Abstract
Postoperative complications contribute to recurrences and poor long-term outcomes for gastric cancer patients, especially among the elderly. However, the prognostic effect of postoperative complications on non-cancer-related death in elderly patients with gastric cancer has not been reported. Two hundred and twenty elderly (> 75 years of age) patients with stage I gastric cancer were retrospectively identified from consecutive admissions between 1995 and 2020. Non-cancer-related death following gastrectomy occurred in 13.6% (30/220) of patients. Non-cancer-related death was associated with respiratory disease in 46.7% (14/30) of cases. Although there was no association with any preoperative comorbidities, postoperative complications [P < 0.001, HR 4.16 (95% CI: 1.91-9.02)] and open gastrectomy [P=0.002, HR 3.87 (95% CI: 1.54-9.66)] were independently associated with a poorer prognosis for non-cancer-related death. Poor nutritional status [P=0.028, OR 4.25 (95% CI: 1.17-15.4)] was an independent risk factor for postoperative complications. Postoperative complications shortened life expectancy from 8.8 years to 6.1 years. Specifically, postoperative complications shortened life expectancy from 6.7 years to 3.9 years in elderly patients over 80 years of age. Postoperative complications and open gastrectomy affected the incidence of non-cancer-related death among elderly patients with gastric cancer, primarily attributed to respiratory disease. Efforts should be made to perform minimally invasive surgery, improve preoperative nutrition, and avoid postoperative complications.
Keywords: Non-cancer-related death, postoperative complication, prognosis, risk factor, gastric cancer
Introduction
Gastric cancer is the fifth most common type of cancer and the third-leading cause of death worldwide [1-3]. Recent developments in diagnostic technology, clinical collaboration, and an established evidence base have enhanced detection rates and drastically improved early and long-term outcomes for gastric cancer patients. However, gastric cancer remains a global health problem with various clinical issues complicating the selection of appropriate treatments [4-7]. Especially in elderly patients, the effects of surgical stress on physiological status and putative decreases in life expectancy following gastrectomy are pivotal clinical issues to be resolved.
There is a high incidence (12.8% to 14%) of postoperative complications following curative gastrectomy [8-10]. Several studies have confirmed that postoperative complications following gastrectomy lead to poor oncological prognosis [11-14]. Namely, patients with postoperative complications may be at increased risk of hyperinflammation and hypercytokinemia, resulting in poor immune function and a high incidence of cancer recurrence [15-17]. However, the prognostic effect of postoperative complications on non-cancer-related death and the life expectancy of elderly patients have not been reported. It is foreseeable that excessive surgical stress and postoperative complications might have a negative physiological effect and shorten life expectancy due to non-cancer-related death.
In this study, we firstly investigated the most common cause of non-cancer-related death in gastric cancer. Next, the independent prognostic factors of non-cancer-related death were examined, and we further investigated the putative risk factors affecting these prognostic factors. Finally, we elucidated the effect of these factors on life expectancy. The results of this study may provide clear evidence of an association between gastrectomy and non-cancer-related death in patients with gastric cancer.
Methods
Patients and procedures
The study was institutionally approved by the Kyoto Prefectural University of Medicine, and each participant provided written informed consent. A total of 220 patients who underwent gastrectomy for pathological stage I gastric cancer (stage IA and IB according to the Japanese guidelines for the treatment of gastric cancer [18,19]) at Kyoto Prefectural University of Medicine between 1995 and 2020 were included in this study. Only stage I gastric cancer patients were included to remove the influence of cancer-related death from the analysis. Patients underwent preoperative assessments, including gastric endoscopy, computed tomography (CT) scans, and laboratory tests. Based on the preoperative diagnosis, all patients were scheduled for curative gastrectomy and lymphadenectomy, according to the Japanese guidelines for treating gastric cancer. Patients with clinical T1 and N0 tumors underwent D1 or D1+ lymphadenectomy, while patients with more advanced tumors underwent D2 or D2+ lymphadenectomy. In D2 dissections, peri-gastric lymph nodes and all second-tier lymph nodes were completely retrieved. Combined resection was defined as the resection of the other organ involved in direct tumor invasion or concurrent cancer [19,20].
Patients with postoperative complications, grade II or more according to the Clavien-Dindo classification system, were enrolled in this study. We defined non-cancer-related death as all-cause mortality, excluding deaths from primary gastric cancer and other cancers. After categorizing patients by sex, postoperative complications (with/without), and age (≥ 85 years), life expectancy was calculated using the expected years of postoperative survival.
Statistical analysis
All analyses were performed using R software (R Foundation for Statistical Computing). Pearson’s chi-square (χ2) test and Fisher’s exact probability test were performed for categorical variables. Student’s t-test and Mann-Whitney U tests were used to compare clinicopathological characteristics for unpaired continuous variables between the two groups. Survival curves were estimated using the Kaplan-Meier method, and statistical differences were examined using the log-rank test. The data were stratified for multivariate analysis using both forward and backward stepwise Cox regression procedures. A p-value of < 0.05 was considered statistically significant. Life expectancy was evaluated with the restricted mean survival time (RMST) method.
Results
Common reasons for non-cancer-related death
A total of 30 (13.6%) patients died from non-cancer-related causes. Table 1 shows that 14 (47%) of these deaths were related to respiratory disease, three (10%) were attributed to senility, two (6.7%) were related to cardiovascular disease, and two (6.7%) patients died of infection. Non-cancer-related deaths from respiratory disease were most common and considered extremely high-risk in these gastric cancer patients.
Table 1.
Common reasons for non-cancer-related death
| Reasons for non-cancer-related death | n=30 | |
|---|---|---|
| Respiratory-related death | 14 | (47%) |
| Senility | 3 | (10%) |
| Cardiovascular-related death | 3 | (10%) |
| Infection-related death | 2 | (7%) |
| Liver-related death | 2 | (7%) |
| Accidental death | 1 | (3%) |
| Renal-related death | 1 | (3%) |
| Nerve-related death | 1 | (3%) |
| Unknown | 3 | (10%) |
Prognostic effects of postoperative complications on non-cancer-related death
Comparing elderly patients with or without postoperative complications, Figure 1 shows the cumulative incidences of non-cancer-related death and survival curves following gastrectomy. Elderly patients with postoperative complications had a significantly elevated cumulative incidence of non-cancer-related death and poorer long-term survival (P < 0.001). Univariate and multivariate analyses using Cox’s proportional hazards model revealed that patients with postoperative complications [P < 0.001, HR 4.16 (95% CI: 1.91-9.02)] and having received open gastrectomy [P=0.002, HR 3.87 (95% CI: 1.54-9.66)] independently contributed to a poorer prognosis for non-cancer-related death (Table 2). There was no association between any preoperative comorbidities and non-cancer-related death. Among the reasons for non-cancer-related death, postoperative complications were significantly associated with respiratory-related deaths (Table 3).
Figure 1.
The cumulative incidence of non-cancer-related deaths among elderly patients with or without postoperative complications following gastrectomy, generated by the Mantel-Cox log-rank test method.
Table 2.
Univariate and multivariate analyses of clinical factors affecting non-cancer-related death using the Cox’s proportional hazard model
| Variable | Univariatea | Multivariateb | |||||
|---|---|---|---|---|---|---|---|
|
|
|
||||||
| p-value | HRc | 95% CId | p-value | ||||
| Age | < 80 | 80 ≤ | 0.059 | ||||
| Gender | Male | vs. | Female | 0.064 | |||
| BMI | < 22 | vs. | 22 ≤ | 0.029 | - | ||
| Albumin | < 3.5 | vs. | 3.5 ≤ | 0.003 | - | ||
| Cardiovascular disease | (+) | vs. | No | 0.440 | - | ||
| Digestive disease | (+) | vs. | No | 0.622 | - | ||
| Endocrine and autoimmune disease | (+) | vs. | No | 0.481 | - | ||
| Hepatic disease | (+) | vs. | No | 0.600 | - | ||
| Malignant disease | (+) | vs. | No | 0.369 | - | ||
| Neurological disease | (+) | vs. | No | 0.544 | - | ||
| Renal and urologic disease | (+) | vs. | No | 0.397 | - | ||
| Respiratory disease | (+) | vs. | No | 0.326 | - | ||
| Total gastrectomy | (+) | vs. | No | 0.087 | - | ||
| Surgical approach | (+) | vs. | No | 0.001 | 4.21 | 1.70-10.4 | < 0.001 |
| Complication | Grade II ≤ | vs. | < Grade II | < 0.001 | 4.98 | 2.36-10.5 | < 0.001 |
Kaplan-Meier method; significance was determined by log-rank test.
Multivariate survival analysis was performed using Cox’s proportional hazard model.
HR: Hazard ratio.
CI: Confidence interval.
Table 3.
Comparison of the incidences in each reason for non-cancer-related death according to the presence of postoperative complications
| Reason for non-cancer death | n | Postoperative complications | p-value | |||
|---|---|---|---|---|---|---|
|
| ||||||
| (+) | (n=45) | (-) | (n=175) | |||
| Respiratory-related death | 14 | 7 | (15.6%) | 7 | (4%) | 0.011 |
| Senility | 3 | 1 | (2.2%) | 2 | (1.1%) | 0.498 |
| Cardiovascular-related death | 3 | 2 | (4.4%) | 1 | (0.6%) | 0.498 |
| Infection-related death | 2 | 1 | (2.2%) | 1 | (0.6%) | 0.368 |
| Liver-related death | 2 | 1 | (2.2%) | 1 | (0.6%) | 0.368 |
| Accidental death | 1 | 0 | (0%) | 1 | (0.6%) | 1.000 |
| Renal-related death | 1 | 0 | (0%) | 1 | (0.6%) | 1.000 |
| Nerve-related death | 1 | 0 | (0%) | 1 | (0.6%) | 1.000 |
| Unknown | 3 | 2 | (4.4%) | 1 | (0.6%) | 0.107 |
Clinicopathological factors affecting postoperative complications
Next, we compared clinicopathological factors between patients with and without postoperative complications (Table 4). By univariate analysis, postoperative complications were associated with poorer nutritional status (serum albumin (Alb) level < 3.5 mg/mL; P=0.032) and total gastrectomy (P=0.038). Multivariate analysis revealed that poorer nutritional status (Alb < 3.5; P=0.028, OR 4.25) was an independent risk factor for postoperative complications (Table 4).
Table 4.
Univariate and multivariate analyses to detect possible risk factors for postoperative complications
| Variables | Postoperative complication | Univariatea | Multivariateb | ||||||
|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||
| (+) | (n=45) | (-) | (n=175) | p-value | ORc | 95% CId | p-value | ||
| Age | < 80 | 24 | (53%) | 102 | (58%) | 0.613 | |||
| ≥ 80 | 21 | (47%) | 73 | (42%) | |||||
| Gender | Female | 15 | (33%) | 70 | (40%) | 0.493 | |||
| Male | 30 | (67%) | 105 | (60%) | |||||
| BMI (kg/m2) | < 22 | 17 | (38%) | 93 | (53%) | 0.094 | |||
| ≥ 22 | 28 | (62%) | 82 | (47%) | |||||
| Nutritious status (Alb (g/dl)) | ≥ 3.5 | 40 | (89%) | 170 | (97%) | 0.032 | 1 | ||
| < 3.5 | 5 | (11%) | 5 | (3%) | 4.25 | 1.17-15.4 | 0.028 | ||
| Cardiovascular disease | (-) | 23 | (51%) | 91 | (52%) | 1.000 | |||
| (+) | 22 | (49%) | 84 | (48%) | |||||
| Digestive disease | (-) | 33 | (73%) | 136 | (78%) | 0.555 | |||
| (+) | 12 | (27%) | 39 | (22%) | |||||
| Endocrine and autoimmune disease | (-) | 38 | (84%) | 141 | (81%) | 0.670 | |||
| (+) | 7 | (16%) | 34 | (19%) | |||||
| Hepatic disease | (-) | 42 | (93.3%) | 162 | (93%) | 1.000 | |||
| (+) | 3 | (6.7%) | 13 | (7%) | |||||
| Malignant disease | (-) | 30 | (67%) | 127 | (73%) | 0.462 | |||
| (+) | 15 | (33%) | 48 | (27%) | |||||
| Neurological disease | (-) | 39 | (87%) | 161 | (92%) | 0.257 | |||
| (+) | 6 | (13%) | 14 | (8%) | |||||
| Renal and urologic disease | (-) | 42 | (93%) | 169 | (97%) | 0.394 | |||
| (+) | 3 | (7%) | 6 | (3%) | |||||
| Respiratory disease | (-) | 42 | (93%) | 159 | (91%) | 0.394 | |||
| (+) | 3 | (7%) | 16 | (9%) | |||||
| Surgical approach | Open | 23 | (51%) | 77 | (44%) | 0.406 | |||
| Laparoscopic | 22 | (49%) | 98 | (56%) | |||||
| Total gastrectomye | (-) | 33 | (73%) | 152 | (87%) | 0.038 | |||
| (+) | 12 | (27%) | 23 | (13%) | |||||
Univariate analysis was assessed using Chi squared test and Fisher’s exact probability test.
Multivariable logistic regression was used to assess the risk factors for severe complications.
OR: Odds ratio.
CI: confidence interval.
Including completion gastrectomy.
Postoperative complications and life expectancy
Table 5 shows life expectancy according to the presence of postoperative complications. Postoperative complications shortened the life expectancy of elderly patients (≥ 75 years of age) following curative gastrectomy for gastric cancer. Life expectancy was 8.8 years for patients without postoperative complications, which was longer than the 6.1 years found among patients with postoperative complications. Specifically, patients aged 80 years or older without postoperative complications had 6.7 years life expectancy, whereas patients of the same age group with postoperative complications had a life expectancy of only 3.9 years.
Table 5.
Postoperative complications and life expectancy
| Age (years old) | Total* | Postoperative complications | ||
|---|---|---|---|---|
|
| ||||
| (+)* | (-)* | |||
| All ages | all | 8.3 | 6.1 | 8.8 |
| Age < 75 | male | 7.7 | 5.8 | 8.2 |
| female | 6.8 | 5.6 | 7.0 | |
| 75 ≤ Age < 80 | all | 8.6 | 7.2 | 8.9 |
| male | 8.2 | 7.5 | 8.3 | |
| female | 4.8 | 4.5 | 4.8 | |
| 80 ≤ Age | all | 6.1 | 3.9 | 6.7 |
| male | 4.5 | 3.1 | 5.1 | |
| female | 6.7 | 5.6 | 7.0 | |
Year of life expectancy.
Discussion
Postoperative complications are known to impair oncological prognosis following gastrectomy [11-14]. However, there have been no studies of the prognostic effect postoperative complications and open gastrectomy have on non-cancer-related death in patients with gastric cancer. In this study, we demonstrated that postoperative complications and open gastrectomy independently affected a poorer prognosis for non-cancer-related death in elderly patients. Indeed, postoperative complications shortened life expectancy from 8.8 years to 6.1 years in elderly patients (≥ 75 years of age). Specifically, the life expectancy of patients 80 years or older with postoperative complications fell from 6.7 years to 3.9 years. Poor nutritional status proved to be an independent risk factor for postoperative complications in elderly gastric cancer patients. Respiratory disease was the most common cause of non-cancer-related death, accounting for 46.7% of cases. These novel findings provide pivotal clinical evidence imperative for managing elderly patients with gastric cancer.
Previous research has identified the common causes of non-cancer-related death from various cancers [21]. Newschaffer et al. reported that non-cancer-related death from prostate cancer was most commonly attributed to heart disease, followed by cerebrovascular disease [22]. Similarly, Afifi et al. also reported that heart disease and cerebrovascular disease were the first and second most common causes of non-cancer-related deaths in breast cancer patients within ten years of diagnosis [23]. On the contrary, non-cancer-related deaths among gastric cancer patients are most commonly caused by respiratory diseases, such as aspiration pneumonia. Sugawara et al. reported that preoperative restricted pulmonary dysfunction and total gastrectomy increased non-cancer-related death after gastrectomy and pneumonia was one of the most common death [24]. Patients with preoperative restricted pulmonary dysfunction have poor physical status, leading to a potential increase of non-cancer-related death after gastrectomy, especially respiratory-related death. Furthermore, the increased incidence of respiratory-related death may be caused by intestinal juice reflux following sub or total gastrectomy and adhesion, in addition to the impaired swallowing reflex in elderly patients. Previously, we reported that elderly gastric cancer patients have a higher risk of respiratory disease compared to their younger counterparts [13]. Therefore, it is important to bear in mind that respiratory-related disease is a pivotal cause of non-cancer-related death for gastric cancer patients.
Another striking and unexpected finding of this study was that open gastrectomy was an independent risk factor for non-cancer-related death. In other words, less invasive laparoscopic gastrectomy independently reduced the occurrence of non-cancer-related death. Similarly, several recent studies have demonstrated that laparoscopic surgery reduced postoperative complications. Inokuchi et al. reported that laparoscopic gastrectomy reduced postoperative pneumonia and cardiac complications in high-risk (ASA-3 <) patients compared with open gastrectomy [25]. Lee et al. reported that laparoscopic distal gastrectomy for locally advanced gastric cancer was safe and showed important benefits, such as a lower complication rate, compared to open surgery [26]. Thus, laparoscopic surgery, including robotic surgery, may be less disruptive to the abdominal wall than open surgery and thereby maintain postoperative abdominal breathing, which prevents the decrease of vital capacity and reduce respiratory-related diseases such as pneumonia, particularly in the elderly. In addition, these procedures may reduce the long-term risk of respiratory-related death. Therefore, a less invasive surgical approach is recommended to reduce inflammation and postoperative complications and adhesions, as well as to extend life expectancy and long-term outcomes. Currently, a prospective study is underway to examine these potential benefits.
The present study was limited by its retrospective design with a small cohort. Additionally, the prolonged recruitment period over which the retrospective analysis was performed at a single institution may be influenced by possible variations in treatment strategies over time. Therefore, a prospective observational study with several large cohorts or a nationwide clinical database study may be needed to validate the significance of postoperative complications and open gastrectomy on non-cancer-related death among gastric cancer patients.
In conclusion, postoperative complications were shown to be associated with non-cancer-related death, particularly respiratory-related death, and decreased life expectancy in elderly patients with gastric cancer. Careful consideration should be given to patient nutrition and surgical approach (less invasive) to prevent non-cancer-related deaths.
Disclosure of conflict of interest
None.
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