Prognostic Significance of Preoperative Nutritional Assessment in Elderly Patients who Underwent Laparoscopic Gastrectomy for Stage I-III Gastric Cancer

Background/Aim: Surgery for elderly patients with gastric cancer is becoming more common. However, the risk factors of the laparoscopic surgery for these patients are unknown, and thus it is difficult to determine appropriate treatments for such patients. The aim of this retrospective study was to clarify the risk factors for the treatment outcomes after laparoscopic gastrectomy in elderly patients. Patients and Methods: Two hundred twenty-two patients who underwent laparoscopic gastrectomy for primary gastric cancer between January 2014 and December 2017 were enrolled. Clinical characteristics and short- and long-term prognoses were analyzed in 47 patients aged 75 years or older (elderly group) and in 175 patients who were under 75 years old (non-elderly group). Results: The presence of comorbidities was more common in the elderly group than in the non-elderly group (91.5% vs. 61.7%, p<0.0001). The rate of postoperative complications in the elderly group was significantly higher than that in the non-elderly group (42.6% vs. 22.9%, p=0.01). The 5-year overall survival rate was significantly lower in the elderly group than in the non-elderly group (66.9% vs. 92.2%; p<0.0001). In the elderly group, 5-year overall survival in patients with a low preoperative prognostic nutritional index (PNI) was significantly worse than that in patients with a high preoperative PNI (25.0% vs. 80.9%; p<0.05). Multivariate analysis showed that the PNI value was independently associated with overall survival in elderly patients who underwent laparoscopic gastrectomy (p<0.05). In particular, the rate of non-cancer deaths after surgery in elderly patients was significantly higher than that in non-elderly patients (p<0.05). Conclusion: PNI value is an independent prognostic factor for overall survival in elderly patients who have undergone laparoscopic gastrectomy for gastric cancer; therefore, in elderly patients with low preoperative PNI, attention should be paid not only to recurrence of cancer, but also to the deterioration of general condition caused by malnutrition.

Abstract.Background/Aim: Surgery for elderly patients with gastric cancer is becoming more common.However, the risk factors of the laparoscopic surgery for these patients are unknown, and thus it is difficult to determine appropriate treatments for such patients.The aim of this retrospective study was to clarify the risk factors for the treatment outcomes after laparoscopic gastrectomy in elderly patients.Patients and Methods: Two hundred twenty-two patients who underwent laparoscopic gastrectomy for primary gastric cancer between January 2014 and December 2017 were enrolled.Clinical characteristics and short-and long-term prognoses were analyzed in 47 patients aged 75 years or older (elderly group) and in 175 patients who were under 75 years old (non-elderly group).Results: The presence of comorbidities was more common in the elderly group than in the non-elderly group (91.5% vs. 61.7%,p<0.0001).The rate of postoperative complications in the elderly group was significantly higher than that in the non-elderly group (42.6% vs. 22.9%, p=0.01).The 5-year overall survival rate was significantly lower in the elderly group than in the nonelderly group (66.9% vs. 92.2%;p<0.0001).In the elderly group, 5-year overall survival in patients with a low preoperative prognostic nutritional index (PNI) was significantly worse than that in patients with a high preoperative PNI (25.0% vs. 80.9%; p<0.05).Multivariate analysis showed that the PNI value was independently associated with overall survival in elderly patients who underwent laparoscopic gastrectomy (p<0.05).In particular, the rate of non-cancer deaths after surgery in elderly patients was significantly higher than that in non-elderly patients (p<0.05).Conclusion: PNI value is an independent prognostic factor for overall survival in elderly patients who have undergone laparoscopic gastrectomy for gastric cancer; therefore, in elderly patients with low preoperative PNI, attention should be paid not only to recurrence of cancer, but also to the deterioration of general condition caused by malnutrition.
Gastric cancer is the fifth most common cancer type and the third leading cause of cancer-related death worldwide (1).Surgery is the only curative treatment for gastric cancer and has been increasing recently.However, abdominal surgery in elderly patients is often considered high-risk due to decreased organ function and increased comorbidities.Since the risk factors of gastrectomy-related complications in elderly patients are unknown, it is difficult to determine the appropriate strategy for gastric cancer in these patients.
Since the first reported laparoscopic gastrectomy for gastric cancer was performed in 1994 (2), this approach has become widely accepted as a therapeutic option for gastric cancer.The reason for the widespread acceptance of this technique is primarily because it is superior to open surgery in terms of minimal surgical trauma, reduced post-operative pain, decreased blood loss, reduced post-operative complications, and the decreased length of hospital stay after surgery (3)(4)(5)(6).Furthermore, several studies have reported the feasibility of laparoscopic gastrectomy in elderly patients, especially regarding short-and long-term outcomes compared with open surgery (7)(8)(9).However, other studies have reported that elderly patients with gastric cancer have a higher incidence of postoperative complications than nonelderly patients (10,11), and thus there is still controversy as to whether laparoscopic surgery contributes to the longterm prognosis of elderly patients with gastric cancer.
In general, elderly people are physically and nutritionally poor and have some degree of frailty, and even if gastric cancer can be cured by gastrectomy, they are likely to die from other diseases.Previous studies reported the assessment of nutritional status and the usefulness of predicting the prognosis of patients with cancer, including modified Glasgow prognosis score (12), Controlling Nutritional Status (13), neutrophil to lymphocyte ratio (NLR) (14), and prognostic nutritional index (PNI) (15).Serum albumin, the main component of plasma proteins, reflects nutritional status and lymphocytes, which are also an important component of the immune system, eliminating cancer cells and reflecting immunological status (16).
It is important to avoid performing invasive surgery such as open surgery and total gastrectomy, which has been reported to be associated with reduced postoperative oral intake and poor nutritional status, in elderly patients (17)(18)(19).Considering the background characteristics of older individuals, treatment strategies for elderly patients with gastric cancer should be determined by considering both the curability of gastric cancer and the possibility of death from other disease.This study was performed as a retrospective analysis to evaluate the relationship between short-and long-term outcomes after laparoscopic gastrectomy for stage I-III gastric cancer and preoperative nutritional status in elderly patients.

Patients and Methods
Patients.Between January 2014 and December 2017, 361 consecutive patients underwent curative laparoscopic surgical resection for gastric cancer at the National Hospital Organization Kyushu Cancer Center.A total of 222 patients who underwent laparoscopic gastrectomy for primary gastric cancer were enrolled in this study.All tumors were histologically diagnosed as adenocarcinoma of the stomach.The median follow-up period for all patients was 60.5 months (range=1-93), and 50 month (range=1.6-90.9)and 60.8 months (range=0.7-92.4) in the elderly group (E group) and non-elderly group (N-E group), respectively.
Ethics approval and consent to participate.This study was reviewed and approved by the ethics committee of National Hospital Organization Kyushu Cancer Center.Written informed consent was from all participants.All methods were performed in accordance with the ethical standards of the institutional review board of ethics committee and national research committee with the Helsinki Declaration of 1964 and later versions.
Data collection and management.Patients were preoperatively staged by upper gastrointestinal endoscopy for biopsy and lesion evaluation by contrast enhanced chest-abdomen-pelvis computed tomography.We collected the following clinical data: preoperative characteristics [age, sex, American Society for Anesthesia-physical Status (ASA-PS), comorbidities, presence of multiple cancers, serum albumin levels, PNI, serum carcinoembryonic antigen (CEA) levels, carbohydrate antigen 19-9 levels, clinicopathological findings], short-term outcomes (surgical method, lymph node dissection, reconstruction method, surgery time, blood loss, postoperative complications, postoperative hospital stay), and long-term outcomes (5-year overall survival, 5-year disease-free survival, cause of death).We divided all patients into two groups: the E group (≥75 years) and the N-E group (<75 years).The PNI value was calculated using the following formula: 10×serum albumin(g/dl)+0.005×totallymphocyte count (20).In the present study, comorbidities were classified into four groups: cardiovascular diseases including hypertension, endocrine disorders including diabetes mellitus, cerebrovascular disease, and other (i.e., liver disease, renal disease, and other diseases).The clinicopathological findings of the patients were evaluated based on the Japanese Classification of Gastric Carcinoma (14th edition) published by the Japanese Gastric Cancer Association (JGCA) (21).Post-operative complications were classified according to the Clavien-Dindo (C-D) classification system (22).C-D grade III or higher was defined as severe complications.
Surgical procedure.Under general anesthesia, the patient was placed in a modified lithotomy position in a reverse Trendelenburg fashion.The first port was inserted trans-umbilically by the open method.CO 2 insufflation was maintained at 10 mmHg and four working ports were placed.Once a camera port and one or two ports were inserted, adhesiolysis was performed laparoscopically if needed for the other trocars.The extent of the lymphadenectomy was determined using the Japanese gastric cancer treatment guidelines 2014 (version 4) (23).After the resected specimen was removed, intracorporeal reconstruction was performed with the Billroth-I or Roux-en-Y method.
Statistical analysis.The clinicopathological data of all 222 patients were collected and retrospectively reviewed.All statistical analyses were performed using the JMP14 software program (SAS Institute Japan Ltd. Tokyo Japan).Categorical variables were assessed using Fisher's exact test.Continuous variables were evaluated using Wilcoxon's rank-sum test, Student's t-test, or Welch's t-test, according to the data distribution.Patient survival was calculated using the Kaplan-Meier method.Univariate analyses were performed to identify prognostic variables related to overall survival.Univariate variables were selected for inclusion in the multivariate Cox proportional hazard regression model.p-Values of <0.05 were considered to indicate statistical significance.The receiver operating characteristic (ROC) analysis was used to assess the optimal cut-off value of PNI, with maximum sensitivity and specificity for predicting postoperative overall survival.In the assessment of the PNI for predicting survival, the area under the curve and the sensitivity and specificity of survival were 0.719, 50%, and 91.9%, respectively.The optimal cut-off point was 43.622 to categorize high PNI and low PNI with similar results to previous reports (17,24,25).

Results
Clinical characteristics and surgical findings.Clinical characteristics of the included patients are listed in Table I.The E group consisted of 47 patients and the N-E group consisted of 175 patients.ASA-PS score ≥2 in the E group was higher than that in the N-E group (95.7% vs. 65.1%,p<0.0001).The rate of comorbidities in the E group was larger than that in the N-E patients (91.5% vs. 61.7%,p<0.0001); in particular, the rates of cardiovascular disease, metabolic endocrine disorders, and cerebrovascular disease in the E group were significantly higher than those in the N-E group.Regarding preoperative nutritional assessment, the PNI value of patients in the E group was significantly lower than that in the N-E group (47.3 vs. 51.2,p<0.001).Serum CEA level was significantly higher in the E group than that in the N-E group (p<0.001).Table II shows the surgical findings of the two groups.There was no significant difference in the surgical procedure, resection method, lymph node dissection, reconstruction method, or pStage.
Short-term outcomes.The short-term outcomes for patients in both groups are shown in Table III.There were no significant differences in the surgery time or intraoperative blood loss volume.The rate of postoperative complications in the elderly group was significantly higher than that in the non-elderly group (42.6% vs. 22.9%, p=0.01).In particular, the rate of mild complications (C-D I/II) in the E group was significantly higher than that in the N-E group (27.7% vs. 12.6%, p<0.05), though the rate of severe complications (C-D III/IV) did not significantly differ between the two groups (14.9% vs. 10.3%, p=0.43).The length of postoperative stay of the E group was significantly longer than that of the N-E group (20 vs. 13, p<0.0001).
Long-term outcomes.The 5-year overall survival rate in the E group was significantly lower than that in the N-E group (66.9% vs. 92.2%,p<0.0001; Figure 1B), although the 5year disease-free survival rate did not differ between the two groups (97.7% vs. 96.4%,p=0.735; Figure 1A).In the E group, the 5-year overall survival of patients with low

Figure 1. Kaplan-Meier analysis of disease-free survival (DFS) and overall survival (OS) in patients with stage I-III gastric cancer in the elderly group (n=47) and in the non-elderly group (n=175). (A) DFS and (B) OS among patients who underwent laparoscopic gastrectomy for stage I-III gastric cancer.
PNI was significantly worse than of patients with high PNI (25% vs. 80.9%, p=0.01), although the 5-year disease-free survival rate did not differ between the two groups (Figure 2A, B).We also examined the cause of death (gastric cancer or other disease) and found that the rate of death from gastric cancer in patients with low PNI in the N-E group was significantly higher than in those with high PNI, while the rate of death from other disease in patients with low PNI in the E group was higher than in those with high PNI (Table IV).

Univariate and multivariate analyses of prognostic factors.
Univariate and multivariate analyses of prognostic factors for overall survival are shown in Table IV.Univariate analyses demonstrated that the presence of comorbidities (p=0.01) and pathological T2 or more (p<0.01)were significantly associated with reduced overall survival after laparoscopic gastrectomy in the N-E group (Table V).The multivariate analysis revealed that pathological T2 or more was independently associated with overall survival in the N-E group (Table V).In the E group, univariate analyses showed that the presence of multiple cancers (p=0.01) and the PNI value (p<0.01) were significantly associated with reduced overall survival (Table VI), while PNI value (p<0.05) was independently associated with overall survival in multivariate analysis (Table VI).

Discussion
This retrospective study of a consecutive patient cohort evaluated the short-and long-term outcomes after laparoscopic gastrectomy for stage I-III gastric cancer and identified risk factors of long-term outcomes in elderly patients.Cohort analysis revealed that the elderly patients had higher rate of mild (C-D I/II) postoperative complications and longer postoperative hospital stays than the non-elderly patients.Overall survival in the elderly patients was significantly worse than that in the non-elderly patients, although disease-specific survival was not significantly different between the two groups.Multivariate analyses showed that the preoperative PNI was an independent risk factor for overall survival in the elderly patients.Moreover, low PNI was related to non-cancer death in elderly patients.
The PNI was first reported by Buzby et al. in 1980 (20), and emerging evidence has demonstrated the prognostic value of PNI in different types of malignant tumors, including hepatocellular, nasopharyngeal, and colorectal carcinoma.Both serum albumin and lymphocytes are associated with the survival of cancer patients (26)(27)(28).Previous studies reported the assessment of nutritional status and the usefulness of predicting the prognosis of patients with cancer with factors including platelet to lymphocyte ratio (PLR) (13), NLR (14), and PNI (15).In the present

. Kaplan-Meier analysis of disease-free survival (DFS) and overall survival (OS) in the elderly group with stage I-III gastric cancer by prognostic nutritional index (PNI). (A) DFS and (B) OS among elderly patients who underwent laparoscopic gastrectomy for stage I-III gastric cancer with low PNI (grouped by 43.662 as the cut-off value).
study, the PNI value was significantly lower in elderly patients than in non-elderly patients, although the PLR and NLR values did not differ between the two groups (Table I).Therefore, we selected PNI value for multivariable analysis.
Several investigators have discussed the relationship between PNI value and the efficacy of chemoradiotherapy, prognosis or postoperative complications after gastrectomy for gastric cancer (29)(30)(31).The relationship between the prognosis and the preoperative PNI has been reported in detail.It has been shown that low preoperative PNI is related to recurrence-free survival, overall survival, or non-cancer-related death in patients after gastrectomy for gastric cancer (32,33).In addition, it has been previously reported that low PNI may be associated with a higher stage of gastric cancer or the degree of lymph node metastases (34).In this study, we showed that elderly patients with low preoperative PNI had a poor prognosis after curative laparoscopic gastrectomy in terms of overall survival, as well as a higher rate of non-cancer-related deaths, compared to elderly patients with high PNI.Takechi et al. (33) reported that low preoperative PNI was associated with non-cancer-related deaths after gastrectomy, regardless of age.It is necessary to take into account that in their study about half of the cases underwent open gastrectomy and the median age of patients was 70 years.We assume that elderly patients with low PNI and are more susceptible to the effects of a gastrectomy, such as exacerbation of undernutrition due to decrease oral intake, decreased active daily life, aspiration pneumonia and disuse syndrome.Japan has one of the longest life expectancies among all countries, which is growing at an unprecedented rate compared with others.In recent years, progress in minimally invasive surgery and perioperative management has been made in Japan, and opportunities for surgery in elderly patients have increased.In elderly patients, physiological functions (e.g., cardiopulmonary function, swallowing, metabolic functions) tend to be worse, and they often have preoperative comorbidities (35)(36)(37)(38).We have previously reported the feasibility of laparoscopic surgery for elderly patients with gastric cancer in that the incidence of postoperative complications was lower compared to open surgery (39,40).Moreover, Suematsu et al. have also demonstrated that laparoscopic total gastrectomy for gastric cancer was feasible for the elderly patients, with comparable short and long term outcomes between elderly and non-elderly groups (41).Several reports have revealed that elderly patients with low PNI after gastrectomy for gastric cancer had a poor prognosis (29,42,43).In this study, low PNI was related to non-cancer death in elderly gastric cancer patients after laparoscopic gastrectomy; however, the reason is unclear.It is known that patients with postoperative complications of C-D grade II or more after curative open gastrectomy for gastric cancer have a poor prognosis (44).We assume that postoperative complications were not prognostic factor in our study, because the rates of postoperative complications are lower for laparoscopic surgery compared to open surgery for gastric cancer.Hashimoto et al. demonstrated blood loss (>170 ml) as risk factor for postoperative complications, and postoperative complications and low PNI as independent prognostic factors for worse overall survival in patients >80 years old (45).In the present study, T stage in non-elderly patients and low PNI in elderly patients were independent prognostic factors for overall survival (Table V, Table VI).It is interesting that the risk factors associated with overall survival after curative surgery for gastric cancer differ between the elderly and the non-elderly patients, and it is an important to determine the treatment strategy for gastric cancer.
Despite our findings, there are some limitations of the present study.First, this was a retrospective study and the number of patients was limited to a single low-volume institution.Second, although there were no significant differences, there were differences in the stage and surgical methods.Particularly, our surgical teams consisted of three surgeons, including one or two qualified surgeons, to equalize the surgical technique standards.Third, in this study, there were more cases of early cancer than advanced cancer, which may have biased the oncological prognosis.Finally, follow-up assessments of the PNI after surgery were not available, which resulted in a lack of dynamic observations of the nutritional status.

Conclusion
Elderly patients with low PNI had a poor prognosis after laparoscopic curative resection for gastric cancer and the risk of death from other diseases was shown to be significantly higher in this study.It is suggested that the risk of noncancer-related death was increased in elderly patients with low PNI due to the effect of surgery, thus it is necessary to determine the surgical indications before the operation.

Figure 2
Figure 2. Kaplan-Meier analysis of disease-free survival (DFS) and overall survival (OS) in the elderly group with stage I-III gastric cancer by prognostic nutritional index (PNI).(A) DFS and (B) OS among elderly patients who underwent laparoscopic gastrectomy for stage I-III gastric cancer with low PNI (grouped by 43.662 as the cut-off value).

Table I .
Comparative analysis of clinical characteristics between the elderly and the non-elderly group.

Table II .
Comparative analysis of surgical findings between the elderly and the non-elderly groups.

Table III .
Comparative analysis of short-term outcomes between the elderly and the non-elderly groups.

Table V .
Univariate and multivariate Cox proportional hazards models for overall survival in the non-elderly group.

Table VI .
Univariate and multivariate Cox proportional hazards models for overall survival in the elderly group.

Table IV .
Correlation between the PNI and the cause of death in the elderly group and the non-Elderly group.