PDF
Citation
Print
INTRODUCTION
Pancreatic cancer is one of the most lethal malignancies, typically diagnosed at advanced stages and associated with a poor prognosis. Identifying the potential contributing risk factors is critical to improving early detection and patient outcomes.1 Gastroparesis, a condition characterized by delayed gastric emptying in the absence of a mechanical obstruction, has recently emerged as a potential risk factor linked to malignancy.2,3 Although gastroparesis is often associated with underlying conditions, such as diabetes mellitus, it can also manifest as malignancy-associated gastroparesis (MAG), arising from paraneoplastic syndromes, autonomic nervous system involvement, or complications related to oncologic treatments.4,5 The true prevalence of MAG is not completely understood, but its occurrence underscores the relevance of impaired gastric motility in oncologic disease.
Gastroparesis is associated with prolonged stasis within the gastrointestinal tract, which predisposes patients to small intestinal bacterial overgrowth (SIBO), defined by excessive bacterial proliferation in the small intestine. Studies estimate that up to 39% of individuals with gastroparesis show evidence of SIBO, suggesting a strong relationship between delayed gastric emptying and microbial dysbiosis.6,7 This bacterial imbalance can facilitate the translocation of bacterial metabolites into the adjacent organs, including the pancreas, potentially triggering chronic inflammation and carcinogenic processes. Furthermore, microbial dysbiosis exacerbates oxidative stress, modulates the immune responses, and alters the cellular signaling pathways, all of which have been implicated in the tumorigenesis of pancreatic and other gastrointestinal tissues.8-11
Emerging evidence suggests that gastroparesis may be linked to gastrointestinal malignancies such as gastric, esophageal, and gallbladder cancers.3,12-14 This broader oncologic significance suggests that gastroparesis could be a systemic marker of a malignancy. The relationship between impaired gastrointestinal motility and microbial dysbiosis emphasizes the importance of exploring gastroparesis as a potential clinical indicator for earlier cancer diagnosis.
This study examined the association between gastroparesis and pancreatic cancer, hypothesizing that delayed gastric emptying may indicate an increased risk of pancreatic cancer. Using data from the Nationwide Inpatient Sample (NIS), this study sought to provide a nationally representative perspective on the potential link between gastroparesis and pancreatic cancer risk.
SUBJECTS AND METHODS
1. Data source
This study analyzed the data from the NIS, a part of the Healthcare Cost and Utilization Project (HCUP). The NIS is the largest publicly available all-payer inpatient care database in the United States, containing health information from approximately eight million hospital stays each year. It provides a stratified 20% sample of hospital discharges from non-federal hospitals across 48 states, offering a nationally representative dataset. Each record within the NIS is weighted to allow for the generation of nationwide estimates related to healthcare utilization, hospitalizations, and outcomes. This study used the data from 2016 to 2021, encompassing more than 120 million discharges during that period. Notably, the NIS database contains de-identified data, with no patient-specific clinical details. Additional information on the NIS database can be found at HCUP NIS (https://hcup-us.ahrq.gov/nisoverview.jsp).
2. Study population
The study population was derived from the NIS dataset from 2016 to 2021. The analysis included adult patients (aged 18 years and older) with a documented diagnosis of pancreatic cancer, with or without coexisting gastroparesis, identified using International Classification of Diseases, Tenth Revision (ICD-10) codes. The ICD-10 codes used to identify pancreatic cancer included C25.x. This study focused on incident or primary pancreatic cancer-related admissions, reducing the inclusion of repeated hospitalizations and restricting primary pancreatic cancer diagnoses. Nevertheless, the analysis may reflect hospitalization-level associations, and some duplicate admissions may persist because the NIS lacks unique patient identifiers.
For gastroparesis, the ICD-10 code utilized was K31.84. Patients were included if they had any inpatient admission with either gastroparesis or pancreatic cancer. Misclassification was mitigated by excluding patients with prior gastric surgery, pancreatectomy, or pancreaticoduodenectomy (Whipple procedure), which is associated with post-operative delayed gastric emptying and could be miscoded as gastroparesis. In addition, patients with incomplete demographic or clinical data were excluded (Fig. 1).
3. Outcome measures
The primary outcome was the presence of pancreatic cancer, which was used to evaluate the association with a coexisting diagnosis of gastroparesis. This study analyzed the hospitalizations with pancreatic cancer as the primary diagnosis. The primary exposure was the presence of gastroparesis. In the subgroup analysis of pancreatic cancer patients, this study assessed the clinical outcomes, including in-hospital mortality, defined as death occurring during the index hospitalization within an acute care hospital, as recorded in the NIS database. This definition excludes deaths occurring in non-acute care settings, such as hospice facilities or post-discharge. The length of hospital stay and total hospitalization costs were also evaluated. The outcomes of pancreatic cancer patients with gastroparesis were compared with those without gastroparesis. Secondary variables assessed in full and subgroup analyses included the patients’ demographics (age, sex, race, and insurance status), hospital characteristics (teaching status, geographic region, and bed size), and clinical comorbidities.
4. Statistical analysis
Weighted discharge data were used to generate national estimates, accounting for the complex sampling design of the NIS. Descriptive statistics were calculated to summarize the demographic, clinical, and hospital characteristics among patients with and without pancreatic cancer. The continuous variables are reported as the means with standard deviations, while the categorical variables are presented as frequencies and percentages. Comparisons between groups were conducted using t-tests for the continuous variables and chi-square tests for the categorical variables. Multivariable logistic regression analysis was conducted to examine the association between gastroparesis and pancreatic cancer. Model 1 was unadjusted, including only the primary predictor (gastroparesis) and the outcome (pancreatic cancer). In Model 2, demographic variables, including age, sex, and race, were considered and adjusted for. Model 3 included additional adjustments for comorbidities such as hypertension, diabetes (uncomplicated and complicated), obesity, and chronic kidney disease. The interaction terms were developed for gastroparesis with age, sex, and race to evaluate the potential effect modification, which were added to the fully adjusted model.
The multicollinearity among the covariates was assessed using the variance inflation factors, and no significant collinearity was identified. The model performance was evaluated using the Hosmer–Lemeshow goodness-of-fit test, with a p-value <0.05 indicating a good fit. Model comparisons were performed using −2 log-likelihood values and pseudo R2 metrics (Cox & Snell, Nagelkerke). Sensitivity analyses, including stratified logistic regressions by demographic subgroups and adjustments for sampling weights, were performed to ensure the robustness of the findings. The results are reported as odds ratios (ORs) with 95% confidence intervals (CIs), and statistical significance was set at p<0.05. All statistical analyses were conducted using SAS software version 9.4 (SAS Institute, Cary, NC, USA); p-values <0.05 were considered significant.
RESULTS
1. Study population
The study population included 207,629,866 hospitalizations from the NIS database between 2016 and 2021. Among these, 603,075 hospitalizations (0.3%) had a diagnosis of pancreatic cancer. Table 1 lists the demographic and clinical characteristics of patients with and without pancreatic cancer. Patients with pancreatic cancer were older, with a mean age of 62.1 years compared to 50.4 years among those without pancreatic cancer (p<0.001). Most of the pancreatic cancer patients were male (52.2%), whereas the majority of non-pancreatic cancer patients were female (55.9%). The age distribution also differed significantly, with 78.6% of pancreatic cancer patients being 60 years or older, compared to only 44.6% of non-pancreatic cancer patients in the same age group. The racial composition showed that 71% of pancreatic cancer patients were White, while Black and Hispanic patients accounted for 13.8% and 8.4%, respectively. Gastroparesis was 43% more prevalent among pancreatic cancer patients (1.0%) than non-pancreatic cancer patients (0.7%) (p<0.001). Pancreatic cancer patients had a higher prevalence of hypertension (46.9% vs. 28.5%, p<0.001), anemia (12.8% vs. 7.8%, p<0.001), diabetes (uncomplicated: 14.6% vs. 8.2%; complicated: 12.0% vs. 10.8%; p<0.001), and liver disease (4.8% vs. 2.7%, p<0.001).
2. Association of gastroparesis with pancreatic cancer
The relationship between gastroparesis and pancreatic cancer was evaluated using multivariable logistic regression models (Table 2). In unadjusted analysis (Model 1), the odds of pancreatic cancer were 36% higher in patients with gastroparesis than in those without (OR 1.36, 95% CI 1.32–1.39; p<0.001). After adjusting for demographic factors (Model 2), the odds ratio was 1.20 (95% CI 1.17–1.24; p<0.001). The association remained significant after adjusting for comorbidities (Model 3) (OR 1.12, 95% CI 1.08–1.16; p<0.001). The pancreatic cancer cohort was further categorized into patients with gastroparesis (n=6,095) and those without gastroparesis (n=590,885) to compare the baseline hospital characteristics and clinical profiles. Among the pancreatic cancer patients, those with gastroparesis were more likely to be younger (mean age 65.55±11.61 years) and female (54.2%) than pancreatic cancer patients without gastroparesis (mean age 68.46±11.44 years; 45.8% male, p<0.001), as shown in Table 3. Comorbidities such as anemia, complicated diabetes, and hypertension were significantly more prevalent in the gastroparesis group (Table 3). In addition, patients with gastroparesis had a more extended mean hospital stay (8.48±8.30 days vs. 5.70±5.70 days, p<0.001) and incurred significantly higher total hospital charges ($86,385.90±$105,352.67 vs. $63,250.12±$78,421.65, p<0.001).
3. Effect of gastroparesis on in-hospital mortality among patients with pancreatic cancer
The in-hospital mortality rate was lower among pancreatic cancer patients with gastroparesis than in those without gastroparesis (4.2% vs. 8.0%, p<0.001). Logistic regression analysis showed that gastroparesis was independently associated with approximately a 50% reduction in the odds of in-hospital mortality among pancreatic cancer patients (adjusted OR [aOR] 0.51, 95% CI 0.44–0.58; p<0.001) (Table 4). Other factors associated with reduced mortality included uncomplicated diabetes (aOR 0.52, 95% CI 0.51–0.54) and obesity (aOR 0.730, 95% CI 0.692–0.770). By contrast, the odds of mortality were significantly higher in patients with metastatic cancer (aOR 2.091, 95% CI 1.985–2.203), electrolyte/ fluid disorders (aOR 1.42, 95% CI 1.39–1.45), and congestive heart failure (aOR 1.56, 95% CI 1.51–1.63). Black patients had a 35% higher risk of death (aOR 1.35, 95% CI 1.31–1.38), while Hispanic patients had a 3% higher risk (aOR 1.03, 95% CI 1.01–1.07) than White patients. A more extended hospital stay was associated with higher mortality because patients hospitalized for ≥13 days had a 55% greater risk of death (aOR 1.55, 95% CI 1.51–1.62) compared to those with stays ≤3 days.
DISCUSSION
This study represents the largest investigation to date exploring the association between gastroparesis and pancreatic cancer. Gastroparesis was independently associated with an increased risk of pancreatic cancer. Among the pancreatic cancer patients, those with gastroparesis had distinct demographic and clinical profiles, including younger age and a higher prevalence of specific comorbidities. In particular, a lower in-hospital mortality rate was observed among pancreatic cancer patients with gastroparesis compared to those without. These findings suggest that gastroparesis may serve as an early clinical indicator in the diagnostic pathway for pancreatic cancer.
The literature has no evidence on the association between gastroparesis and pancreatic cancer. Most findings have been limited to case reports and smaller cohort studies, which focused primarily on paraneoplastic gastroparesis in the context of other malignancies, such as small-cell lung carcinoma. These reports have underscored the diagnostic challenges and clinical implications of gastrointestinal dysmotility.2,13,15 The present study is the first to report an association between gastroparesis and pancreatic cancer using an extensive national inpatient database. The study significantly adds to this body of knowledge by providing substantial epidemiological evidence, specifically in the context of pancreatic cancer, and emphasizes the potential role of gastroparesis as a clinical feature that may prompt further diagnostic evaluation.
Gastroparesis has previously been shown to increase the risk of SIBO through prolonged stasis, allowing bacteria to proliferate and disrupt the gut microbiome.6 This imbalance can lead to the production of bacterial metabolites, toxins, and inflammatory mediators that translocate to the adjacent organs or the systemic circulation, inducing chronic low-grade inflammation. Inflammation, a known risk factor for carcinogenesis, may contribute to pancreatic cancer. Persistent bacterial byproducts and inflammatory pathways compromise the gastrointestinal barrier, promoting oxidative stress, genomic instability, and dysregulated cell signaling in the pancreatic tissue.15,16
Ma et al.17 reported that the prevalence of SIBO was significantly higher among pancreatic carcinoma patients (63.3%) compared to healthy controls (13.3%), with a positive correlation between SIBO and the activation of the Toll-like receptor 4 (TLR-4) pathway in pancreatic tissue by bacterial metabolites. The LPS/TLR-4 signaling cascade amplifies the inflammatory responses and enhances tumor cell proliferation by inhibiting apoptosis, which drives pancreatic carcinogenesis.18 Considering the significant overlap between gastroparesis and SIBO, gastroparesis may be a permissive factor for this inflammatory cascade. This study further corroborated this connection, finding that the prevalence of gastroparesis was 43% higher in pancreatic cancer patients compared to non-pancreatic cancer patients (1.0% vs. 0.7%, p<0.001). In addition, gastroparesis was associated with a 12% increased likelihood of pancreatic cancer after adjusting for demographics and comorbidities (adjusted OR 1.12, 95% CI, 1.08–1.16; p<0.001). These findings align with prior evidence suggesting gastroparesis may act as a clinical indicator of malignancy, warranting a closer evaluation in symptomatic individuals.
A recent meta-analysis by Beas et al.19 further highlighted the prevalence of SIBO in approximately half of gastroparesis patients, reinforcing the potential association between gastroparesis and pancreatic cancer. In addition, evidence from other studies, such as those exploring gastric cancer, suggests that gastroparesis may precede a malignancy, highlighting its potential role as an early manifestation of cancer.14 These findings highlight the importance of investigating gastroparesis in patients with persistent symptoms. Future longitudinal studies will be needed to delineate the temporal relationship between gastroparesis and pancreatic cancer and to establish causality.
Pancreatic cancer patients with gastroparesis experienced significantly lower in-hospital mortality, with gastroparesis associated with a 50% decrease in the odds of mortality. The reduced in-hospital mortality observed among pancreatic cancer patients with gastroparesis may be attributed to an earlier diagnosis facilitated by gastroparesis-related symptoms such as early satiety, postprandial fullness, nausea, and vomiting.20 These symptoms may prompt healthcare-seeking behavior, leading to the detection of pancreatic cancer at an earlier stage. This contrasts with the typical silent presentation of pancreatic cancer, which often results in advanced-stage diagnoses. A similar hypothesis was proposed in case studies where early gastrointestinal symptoms led to the identification of underlying malignancies. On the other hand, the NIS does not capture the nutritional status or end-of-life care settings, such as hospice care, which could influence the mortality rates. Patients with gastroparesis may face nutritional challenges that necessitate prolonged hospitalization, potentially affecting the in-hospital mortality rates. Future studies should examine whether nutritional difficulties contribute to prolonged hospital stays and impact mortality outcomes. Higher in-hospital mortality may partly reflect the complex nutritional and supportive care needs of patients with advanced pancreatic cancer who may be less suitable for discharge. Nevertheless, the multivariable analysis attempts to account for these confounders by adjusting for comorbidities and length of stay. This association warrants further investigation to understand whether gastroparesis contributes to a survival advantage or instead reflects differences in healthcare utilization patterns.
This study found that several factors significantly influenced the in-hospital mortality among pancreatic cancer patients. Male sex, Black race, and the presence of comorbid conditions, such as metastatic cancer, congestive heart failure, and electrolyte or fluid disorders, were associated with an increased odds of in-hospital mortality. These results were consistent with prior research on the impact of the demographic and clinical variables on pancreatic cancer outcomes.21 Conversely, factors such as gastroparesis and uncomplicated diabetes were associated with a reduced odds of in-hospital mortality. The decreased mortality associated with gastroparesis may reflect the earlier diagnosis prompted by symptomatic presentation, as suggested in previous findings. These associations highlight the complex interplay of demographic, clinical, and systemic factors in determining the outcomes for pancreatic cancer patients, highlighting the need for tailored management strategies to address these risks.22
This study has several strengths and limitations. Its primary strength lies in being the largest investigation to explore the association between gastroparesis and pancreatic cancer, using a nationally representative dataset from the NIS. The large sample size provides robust statistical power, enabling detailed subgroup analyses and meaningful comparisons. Comprehensive multivariable adjustments strengthen the reliability of the results, while the novel observation of reduced in-hospital mortality among pancreatic cancer patients with gastroparesis offers valuable clinical insights.
A significant limitation of this study was the reliance on the NIS, an administrative dataset that lacks patient-level clinical details, such as the timing of symptom onset or diagnostic sequence. This precludes making definitive conclusions about the temporal relationship between gastroparesis and pancreatic cancer, limiting the ability to infer causality. Consequently, these findings should be interpreted as associative rather than causal, and further longitudinal studies with granular clinical data are needed to clarify the sequence and potential mechanistic links between these conditions. Another key limitation is the potential for misclassification because of the reliance on ICD-10 code K31.84 for gastroparesis, the accuracy of which may vary across institutions and coding practices. Conditions such as mechanical gastric outlet obstruction or post-surgical delayed gastric emptying could be miscoded as gastroparesis, introducing diagnostic uncertainty. Although this was mitigated by excluding patients with prior gastric or pancreatic surgeries, residual misclassification may still affect the results, highlighting the need for validation studies using the clinical diagnostic criteria, such as gastric emptying scintigraphy, to confirm gastroparesis diagnoses. Third, chemotherapy exposure or cancer staging could not be considered, both of which may influence gastric motility and clinical outcomes. In addition, causality between gastroparesis and pancreatic cancer could not be established due to the cross-sectional nature of the dataset. Metastatic disease may be under-represented because of incomplete documentation or coding limitations. The NIS database does not include cancer staging or clinical context, which limits the ability to differentiate between metastatic pancreatic cancer and other concurrent malignancies.
In conclusion, this study identified an association between gastroparesis and pancreatic cancer, suggesting that gastroparesis may be a clinical feature associated with pancreatic cancer. Nevertheless, the role of gastroparesis as an early diagnostic marker remains speculative due to the inability to establish causality or the temporal sequence of these conditions. Therefore, further prospective studies will be needed to validate its clinical utility in the earlier detection of pancreatic cancer. The observed reduction in in-hospital mortality may reflect the differences in early symptom presentation or diagnostic pathways, but causality could not be established because of the retrospective design. Clinically, new-onset gastroparesis, particularly in older adults, should prompt the consideration of alternative etiologies, including a deadly pancreatic cancer, with appropriate diagnostic studies to ensure a timely detection. Hence, further research will be needed to establish prompt screening protocols and investigate the biological mechanisms underlying these associations.
XML Download