Differences of clinical features and outcomes between male and female elderly patients in gastric cancer

Although the average life span differs between males and females, little is known about differences in clinical features and short and long-term outcomes between elderly male and female gastric cancer patients. This study was designed to clarify these issues to identify the possibility for sex-based treatment strategies in elderly gastric cancer patients. This study included 295 consecutive elderly gastric cancer patients (75 years or older) who underwent curative gastrectomy between 1997 and 2016. We defined postoperative complications as Clavien–Dindo classification grade II or higher. Comorbidities were present in 67% of all patients. Males tended to have more comorbidities than females (P = 0.077). Male patients had significantly more upper gastric cancers (P = 0.001), a higher incidence of postoperative complications (P = 0.045), and poorer prognoses than females (P = 0.003). Multivariate analysis revealed that being male was an independent risk factor for postoperative complications (Odds ratio 2.5, P = 0.045) and a poor prognostic factor (Hazard ratio 1.81, P = 0.008). Patients who underwent limited surgery without postoperative complications tended to have a better prognosis than patients receiving standard surgery with postoperative complications (3-year overall survival: 78% vs. 55%, P = 0.156). Male was an independent risk factor for postoperative complications and an independent poor prognostic factor in elderly gastric cancer patients. To avoid postoperative complications, the limited surgery might be justified for high-risk elderly male patients.

Remarkably, aging societies are increasing worldwide, particularly in developed countries [1][2][3] .In Japan, the incidence of elderly persons 65 years or older is 28.9%, which is considerably higher than the average incidence of 8.9% globally.Elderly gastric cancer patients are also rising because of an aging society 4 .Elderly patients have frailties across multiple organ systems 5 , which is a risk factor for postoperative complications following gastrectomy 6,7 .Because several studies have already identified that postoperative complications are a poor prognostic factor for patients with gastric cancer [8][9][10][11] , establishing appropriate treatment strategies for elderly gastric cancer patients is pivotal to improving short and long-term outcomes.
The average life span differs between male and female elderly persons.Specifically, the average life expectancy of males is 6 years shorter than females (male vs. female: 82 vs. 88 years old) in Japan 12 .However, little is known about differences in clinical features and short and long-term outcomes between males and females following gastrectomy.In this study, we investigated these parameters to clarify these issues.
We hypothesized that the prognosis may be improved by reducing complications in male, which was an independent risk factor for complications.Thus, we proposed that limited surgery could be an effective strategy, especially for patients with comorbidities.

Patients and procedures
The study was institutionally approved by the Kyoto Prefectural University of Medicine (the approved number from the review board, ERB-C-67-5), and each participant provided written informed consent.All methods were performed based on the Declaration of Helsinki.A total of 291 patients aged 75 years or older who underwent curative gastrectomy at Kyoto Prefectural University of Medicine between 1997 and 2016 were included in the study.The clinical characteristics of the patients are shown in Table 1.In this study, we retrospectively analyzed clinicopathological features and early and long-term outcomes.
The postoperative follow-up program at our institution comprises a regular physical examination, laboratory blood tests, and chest X-rays every 3 or 6 months.Endoscopy and ultrasonography, or computed tomography, were performed annually for the first 5 years, if possible.All enrolled patients underwent pathological or macroscopic curative resection (R0).Histological types were classified as differentiated (papillary adenocarcinoma, or moderately or well-differentiated adenocarcinoma) or undifferentiated (poorly differentiated or undifferentiated adenocarcinoma, signet-ring cell carcinoma, or mucinous adenocarcinoma) based on the 15th edition of the

Clinical effect of sex differences and clinicopathological factors on postoperative complications
First, we compared clinicopathological factors between patients with and without postoperative complications.Multivariate analysis using logistic regression revealed that being male [P = 0.040, OR (Odds ratio) 2.15 (95% CI 1.03-4.46)]and having open gastrectomy [P = 0.021, OR 2.73 (95% CI 1.16-6.39)]were independent risk factors for postoperative complications (Table 2).

Prognostic factors of elderly male gastric cancer patients
Next, we investigated the prognostic factors of elderly male gastric cancer patients.In our cohort of 181 elderly male patients with gastric cancer, 36 patients died due to metastasis or recurrence of gastric cancer, 8 patients died from other types of cancer, and 44 patients died from other diseases (Supplementary Table S3).Among these patients, only one patient undergone neoadjuvant chemotherapy (S-1 oral administration).As for adjuvant chemotherapy, only a few patients did receive this treatment: 19 patients were administered S-1 orally, 6 patients received UFT orally, 2 patients were given 5-FU, and 2 other patients received other treatments.Univariate analysis using a log-rank test revealed that elderly male patients had poorer prognoses than female patients after gastrectomy (P = 0.003) (Fig. 1).Multivariate analysis using Cox's proportional hazards model revealed that being male [P = 0.008, HR (Hazard ratio) 1.81 (95% CI 1.17-2.3).Regarding male patients, total gastrectomy was an independent poor prognostic factor [P = 0.036, OR 2.25 (95% CI 1.06-4.78)],determined using logistic regression (Supplementary Table S4).www.nature.com/scientificreports/underwent standard surgery had better prognoses than patients who underwent limited surgery (3-year overall survival: 78% vs. 72%, P = 0.186).However, regarding the efficacy of limited surgery to avoid postoperative complications in male patients, patients who underwent limited surgery without postoperative complications tended to have a better prognosis than patients receiving standard surgery who developed postoperative complications (3-year overall survival: 78% vs. 55%, P = 0.156) (Fig. 2).

Discussion
Gastric cancer is among the most common causes of cancer-related death worldwide 16 .Recent advances in diagnostic techniques, minimally invasive surgical methods, and perioperative management have led to the early detection of gastric cancer and declines in mortality and morbidity [17][18][19] .However, little is known about differences in clinical features and short and long-term outcomes between male and female elderly gastric cancer patients.In this study, we clearly demonstrated that changes associated with advancing age that differ between males and females affect clinical features, postoperative complications, and long-term outcomes in gastric cancer.Namely, being male was an independent risk factor for postoperative complications and an independent poor prognostic factor in elderly gastric cancer patients.Receiving limited surgery without developing postoperative complications contributed to a better prognosis than standard surgery with postoperative complications in male gastric cancer patients.Our results may provide evidence that changes associated with advancing age that differ between elderly male and female gastric cancer patients affect clinical features, postoperative complications, and long-term outcomes and that sex-based treatment strategies might be needed to improve outcomes.Several studies have examined the relationship between prognosis and sex in various types of cancer, including gastric cancer.Using a large database 20 in Korea, Huafu et al. reported that male gastric cancer patients had worse prognoses than female patients.On the other hand, Kim et al. reported that males had better prognoses than females in young gastric cancer patients because younger males had a lower incidence of signet ring cell carcinoma 21,22 .In colorectal cancer, Yang et al. conducted a meta-analysis to reveal that males had worse overall survival and cancer-specific survival than females 23 .Previous studies and several meta-analyses in various solid tumors including gastric cancer suggested that males are tended to have postoperative complications more frequently than females as shown in our results 24,25 .Whereas Sah et al. indicated that females were more prone to have postoperative complications following gastric cancer surgery 26,27 .The authors report that females were more prone to serious complications, possibly due to the influence of sex hormones on the overall prognosis.Azzurra et al. suggested the theory that female hormones could maintain the immune tolerance and prevent the excessive inflammatory responses 28 .Thereby, female hormones might potentially contribute to postoperative recovering and reducing the risk of postoperative complications.We also suggest that the hormonal differences  between male and female might affect the aging phenomenon and postoperative complications.These issues are currently under evaluation by investigating the various hormone levels, and we will report details in near future.
Another striking finding in this study was that limited surgery without postoperative complications might contribute to a better prognosis than standard surgery with postoperative complications in elderly male patients.Indeed, 3-year overall survival following limited surgery without postoperative complications was higher than for standard surgery with postoperative complications (78% vs. 55% (P = 0.156)) in elderly male patients.Regarding the extent of lymphadenectomy, various studies have shown the efficacy of D2 gastrectomy to be controversial compared to D1 gastrectomy in elderly gastric cancer patients [29][30][31][32] .However, two recent studies report that standard D2 surgery contributes to a better prognosis compared to limited surgery, even in elderly gastric cancer patients 33,34 .In real-world data from nationwide general hospitals, patients had more high-risk comorbidities than those in high-volume centers.Therefore, a safer operation strategy might be performing limited surgery to avoid postoperative complications.A recent pivotal study identified that, postoperatively, elderly gastric cancer patients are more likely to die from other diseases rather than from gastric cancer 35 .Moreover, postoperative complications affect the incidence of death from other diseases, especially respiratory disease 36 .Therefore, performing limited surgery for high-risk and/or elderly male patients could be a sex-based treatment strategy for elderly gastric cancer patients.
The European Society for Medical Oncology (ESMO) recommends a geriatric assessment to evaluate functional age for treatment in elderly gastric cancer patients as it is a better predictor of treatment response than chronological age 37 .In the ESMO guideline, limited surgery is already recommended for high-risk patients evaluated using the geriatric assessment.This guideline is very useful considering the aging society globally.On the other hand, a recent Japanese nationwide study proved that the introduction of minimally invasive surgery reduced postoperative complications in high-risk patients, including elderly patients 38 .Indeed, robotic surgery can reduce postoperative complications 39,40 .Therefore, minimally invasive surgery with standard lymphadenectomy may reduce postoperative complications and be an alternative strategy in elderly patients 41 .This issue is also under evaluation at our institute and will be reported in the near future.
A limitation of our study was that the results were retrospectively demonstrated in a small cohort.The long accrual period of this retrospective analysis at a single institute may have incorporated variations in treatment strategies.Therefore, a prospective observational study using several large cohorts or a nationwide clinical database study may be needed to validate our finding that being male is a poor prognostic factor and proposal for a sex-based surgical strategy.Nevertheless, elderly male patients had higher frequencies of comorbidities and postoperative complications.They should be specifically targeted in an effort to improve prognosis by considering comorbidities and performing limited surgery to avoid complications.Also, minimally invasive surgery may be the future strategy for avoiding postoperative complications and improving prognosis.The findings of our research are awaiting confirmation through a prospective trial.

FemaleFigure 1 .
Figure1.Comparison of overall survival curves between elderly male and female patients.Elderly male patients had poorer prognoses after gastrectomy than female patients (P = 0.003).

Figure 2 .
Figure 2. Comparison of overall survival curves with elderly male patients according to the extent of lymphadenectomy and the presence of postoperative complications.Patients who underwent standard surgery had better prognoses than patients who underwent limited surgery (3-year overall survival: 78% vs. 72%, P = 0.186).However, patients who underwent limited surgery without developing postoperative complications tended to have a better prognosis than patients receiving standard surgery with postoperative complications (3-year overall survival: 78% vs. 55%, P = 0.156).

Table 1 .
Comparison of clinicopathological factors between female and male patients.

Table 2 .
Univariate and multivariate analyses to detect possible risk factors for postoperative complications.

Table 3 .
Univariate and multivariate analyses of overall survival after surgery in elderly patients.