gastric cancer patients who underwent a preoperative exercise program were compared against control patients from an institutional database. In this small pilot study, patients who underwent prehabilitation experienced a lower postoperative complication rate.¹⁷ A single-center randomized trial comparing an ERAS protocol that included preoperative incentive spirometry among other interventions against conventional management found reduced LOS and a smaller reduction in postoperative peak expiratory flow in the ERAS group; however, the relative contributions of prehabilitation versus other ERAS entities was unclear.¹⁸ A recent systematic review encompassing gastric and esophageal surgeries noted conflicting evidence regarding prehabilitation and postoperative pulmonary complications.¹⁹ The PREFOG trial will randomize patients to a multimodal preoperative regimen, including nutritional, exercise, and psychological support prior to gastrectomy for cancer, and should shed further light on the impact of prehabilitation.²⁰

Preoperative Fasting

The philosophy that complete fasting after midnight prior to surgery significantly reduces the risk of aspiration is not supported by gastric physiology. For iso-osmolar fluids such as saline, there is near complete passage beyond the pylorus within 2 h of ingestion. For easily-digested solids, the rate of gastric emptying is in the order of 4 h.²¹ In line with recommendations from the American Society of Anesthesiology, the ERAS-GC recommends clear fluid intake up to 2 h before and solids up to 6 h before induction.²² Prolonged fasting produces a state of insulin resistance, depletes glycogen stores, and promotes hyperglycemia. These effects are compounded by the stress of surgical trauma. Preoperative carbohydrate loading via either infusion or oral clear liquid intake within 4 h before surgery aims to counter these deleterious effects. In a Cochrane review of 27 randomized trials, preoperative carbohydrate loading was associated with shorter LOS, earlier return of bowel function, and increased insulin sensitivity, but was not associated with postoperative complications.²³

REGIONAL ANALGESIA

Regional anesthesia is often incorporated into ERAS protocols because its potential benefits—reduced intraoperative anesthetic requirement, improved postoperative pain control, reduced opioid use and associated adverse effects, earlier mobilization and return of gastrointestinal function, and tempering of the physiological stress response to surgery—are central to the goals of an early recovery paradigm.² However, there is a paucity of evidence on regional anesthesia specific to open or laparoscopic gastrectomy, and this is further confounded by the fact that it is typically bundled with other interventions in randomized controlled trials. The two main regional techniques in use for gastrectomies are thoracic epidural analgesia and transversus abdominus plane (TAP) blocks. Thoracic epidural analgesia facilitates continuous infusion of local anesthetic into the epidural space, allowing for titratable density, coverage, and duration of sensory blockade. Interestingly, in several retrospective studies, epidural analgesia has also been found to be associated with reduced cancer recurrence among a range of solid tumors (albeit not specifically studied in gastric cancer), possibly from preventing inhibition of the immune system and attenuating the surgical stress response.^24–26 On the other hand, TAP blocks deposit a bolus of local anesthetic into a fascial plane, providing analgesia to the anterolateral abdominal wall. TAP blocks have the advantage of being less invasive and avoid the hypotension often seen with epidurals; however, their effect does not extend beyond 24–48 h and analgesic coverage can be variable depending on approach.²⁷

There is strong evidence supporting the use of TAP blocks and epidural analgesia for abdominal surgeries in general, but gastrectomy-specific evidence is somewhat limited.² In a small, prospective study of patients undergoing open radical gastrectomy, patients randomized to morphine-bupivacaine patient-controlled epidural analgesia (PCEA) had lower static and dynamic pain scores, lower fasting blood glucose levels, shorter time to first passage of flatus, and shorter length of hospital stay, without increased complication rates, compared with patients randomized to morphine intravenous patient-controlled analgesia (PCA).²⁸ In a more recent study, local anesthetic PCEA provided superior pain control compared with opioid intravenous PCA in patients undergoing totally laparoscopic distal gastrectomy.²⁹ Improved pain control further promotes earlier mobilization and diet tolerance. TAP blocks have also been shown to be effective. In studies of patients undergoing open gastrectomy, TAP blocks were shown to blunt stress hormone levels and fluctuations in intraoperative hemodynamics, as well as provide effective pain relief for 12 h postoperatively.³⁰ In terms of which technique to employ, PCEA has been shown to provide superior pain control and reduce opioid requirements compared with TAP blocks for open gastrectomy.³¹ But some argue that the role of PCEA is limited in laparoscopic gastrectomies and that TAP blocks are sufficient to control pain for less invasive procedures. However, there have been no head-to-head comparisons of the two techniques for laparoscopic gastrectomy, and the choice of which technique is employed often comes down to institutional practices and a weighing of risks and benefits for each patient (e.g. PCEA may be preferable in laparoscopic procedures for patients with poor respiratory reserve). Notably, in several studies from East Asia, where the incidence of gastric cancer is higher, epidural anesthesia is part of the conventional treatment pathway for open and laparoscopic gastrectomies, and their ERAS pain protocol instead focuses on the addition of scheduled adjuncts such as intravenous nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, which were noted to reduce maximum pain scores and the need for additional doses of analgesics.³² Unfortunately, as an intervention, regional anesthesia has been variably embraced in ERAS-GC protocols, and is often one of the practices with lowest compliance.^33,34 More research is needed in this area to drive procedure-specific recommendations and to promote implementation.

INTRAOPERATIVE CONSIDERATIONS

Open Versus Minimally Invasive Approach

The minimally invasive surgery (MIS) approach to gastric cancer resection became increasingly popular between 2000 and 2010, and most randomized studies have shown equivalent oncologic outcomes relative to open gastrectomy.³⁵ While the long-term effects of the MIS approach on post-gastrectomy quality of life remain unclear,³¹ a Cochrane Database meta-analysis suggests that a reduction in postoperative LOS by between 1 and 2 days may be expected.^36–39 The magnitude of impact from MIS appears to vary by geography and by patient population.⁴⁰ Western gastric cancer populations tend to be older and with higher average BMI. Perioperative outcomes, including blood loss, complication rate, and early mortality, appear to be higher in Western series, and these patterns prove true for both the open and MIS approach. In European populations, the MIS approach has been linked to lower blood loss and shorter LOS.⁴¹ Interestingly, this reduction in LOS associated with MIS is not apparent in the East, where a typical post-gastrectomy hospital course lasts approximately 2 weeks.

The original ERAS-GC recommended an MIS approach to early gastric cancer, and early randomized trials on MIS gastrectomy similarly focused on T1 disease.² Three-year outcomes from the CLASS-01 trial in 2019 showed that a laparoscopic approach does not sacrifice oncologic outcomes relative to open surgery, even among patients with locally advanced disease.²⁸ Further expansion of MIS capabilities has come with the spread of robotic assistance. A robotic approach to upper gastrointestinal resection is appealing due to advantages in surgeon comfort, visualization, and articulation for hand-sewn anastomoses. These advantages translate to a shorter MIS learning curve relative to conventional laparoscopy.^42–52 However, robotic gastrectomy has not been shown to be superior to laparoscopic gastrectomy at experienced centers. In a randomized trial, robotic and laparoscopic approaches had similar perioperative outcomes, including conversion rate, diet advancement, and LOS, but the robotic approach required longer operating times and greater overall costs.³⁰ For MIS gastrectomy in general, it is important for providers to remember the priorities of safety and oncologic principles. Surgeons previously unfamiliar with MIS gastrectomy should be cautioned against unmitigated adoption for the sake of ERAS. Particularly for total gastrectomy, return of bowel function will often have a greater impact on postoperative LOS than incisional pain control.

Surgical Drains

The goal of surgical drainage following gastrectomy is as a diagnostic tool to assess for anastomotic leakage, and as a therapeutic tool for infectious source control if such a leak occurs. Practice patterns for drainage vary widely and frequently reflect anecdotal experience and training. Two meta-analyses describing the same four randomized trials were published in 2011, both concluding that intraoperative drainage for gastrectomy has no effect on perioperative mortality, major complications, reoperation, and dietary advancement, but may slightly prolong hospital LOS.³¹ The mechanism of this impact is unclear but may be related to patient discomfort and diagnostic evaluation of abnormal drain features that are often clinically insignificant. While the ERAS-GC recommends against routine drainage, the impact of a surgical drain on perioperative management is relatively minor, and the appropriateness of prophylactic drainage should be left to the surgeon’s clinical judgment on a case-by-case basis.

General Anesthesia

ERAS-GC protocols to date tend to be surgeon-driven and as such tend to not incorporate evidence-based standardization of intraoperative anesthetic management. The 2014 ERAS-GC consensus guidelines made note of several recommendations for anesthetic management for pancreaticoduodenectomy that can likely be extrapolated to gastrectomy. At the core of these recommendations is facilitating rapid and reliable recovery of physical and cognitive function, with minimal adverse effects, while providing ideal operating conditions.

The use of short-acting anesthetic induction drugs, opioids, and neuromuscular blocking agents is preferable. Deep neuromuscular blockade may be helpful in laparoscopic procedures to optimize surgical exposure and reduce postoperative pain, but it may increase the risk of residual paralysis, especially if Sugammadex is not available.^33,34 Thus, the depth of neuromuscular blockade should be monitored throughout and maintained as deep as clinically indicated for the minimum amount of time necessary. Maintenance of general anesthesia is similarly a balance between excess depth, with resultant prolonged emergence and recovery time, and inadequate depth, with risk of intraoperative awareness. Titration of anesthetic agents is typically done through monitoring of end tidal anesthetic concentration, but the addition of bispectral index monitoring may help reduce maintenance anesthetic concentrations and opioid use, which may facilitate earlier recovery from general anesthesia.³⁵ Postoperative nausea and vomiting (PONV) is common, decreases patient satisfaction, and prolongs recovery time. PONV prophylaxis should be a part of any ERAS protocol, with aggressiveness of prophylaxis correlated with the number of risk factors.³¹ Lung protective ventilation strategies have also been suggested, with tidal volumes of 6–8 mL/kg, positive end-expiratory pressure (PEEP) of 6–8 cm of water, and recruitment maneuvers every 30 min shown to reduce major complications and hospital LOS in intermediate to high pulmonary risk patients undergoing major abdominal surgery.^36–39 Lastly, measures to prevent intraoperative hypothermia should be implemented, including the use of active warming devices and consideration of preoperative warming. Hypothermia has several deleterious effects, including increased rates of wound infection, cardiac complications, and bleeding, as well as prolonged post-anesthetic recovery time and impaired immune function.⁴⁰

POSTOPERATIVE MANAGEMENT

Gastric Decompression

Like intraoperative drain placement, practice patterns for prophylactic decompression via nasogastric (NG) tube varies widely. The intention of NG decompression is to reduce gastric distention and anastomotic stress, ameliorate postoperative nausea related to the ileus, and minimize risk for aspiration. However, none of these intentions are based on high-level data. A meta-analysis encompassing eight randomized trials showed that NG decompression did not impact anastomotic leak rate, pulmonary complications, return of bowel function, and overall morbidity or mortality following gastrectomy;⁴¹ however, prophylactic decompression was associated with a longer interval to dietary advancement and longer LOS. In the years following ERAS-GC’s recommendation against routine NG decompression, at least three additional randomized studies have verified that NG decompression has no impact on morbidity or mortality, although its relationship to return of bowel function remains unclear.² Subjectively, NG tubes are uncomfortable, impede early mobilization, and, if used improperly, may actually increase the risk of microaspiration.²⁸

Dietary Advancement

Early oral feeding (EOF) is a fundamental component of ERAS following gastrointestinal surgery. A 2001 meta-analysis of elective gastrointestinal surgeries indicated that EOF reduces infectious complications and LOS.^42–52 In a meta-analysis specific to gastrectomy, EOF did not increase anastomotic leak rate, feeding intolerability, or readmission rate.² Accordingly, ERAS-GC recommends slow advancement of both liquid and solid oral intake beginning on the first postoperative day (POD) for distal and total gastrectomy.²⁸ Following these guidelines, additional gastrectomy-specific prospective data from Asia have linked EOF to reductions in LOS, earlier return of bowel function, and early increases in serum gastrin and motilin, with no increase in morbidity.^42–52 Despite these data, many institutions continue to delay oral feeding until PODs 2–3 due to concerns regarding aspiration and anastomotic integrity.^42–52

Fluid Balance

Fluid management in the perioperative setting of major gastrectomy can be challenging. The combination of intraoperative blood and fluid loss, epidural analgesia, and general anesthesia frequently combine to generate signs of hypovolemia in the early postoperative setting. A common reaction is to encourage crystalloid resuscitation for a positive fluid balance in the first 24 h after surgery. Water and sodium overload places patients at risk for respiratory complications and delayed bowel function. Accordingly, the ERAS-GC recommends a near-zero perioperative fluid balance, even if low doses of temporary vasopressors are necessary to overcome epidural-induced hypotension.³⁰ Most modern ERAS protocols promote a balanced approach to intravenous fluids,³¹ and there are high-level data supporting this philosophy. In a meta-analysis encompassing five randomized trials, net-zero fluid repletion (versus over- or under-resuscitation) was associated with reduced LOS and a lower complication rate following major open abdominal surgery.³² In concordance with an EOF protocol, it is reasonable to wean intravenous fluids once patients demonstrate tolerance of oral intake.^33,34

Urinary Catheter

Like judicious intravenous resuscitation, early removal of urinary catheters has seen wide adoption among ERAS protocols.³⁵ In a meta-analysis of 13 randomized trials involving abdominal and pelvic operations, early catheter removal was associated with a lower risk of urinary tract infection and shorter LOS without a significant increase in the recatheterization rate.³¹ In accordance with ERAS-GC guidelines, early urinary catheter removal on PODs 1–2 is reasonable for cases not requiring epidural analgesia. Management in the setting of epidural analgesia is somewhat more controversial. Two prospective studies have linked early removal in this setting with higher rates of recatheterization;^36–39 however, one randomized trial showed no such relationship, and instead demonstrated a reduction in both urinary infection rate and LOS.⁴⁰ To avoid repeated urethral trauma, patients who require recatheterization in the setting of an epidural should retain their urinary catheter until after the epidural is removed before attempting a second void trial.

Mobilization

Because early mobilization is considered an integral component of most ERAS protocols,⁴¹ it is difficult to isolate its individual impact on postoperative recovery. Nevertheless, early ambulation is almost universally supported due to perceived benefits toward preventing deep vein thromboses, avoiding atelectasis, and improving intestinal and functional recovery. No randomized trials have compared early mobilization as a solo intervention against conventional management in gastric cancer. Clinical trials from the broader abdominal cancer surgery population suggest that early mobilization contributes to earlier inpatient functional recovery, but relationships to return of bowel function and LOS are inconsistent.² In a systematic review encompassing thoracic and abdominal operations, early ambulation had no association with the postoperative complication rate for any of the included studies.²⁸ Dogmatic belief that early mobilization shortens postoperative ileus remains unproven, as ambulation appears to have no impact on intestinal myoelectric activity.^42–52 Acknowledging a lack of high-level evidence, ERAS-GC recommends goal-directed, daily mobilization instructions for patients recovering from gastrectomy.²

OUTCOMES OF EARLY RECOVERY IN GASTRECTOMY

While it is difficult to define the incremental impact of individual components within the ERAS bundle, there is robust evidence that the multimodal ERAS approach is impactful in the gastrectomy population. The concept of ‘fast-track’ surgery has been promoted by centers in East Asia for nearly 15 years and pre-date the ERAS-GC consensus guidelines themselves. Randomized trials in Western populations are lacking, limited by a lower prevalence of gastric cancer. While specifics of ERAS implementation vary across institutions, a recent meta-analysis indicated that the most common components include preoperative counseling, avoidance of NG decompression, attention to fluid balance, early attempts at urinary catheter removal, oral feeding, and mobilization.²⁸ An updated collection of randomized trials pertinent to ERAS in the gastrectomy population is listed in Table 1.^42–52 Overall, ERAS is consistently associated with reductions in LOS and hospital costs and earlier return of bowel function relative to conventional management. Studies that report biochemical correlates also tend to favor ERAS in the recovery of serum nutritional and stress markers; however, with the largest trial comprising only 256 patients, most studies are underpowered to assess differences in complication rates and readmission.

TABLE 1.

Randomized trials involving Early Recovery After Surgery (ERAS) following gastrectomy. Superiority of either the ERAS or conventional treatment arms is noted.

Year	Country	N	Surgery	Pain	LOS	ROBF	Complications	Readmission	Cost	Nutrition markers
2010	China	92	Gastrectomy		ERAS	ERAS	ND	ND	ERAS
2012	China	88	Distal gastrectomy		ND	ERAS	ND		ERAS	ERAS
2012	Korea	47	LADG	ERAS	ERAS	ND	ND	ND
2013	China	119	Total gastrectomy	ERAS	ERAS	ERAS	ERAS	ND	ERAS
2015	China	256	Open gastrectomy		ERAS	ERAS	ND	Conventioanl	ERAS
2015	China	61	LADG		ERAS	ERAS	ND	ND
2016	China	84	Distal gastrectomy		ERAS	ERAS	ND		ERAS	ERAS
2016	Japan	80	Gastrectomy		ND		ND			ND
2017	Japan	148	Gastrectomy	ERAS	ERAS	ND	ERAS	ND	ERAS	ERAS
2017	China	149	Lap gastrectomy		ERAS	ERAS	ND	ND
2018	Korea	97	LADG	ERAS	ERAS		ND	ND

LOS length of stay, ROBF return of bowel function, LADG laparoscopy-assisted distal gastrectomy, ERAS enhanced recovery after surgery, ND no data

Overall, studies on ERAS protocols for gastrectomy and other procedures support the notion that establishing surgical pathways can yield multifaceted benefits. Across prehabilitation programs and perioperative and intraoperative pathways, ERAS promotes coordination amongst physicians, advanced practice providers, and nurses via a true team approach. Furthermore, by defining a unified pathway of ‘normal’ progression, it becomes easier to rapidly recognize patients who deviate from the norm and warrants further investigation into potential complications. While ERAS-GC has come a long way, areas for further research include the differences between perioperative management for total versus subtotal gastrectomy, as well as differences between the minimally invasive and open approaches.