Non cancer causes of death after gallbladder cancer diagnosis: a population-based analysis

Mortality from non cancer causes in patients with gallbladder cancer (GBC) still unclear. This study evaluated the causes and risk factors of non cancer death during different follow-up periods after GBC diagnosis. Non cancer causes of death for GBC patients diagnosed between 2000 and 2017 in Surveillance, Epidemiology and End Results database were analyzed and standardized mortality rates (SMR) for each non cancer death were calculated. Predictors for non cancer death were identified through multivariate competing risk analysis. A total 11,927 GBC patients were identified for further analysis, 9393 died during follow up. The largest proportion of non cancer deaths occurred > 3 years after diagnosis (39.4%). Most common non cancer cause were cardiovascular disease (43.3%), followed by other cause of death (34.4%) and infectious diseases (8.6%). Compared with US general population, GBC patients has higher risk of death from disease of heart (SMR, 1.58; 95%CI, 1.41–1.75), septicemia (SMR,3.21; 95%CI, 2.27–4.40), diabetes mellitus (SMR,1.97; 95%CI, 1.43–2.63), alone with other causes. Non cancer causes accounted for a significant proportion of deaths during the follow-up period after GBC diagnosis. The risk of non cancer death is higher in GBC patients than in the general population. Our study provides comprehensive assessment of death from non cancer cause in GBC patients, which has important implications for health management in GBC patients.


Statistic analysis.
We calculated SMR and corresponding 95% confidence intervals (95%CI) for non cancer deaths within different interval.Multivariate competitive risk analysis was performed to determine independent predictors for non cancer death.Hazard ratios (HRs) and 95%CI were used to represent associations between patient characteristics and cause of death.Non cancer death were defined as events of primary concern, while competitive events were defined as deaths from cancer causes.All tests were double-sided, P < 0.05 were considered statistically significant.Data analysis was performed by R software (version 4.0.0) and SEER*Stat software (version 8.4.0).
For details, see Table 3.

Discussion
Our study showed that most deaths among GBC patients occurred within 1 year after diagnosis and most deaths were caused by GBC.However, the proportion of GBC related deaths decreased over time, while non cancer deaths accounted for an increasing proportion after diagnosis.Among patients who survived more than 3 years in our research, 39.4% of them died from non cancer causes.Common non cancer causes of death in GBC patients included cardiovascular disease, infectious disease and others cause of death.In our analysis, the proportion of non cancer death have changed over time, cardiovascular death (CVD) has consistently dominated.Cancer and heart disease are two main causes of death worldwide 9 .Previous study assessing causes of death in cancer patients pointed to an increased risk of cardiovascular disease in cancer patients 10,11 .A SEER database analysis concluded that CVD in cancer patients was time-dependent, with a high risk of CVD in the first year after diagnosis 2 .Our research get the same conclusion, in our research, GBC patients has higher risk of CVD (SMR, 1.52; 95%CI, 1.38-1.66)during the entire follow-up period, especially within 1 year after diagnosis (SMR, 2.19; 95%CI, 1.87-2.55).The association between GBC and CVD may be attributable to multiple factors, cancer patients tend to have more risk factors for cardiovascular disease, based on previous research, cancer survivors were more likely than cancer-free survivors to have high blood pressure, diabetes, dyslipidemia, overweight and a www.nature.com/scientificreports/history of smoking 12 .In addition, cancer patients are at risk of developing deep vein thrombosis and pulmonary embolism 13 .On the other hand, due to the psychological burden of tumor diagnosis, treatment and monitoring, additional psychological stress may be placed on patients which leading to the occurrence of cardiovascular events 14,15 .Further, GBC related treatments, such as chemotherapy, can lead to the risk of thromboembolic events which resulted ischemic heart disease as well as cerebrovascular disease 16 , radiotherapy is also cardiotoxic, about 10-30% of cancer patients treated with radiation have been reported to develop radiation-induced heart disease 5-10 years after treatment 17 .Therefore, careful evaluation should be performed before and after cancer treatments, routine cardiac imaging and serological monitoring should be considered for high-risk CVD patients 18 .Fatal infections are one of the leading cause of death in cancer patients which be interpreted as results of the immunosuppression caused by the malignancy itself or various modern cancer treatments [19][20][21] .Cancer patients often has poor nutrition lead to low immunity and easy infection 22 .Based on previous study, cancer cell affects immune system through various ways 23 , the process of tumor metastasis damage immune system, which leads to the higher risk of infection 24 , further, due to the aggressive nature of tumor cells, inadequate blood supply due to rapid tumor growth can also result infection 25 .In the present study, GBC patients has higher risk of death caused by septicemia (SMR, 3.21; 95%CI, 2.27-4.40),especially within 1 year after diagnosis (SMR, 6.51; 95%CI, 3.97-10.05).The development of sepsis is often associated with cancer related treatments, both surgery and chemotherapy increase the risk of sepsis 26,27 .In addition, neutropenia as a result of antitumor therapy is a common clinical phenomenon, which has been shown to be independently associated with sepsis [28][29][30] .Compared with general population, cancer patients has greater risk of death from pneumonia 31 , our research get the similar conclusion in GBC patients (SMR, 1.50; 95%CI, 1.03-2.12).The susceptibility of pneumonia in cancer patients comes from several factors, including disease itself, chemotherapy and immune dysfunction 32 , it is reported that 50% of septic shock is caused by bacterial pneumonia within cancer patients 31 .Therefore, regular monitoring of infection indicators and prompt antibiotic treatment are also important parts of the treatment and follow-up strategy for GBC patients.
About 20 percent of cancer patients has diabetes 33 .Previous studies suggested that cancer patients, especially prostate, breast, and colorectal cancer patients, has higher risk of death from diabetes than general population 4 .In our research, GBC patients were more likely to died from diabetes than US general population (SMR, 1.97; 95%CI, 1.43-2.63).Cancer treatment measures can impact blood glucose, it has been suggested that higher risk of diabetes in cancer patients may be due to the processes of chemotherapy 34 .Further, the application of PD-1 in cancer therapy has become more and more widespread in recent years 35 .PD-1 inhibitors can rapidly www.nature.com/scientificreports/induce severe insulin deficiency, leading to worsening of diabetes, which lead to the higher risk of death from diabetes 4 .In addition, because of the gallbladder is anatomically adjacent to the pancreas, small local metastases or compression may also affect blood glucose.Researches related to diabetes management models suggested that patients with diabetes have decreased blood glucose control, medication compliance, and self-management ability after cancer diagnosis 16 , this may lead to poor glycemic control in cancer patients with diabetes, leading to a series of complications that affect prognosis.Therefore, long-term diabetes care for GBC survivors is equally important during follow-up.Based on Yang et al. 's analysis, cancer patients often has chronic comorbidities in the same or adjacent sites.Lung cancer patients, for example, have an increased risk of dying from respiratory diseases, gastrointestinal and liver cancer patients has increased risk of dying from digestive diseases 22 .In our research, GBC patients has higher risk of death caused from stomach and duodenal ulcers (SMR, 4.62; 95%CI, 1.50-10.78)and chronic liver disease and cirrhosis (SMR, 4.19; 95%CI, 2.63-6.34),confirming previous reports.
To screen out patients at high risk of non cancer death, we screened independent risk factors for non cancer death in GBC patients through multivariate competitive risk analysis, the results indicated that GBC patients with older age has higher risk of non cancer death.Elderly patients tend to have more comorbidities, such as hypertension, coronary heart disease and diabetes 36,37 , further, the decline of physical and physiological function in elderly patients are also related to the occurrence of non cancer death 38 .Mo et al. 's study about the risk of CVD in renal cancer patients suggested that black patients has higher risk of CVD than other races 39 , which may be due to that black patients has higher risk of venous thromboembolism 40 .Our study also indicated that black patients has higher risk of non cancer death in GBC patients.GBC patients with poorly differentiated and distant tumor stages has lower risk of non cancer death, these factors were reported to be independent risk factors for prognosis in GBC patients previously 41 .So it is possible that these patients may not live long enough to die from non cancer causes.Compared with married patients, unmarried GBC patients has higher risk of non cancer death, confirming previous reports 39,42 .The fact that marriage provides social support may explain this finding 30 .GBC patients diagnosed between 2010 and 2017 has lower risk of non cancer death than diagnosed between 2004 and 2009, possibly due to the advances in medical technology and growing emphasis on death from non cancer causes 43 .
Previous studies have shown that cancer patients received surgery will increases the risk of venous thromboembolism 44,45 .In addition, Hiong et al. 's studies indicated that cancer patients has an increased risk of postoperative sepsis, which leads to decreased cancer survival rates 26 , these factors may be explain the higher risk of non cancer death in GBC patients treated with surgery.Therefore, the risk of postoperative cardiovascular events in GBC patients should be considered, such as the prevention of acute hypertension and arrhythmia in postoperative care.On the other hand, received chemotherapy were protective factor for non cancer death in our analysis, consistent with previous studies 39,46,47 .This does not seem to fit with the common belief that chemotherapy causes cardiotoxicity and increases the risk of CVD.This may be due to that patients who receive regular chemotherapy can receive better health monitoring during treatment and receive more timely intervention when at healthy risk to avoid subsequent adverse events 47 .However, the underlying mechanism why chemotherapy improves non cancer death outcomes in GBC patients has not been clarified, and further studies still needed.To reduce the risk of non cancer death in GBC patients, we suggest that primary prevention should performed to higher risk patients.For most cancer survivors, the most effective strategies for primary prevention of non cancer death are smoking cessation, weight loss, exercise, proper diet, control of blood pressure and blood sugar, prevent atherosclerosis, etc., in addition, lifelong follow-up are also necessary, such as regular monitoring of some health indicators 48 .
There are several limitations in our analysis, first, information about non cancer comorbidities was not included in SEER database and we were unable to further explore the impact of these comorbidities on non cancer mortality in GBC patients, in addition, different treatment regimens and duration impact non cancer mortality, but the specific dose, type and duration of radiotherapy and chemotherapy regimens are not recorded in detail in SEER database 46 .Second, all patients in SEER database were selected in United States, so cases from Europe and Asia are needed to further validate our study.Finally, because the study was retrospective, which could biased the results.Despite some limitations mentioned above, this study is still meaningful and helpful in the clinical management for GBC patients.

Conclusion
During the whole follow-up period after GBC diagnosis, the proportion of non cancer death in GBC patients gradually increased with the prolongation of diagnosis time, cardiovascular diseases and infectious diseases were the common causes.GBC patients has higher risk of death caused from cardiovascular diseases, infectious diseases, other cause of death and gastrointestinal diseases.These findings have important implications for clinical management in GBC patients.

Table 1 .
Baseline characteristics and distribution of survival time in patients with gallbladder cancer.

Table 2 .
Standardized-mortality ratios for each cause of death following gallbladder cancer diagnosis.NA: Not Applicable.

Table 3 .
Risk factors for non cancer death and cardiovascular death.