Postoperative functional evaluation of gastrectomy for gastric cancer

Eiji Nomura

Department of Gastroenterological and General Surgery,Tokai University Hachioji Hospital,Tokyo 192-0032,Japan

Abstract To improve the quality of surgical procedures for gastric cancer,it is essential to consider many components comprehensively,including gastric motility,small intestinal absorption,hormones that affect gastric motility and appetite,presence or absence of vagus nerve preservation,esophageal regurgitation on endoscopic findings,in addition to whether or not there is a physiological route for food passage through the duodenum.Furthermore,proper functional evaluation cannot be performed without considering the form and amount of energy in the nutritional supplement to be loaded,and the posture at the time of investigation.The results of functional evaluation vary according to the method selected from many available options,but we believe that use of the most physiologically accurate,appropriate and selectable option will enable us to arrive at the best resection/reconstruction technique.We have reported that it is important to consider the preservation of three elements when performing gastrectomy: 1) reduction of the extent of gastrectomy,2) preservation of the pylorus,and 3)preservation of the vagus nerve;among which preservation of the remnant stomach is the most important.Furthermore,the selection of a reconstruction method that maintains secretion of hormones beneficial to gastric motility preserves the energy balance inherent in the human body,and also provides better quality of life.

Keywords: Gastric cancer;gastrectomy;functional evaluation

Introduction

Stomach is the first organ in which ingested food is stored.Stomach functions are performed by diastole and contraction with acid secretion in the fundus and corpus of the stomach,peristaltic motion of the gastric antrum,and gastrin secretion.It also plays an important role in the delivery of ingested food at a constant rate to enable efficient absorption in the small intestine,which is the main organ for nutrient intake (1).To accurately assess its function,it is necessary to understand gastric acid secretion and motility as well as endocrine secretion.Gastrectomy for gastric cancer prevents the stomach from performing these functions.Furthermore,all of these functions are lost following total gastrectomy (TG),and must be compensated for by adjusting the contents of meals and the manner of meal intake.

Due to the increasing number of patients with early stage gastric cancer and prolongation of the survival period by multidisciplinary therapy in patients with advanced gastric cancer,it is desirable to improve the postoperative quality of life (QOL) of gastric cancer patients.For this reason,limited surgery or function-preserving surgery is being actively performed to reduce the functional destruction of the stomach in patients with early gastric cancer (2),and it is hoped that these surgical techniques will be applied as much as possible for advanced cancer.Efforts are also being made to avoid TG.This article describes how gastric functional evaluation has been performed in the past and discusses current thinking,focusing on endocrine(hormonal) aspects and the motility of the upper gastrointestinal tract,with some personal opinions from the author.

What is required for postoperative evaluation of stomach?

Around the 1980s,gastrointestinal motility was actively investigated using techniques such as the strain gauge transducer method and electrogastrography,which were initially trialed in canine and other animal models as methods for evaluating gastric function (3).Changes in gastric motor activity after gastric transection,gastrectomy,and vagus nerve transection were then also clarified in humans (4,5). Recently,questionnaires such as the postgastrectomy syndrome assessment scale-45 (PGSAS-45) have been developed that can be used as a non-invasive method for evaluation for postoperative QOL (6),and have enabled clarification of the relationship between various surgical procedures and postoperative QOL.Evaluating these results in detail has also helped to clarify the function of the celiac branch of the vagus nerve in humans (7).When conducting detailed examinations after upper gastrointestinal surgery,or when developing new surgical procedures,it is necessary to perform a detailed and comprehensive analysis of the types of changes that occur in the upper gastrointestinal tract after gastrectomy and reconstruction.

Figure 1shows methods that can be used to evaluate gastric function and the presence of postgastrectomy disorder syndrome.Most tests that evaluate gastric function focus on the movement of food or motility of the gastric wall.These investigations are generally thought to be sufficient,but I wondered if a more systematic research method might be possible.

Functional evaluation using a drug excretion/absorption test and measurement of gastrointestinal hormones

Figure 1 Methods for evaluating gastric function and detecting postgastrectomy disorder syndrome.Most tests that evaluate gastric function focus on the movement of food or the motility of the gastric wall.RI,radioisotope;QOL,quality of life;13C,stable isotope 13Clabeled;pH,potential of hydrogen;PGSAS-45,postgastrectomy syndrome assessment scale-45;EORTC-QLQ-C30,the European organization for research and treatment of cancer core quality of life questionnaire 30.

If we could conduct a drug excretion/absorption test using the acetaminophen (AAP) method and measure gastrointestinal hormones while applying a constant nutritional load,it would be possible to observe gastric emptying/small intestine absorption dynamics and gastric hormonal secretion at the same time.I thought that this method might make it possible to capture the various changes occurring in the upper gastrointestinal tract.In the AAP method,which is used as a functional evaluation method in Department of Gastroenterological and General Surgery,Tokai University Hachioji Hospital,an alimentary liquid (200 mL of Ensure LiquidR;Meiji,Tokyo,Japan)containing 1.5 g of AAP is swallowed within 2 min,after which the concentration of AAP in the blood is measured every 15 min for 60 min.The concentrations of various hormones [blood sugar,insulin,gastrin,glucagon,glucagon-like peptide-1 (GLP-1),and ghrelin (active ghrelin/inactive ghrelin)] are measured at the same time(8).The author has a long-standing belief that among surgical procedures for gastric cancer,function-preserving surgery best preserves the autonomic nervous system and maintains physiological secretion of gastrointestinal hormones.Among the surgical cases at Tokai University Hachioji Hospital so far,we have evaluated postoperative QOL and function in relation to three surgical elements: 1)reduction of the extent of gastrectomy,2) preservation of the pylorus,and 3) preservation of the vagus nerve.Surgery is considered function-preserving when the postoperative emptying/absorptive dynamics and hormonal secretion are similar to those preoperatively. We found that postoperative function and QOL were maintained in surgical procedures that preserved at least two of these three elements (9).We have reported previously that in terms of maintaining body weight and food intake after surgical procedures,preserving the remnant stomach is the most important of the three elements (10-12).Because pylorus-preserving gastrectomy (PPG) and proximal gastrectomy (PG) preserve all three elements,we judged these as ideal function-preserving surgeries (2).We performed the above-mentioned functional evaluation after these two surgical procedures and found that for PPG,gastric emptying and hormonal secretion dynamics were close to the preoperative conditions (13).

Diversity and its rendering of functional evaluation

Figure 2 Plasma AAP concentrations (A) and gastrin levels (B) in sitting position after PG and after TG.AAP levels are lower in DT group than in other groups,and gastrin levels are lower in DT group than in all other groups (JIP and EG groups) except TG group (Reproduced with permission from Ref.8,Springer Nature).AAP,acetaminophen;PG,proximal gastrectomy;TG,total gastrectomy;DT,double tract;JIP,jejunal interposition;EG,esophagogastrostomy;＊,P＜0.05;＊＊,P＜0.01.

Assessment of preserved function is difficult in PG because the reconstruction procedure can involve any of the jejunal interposition (JIP) method,double-tract (DT) method,and esophagogastrostomy (EG) method (14).In Department of Gastroenterological and General Surgery,Tokai University Hachioji Hospital,the EG method is used if the remnant stomach is relatively large,whereas the JIP method or DT method is used if the remnant stomach is relatively small.Adoption of this policy has led to various reconstructive situations that require attention to many considerations in addition to the size of the remnant stomach.Figure 2shows changes in AAP concentrations and gastrin levels measured in the sitting position after PG,as well as those for TG.AAP levels were lower in the DT group than in the other groups,and gastrin levels were lower in the DT group than in all other groups except the TG group.We believe that the reason for these findings is that in the DT method,the efferent jejunal route acts as an escape route for excessive gastric pressure and/or overflow of excessively large meals that enter the remnant stomach(8).In addition,gastrin levels in the EG group were between those of the JIP and DT groups,indicating that the remnant stomach is larger in the EG method than in the other two methods,and that the area of gastric acid secretion is relatively maintained.In addition,Tossetiet al.(15) stated that gastric emptying and blood gastrin concentration are inversely correlated,and that the possibility of hypergastrinemia affecting gastric emptying cannot be denied.As our study was performed using a liquid diet,if remnant gastric emptying was reduced by the effects of hypergastrinemia,the liquid diet might have emptied promptly due mainly to gravity.In the JIP group,AAP concentration values were higher in the sitting position than in the supine position (Figure 3) (8).These differences might have been caused by gravitational intestinal motion in the sitting position.For reference,Figure 4shows that after distal gastrectomy (DG),AAP concentrations increased slightly from the supine position to the sitting position.However,when we compared AAP levels between the sitting and supine positions in all groups,we found that the levels were markedly increased in the sitting position in the JIP group,whereas they were relatively stable in both positions in the other groups.In general,the sitting position is considered to be the physiological posture at the time of meal intake,but in practice,both peristaltic and gravitational intestinal motion may be observed.Figure 5shows a comparison of active ghrelin levels during fasting.Among the PG groups,active ghrelin levels were the highest for EG,which was influenced by the large size of the remnant stomach in the EG group,and preservation of the upper ghrelin-secreting region in particular.The hormone ghrelin is transmitted to the nucleus tractus solitarius oblongata and the arcuate nucleus via the vagus nerve,and promotes the desire to eat(16-18).Therefore,preservation of the hepatic and celiac branches of the vagus nerve may be associated with increases in food intake and body weight.For these reasons,we can expect a greater amount of food intake in the EG method due to the large remnant stomach,even in the case that the vagus nerve cannot be completely preserved;in many cases,however,a smaller amount of food intake was actually observed in the EG group.This is because the incidence of reflux esophagitis is significantly higher in the EG method than in other methods,according to previous endoscopic observations (14,19).In other words,when a large amount of food is ingested without anti-reflux countermeasures,reflux occurs that leads to refraining from eating,resulting in a decrease in food intake and body weight.For this reason,an adequate antireflux mechanism is essential in PG with the EG method.The EG method can be performed if the remnant stomach is large (3/5-4/5),but it is difficult to completely preserve the vagus nerve in order to lengthen the abdominal esophagus.However,as the remnant stomach is large in the EG method,the ghrelin-secreting region is retained,and gastrin secretion is also suppressed because the acidsecretion area is preserved,and better QOL will be expected if a secure anti-reflux mechanism such as the double-flap technique (20) or side overlap with fundoplication by Yamashita (SOFY) method (21) can be added.In contrast,if the remnant stomach is small(3/5-1/2),the DT method can be used to preserve the hepatic and celiac branches of the vagus nerve as much as possible,to suppress a decline in QOL.Furthermore,the finding of similar postoperative body weights between the JIP and DT groups,even in such a hormonally unfavorable situation,might be caused by food passage through the duodenum.In other words,in addition to the presence (or not) of a physiological route for food passage through the duodenum,it is essential to thoroughly consider many other components,including gastric motility,small intestinal absorption,hormones that affect gastric motility and appetite,the presence or absence of vagus nerve preservation,and esophageal regurgitation on endoscopy.It is not possible to improve the surgical procedures if we fail to take these considerations into account.Furthermore,proper functional evaluation cannot be performed without considering the form and quantity of energy of the nutritional supplement to be loaded,and the posture at the time of investigation.The results of functional evaluation depend to a large degree on the parameters included in the functional evaluation (Table 1).Therefore,we believe that identification of the most physiologically appropriate assessments enables selection of the best resection/reconstruction method.

Figure 3 AAP concentrations in supine position after PG (DT,JIP) and TG.In JIP group,AAP concentration is higher in sitting position (Figure 2) than in supine position at all time points(Reproduced with permission from Ref.8,Springer Nature).AAP,acetaminophen; PG,proximal gastrectomy; TG,total gastrectomy;DT,double tract;JIP,jejunal interposition;＊,P＜0.05;＊＊,P＜0.01.

Figure 4 AAP concentrations in supine position (A) and sitting position (B) after DG procedures.AAP concentrations in all DG procedures are slightly higher in the sitting position than in the supine position.There is no significant difference in AAP concentration of any of these DG procedures compared with JIP reconstruction following PG (Reproduced with permission from Ref.11,Oxford University Press and Ref 22,Springer Nature).AAP,acetaminophen;DG,distal gastrectomy;JIP,jejunal interposition;PG,proximal gastrectomy;＊,P＜0.05;＊＊,P＜0.01.

Figure 5 Comparison of active ghrelin levels during fasting after PG and after TG.Among the PG (DT,JIP and EG) and TG procedures,active ghrelin levels are the highest in the EG group.PG,proximal gastrectomy;TG,total gastrectomy;DT,double tract;JIP,jejunal interposition;EG,esophagogastrostomy;＊,P＜0.05;＊＊,P＜0.01.

Mechanism of maintaining energy homeostasis from viewpoint of ghrelin secretion

Finally,I would like to discuss the change in blood ghrelin concentration after DG.For early gastric cancer in the middle to lower third of the stomach,when 1/2 to 2/3 of the stomach is resected with a safety margin of 2 cm or more,Billroth I (B1) reconstruction is typically performed,whereas Roux en Y (RY) reconstruction is performed for early gastric cancer in the middle to upper third of the stomach,in which 2/3 to 4/5 of the stomach is resected with a similar safety margin.Accordingly,postoperative body weight and meal intake are significantly higher in the B1 group than in the RY group (22).Figure 6shows postsurgical changes in active and inactive ghrelin levels.Inactive ghrelin accounted for most of the measured ghrelin,especially in the RY group;however,levels of active ghrelin were similar between the B1 and RY groups.Shiiyaet al.(23) reported that plasma ghrelin concentrations were lower and higher,respectively,in patients with simple obesity and anorexia nervosa.They also stated that ghrelin secretion is upregulated under conditions of negative energy balance and downregulated in the setting of positive energy balance,although only plasma des-acyl (inactive) ghrelin concentrations were measured in their study because of its stability.Thus,to maintain active ghrelin levels,inactive ghrelin secretion might be more upregulated in the RY group,under conditions of more negative energy balance,compared with the B1 group.The higher inactive ghrelin level might lead to a greater increase in active ghrelin levels due to acylation of inactive ghrelin to active ghrelin.In other words,it can be thought that the human body is equipped with a mechanism for maintaining the homeostasis of energy balance,and making good use of this mechanism may lead to the maintenance of QOL.Further,in TG,it is difficult for some reasons to upregulate ghrelin levels under conditions of negative energy balance (24),and it is therefore essential to preserve as much of the remnant stomach as possible.However,if there is no other option than to perform TG,we might consider administration of a drug such as anamorelin hydrochloride (HCL) (25),whichis an orally active ghrelin receptor agonist in clinical development for the treatment of cancer cachexia.

Table 1 Physiological and non-physiological factors for various measurements of postoperative function and factors considered in selection of operative procedures

Figure 6 Levels of active (A) and inactive (B) ghrelin after DG procedures.As inactive ghrelin accounts for most of the measured ghrelin levels,especially in RY group,active ghrelin levels are similar between B1 and RY groups (Reproduced with permission from Ref.22,Springer Nature).DG,distal gastrectomy;RY,Roux en Y;B1,Billroth I;＊,P＜0.05.

Conclusions

It is important to consider three surgical elements when performing gastrectomy (reduction of the extent of gastrectomy,preservation of the pyloris,and preservation of the vagus nerve),among which preservation of the remnant stomach is the most important.Furthermore,selection of a reconstruction method that maintains secretion of hormones that are beneficial to gastric motility preserves energy homeostasis and leads to a better QOL for the patient.In the case that TG is unavoidable,we have great expectations that efforts to preserve the upper remnant stomach as much as possible,and the use of drugs such as anamorelin HCL could upregulate the negative energy balance.

Acknowledgements

None.

Footnote

Conflicts of Interest: The author has no conflicts of interest to declare.