Factors associated with aggressive care at the end of life for patients with gastrointestinal cancer

Introduction

Cancer is a leading cause of death worldwide, accounting for nearly one in six deaths and one in four deaths from non-communicable diseases (1). In addition to its impact on morbidity and mortality, cancer imposes substantial economic burden on both individuals and society (1,2). As the disease progresses to the end-of-life (EOL) stage, patients often experience a range of distressing symptoms, including pain, nausea, dyspnea, fatigue, and anorexia. Although significant therapeutic advances have been made, particularly with the development of molecularly targeted agents and immunotherapies, many cancers remain refractory, ultimately requiring a focus on EOL care. In this context, patients often seek to achieve important personal goals, such as life review, conflict resolution, and a meaningful farewell (3).

High-intensity or aggressive interventions near EOL often provide limited clinical benefit while increasing healthcare costs, increasing the incidence of severe adverse events, and potentially decreasing both patient quality of life and family satisfaction (4-9). To guide appropriate EOL care, Earle et al. proposed an index of aggressive interventions using data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database in the United States (10). This index comprises several indicators, including the administration of anticancer treatments within the last month of life (e.g., switching to a new regimen within 30 days or administering therapy within 14 days), intensive care unit (ICU) admissions, multiple emergency department (ED) visits and hospitalizations, and late hospice referral (i.e., within three days of death). Luta et al. subsequently extended these indicators in a systematic review (11). Despite growing awareness of the potential harms associated with aggressive care at the end of life (ACEOL), a recent systematic review and meta-analysis reported that such care remains prevalent worldwide (12).

Previous research has identified various risk factors associated with receiving ACEOL. A nationwide retrospective cohort study in Portugal showed that patients with gastrointestinal and hematologic cancers were more likely to receive aggressive care (13). Conversely, older age and metastatic disease were associated with less aggressive treatment, while higher comorbidity scores, treatment in a dedicated cancer center, and admission to a hospital with a medical oncology department were associated with more intensive interventions (13). Early referral to palliative care services has been shown to mitigate this trend by reducing ACEOL (14-16). Therefore, identifying patients at the greatest risk of aggressive interventions may facilitate timely referral to palliative care and potentially improve quality of life.

Although gastrointestinal cancer has been recognised as a risk factor for receiving ACEOL (13), the specific characteristics of patients with gastrointestinal cancer who receive such interventions remain poorly understood. Therefore, the aim of this study was to identify patient-related factors at the time of treatment initiation that are associated with ACEOL in patients with gastrointestinal cancer. We present this article in accordance with the STROBE reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-25-56/rc).

Methods

Design

This is a single institution retrospective cohort study of patients with gastrointestinal cancer in Osaka Medical and Pharmaceutical University Hospital. This general hospital is located in an urban region. In addition, there are palliative care physicians but no palliative care beds in this hospital. Patients in this region have relatively easy access to home care services and palliative care units.

Patients

The main selection criteria were as follows: (I) age ≥20 years; (II) diagnosed with unresectable, recurrent, or metastatic gastrointestinal cancer in our hospital between 2017 and 2022 and died by April 2024; and (III) started first palliative chemotherapy in our hospital. Patients with hepatocellular carcinoma were not included due to their distinct clinical course and treatment strategies, including loco-regional therapies and liver-specific complications.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of the Osaka Medical and Pharmaceutical University (approval No. 2023-154) and patient consent was obtained using the opt-out method.

Measurements

The following data were collected at the start of initial palliative chemotherapy: age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS), Charlson Comorbidity Index score, primary cancer site, living circumstances (living alone or living with others), marital status (married, single, divorced, separated or widowed), opioid use, serum albumin, serum C-reactive protein (CRP), neutrophil count, lymphocyte count. The Glasgow prognostic score (GPS) is a prognostic factor based on serum albumin and CRP. Score 0 is CRP ≤1.0 mg/dL and albumin ≥3.5 g/dL, score 2 is CRP >1.0 mg/dL and albumin <3.5 g/dL, and the other is score 1 (17). In addition, the neutrophil-to-lymphocyte ratio (NLR), defined as the neutrophil count divided by the lymphocyte count, was calculated. A high NLR is known to be a poor prognostic factor in patients with gastrointestinal cancer (18). Referral to palliative care physicians and use of home care services between the start of initial chemotherapy and death were examined.

Factors of ACEOL were defined according to previous studies by Earle et al. (10,19) and Luta et al. (11). They included (I) hospitalization for more than 14 days; (II) initiation of a new chemotherapy regimen (including cytotoxic agents, molecular targeted agents, and immunotherapy); (III) more than one emergency department visit or hospital admission; (IV) use of intensive care units; (V) surgery; (VI) tracheostomy (including emergent and definitive); (VII) dialysis; (VIII) cardiopulmonary resuscitation; (IX) implantation of central vascular catheter; (X) percutaneous gastrostomy; (XI) parenteral nutrition infusion; (XII) mechanical ventilation; (XIII) insertion of endotracheal tube; (XIV) vasopressor support during the last 30 days of life; (XV) administration of chemotherapy (including cytotoxic agents, molecular targeted agents and immunotherapy) during the last 14 days of life; (XVI) death in an acute care hospital; and (XVII) hospice admission within 3 days of death. ACEOL was defined when any one of these factors were present.

Statistical analysis

The patients who received ACEOL were identified and the characteristics of these patients were compared with those who did not receive ACEOL using t-test, Mann-Whitney U test, Chi-squared test, or Fisher’s exact test, as appropriate. The prevalence of each ACEOL factor was also examined. Overall survival (OS) was compared between patients who received ACEOL and those who did not using the Kaplan-Meier method, the log-rank test. OS was defined as the time from initiation of first palliative chemotherapy to death. Multivariate analysis using logistic regression models was also used to determine predictive factors for ACEOL. Patient factors at the start of first chemotherapy included in the multivariate analysis were age (median), sex, ECOG PS (0–1 vs. 2–3), opioid use, living circumstances, GPS, and NLR. A two-tailed P value <0.05 was considered significant. All analyses were performed with EZR ver1.50.

Results

Patient characteristics

A total of 1,506 patients were diagnosed with gastrointestinal cancer in our hospital between 2017 and 2022. Finally, 275 patients were eligible after 1,231 were excluded. The most common reasons for exclusion were not receiving chemotherapy (n=889), followed by not unresectable, recurrent or metastatic status (n=295) and lost to follow-up (n=47) (Figure S1). Baseline characteristics of all eligible patients are shown in Table 1. The median age was 69 years and there were more male than female patients. The most common primary cancer site was stomach (n=79, 28.7%), followed by pancreas (n=71, 25.8%), colorectum (n=66, 24.0%), esophagus (n=33, 12.0%), biliary tract (n=22, 8.0%) and others include small bowel and appendix (n=4, 1.5%). Median OS for all eligible patients was 9.9 months [95% confidence interval (CI): 8.4－11.1] (Figure S2), and the OS for each primary cancer site has been shown in Figure S3. The median time from the start of the last dose of chemotherapy to death was 54 days (interquartile range, 33–91 days).

Prevalence of ACEOL

The proportion of patients receiving ACEOL was 57.8% (n=159/275). Characteristics of patients with and without ACEOL are shown in Table 1. Patients receiving ACEOL were significantly younger (median; 71 vs. 66 years, P<0.01), had a higher proportion of opioids (3.4% vs. 11.9%, P=0.01) than those not receiving ACEOL. Other characteristics were similar between the two groups. Patients who received ACEOL had significantly more referrals to palliative care physicians (20.7% vs. 51.6%, P<0.01) than those who did not receive ACEOL, while they did not use home health care services (34.0% vs. 70.7%, P<0.01) between the start of initial chemotherapy and death. Patients who received ACEOL had a significantly shorter OS than those who did not (median, 12.9 vs. 8.5 months; HR, 1.34; 95% CI: 1.05–1.70; P=0.02) (Figure 1).

Figure 1 Overall survival in patients with or without aggressive care at the end of life. CI, confidence interval; HR, hazard ratio.

The prevalence of each ACEOL factor is shown in Figure 2. The most common factor was death in acute care hospital (n=106, 38.5%). Factors greater than 5% were hospitalization for more than 14 days (n=93, 33.8%), parenteral nutrition infusion (n=72, 26.2%), initiation of a new chemotherapy regimen (n=26, 9.5%), central vascular catheter implantation (n=17, 6.2%), and vasopressor support (n=14, 5.1%). The median number of factors in the patients receiving ACEOL was 2 (range, 1–8) (Figure S4).

Figure 2 Distribution of each individual factors of aggressive care at the end of life. CVC, central vascular catheter.

Predictors of ACEOL

In multivariate analysis, younger age (OR 2.01; 95% CI: 1.21–3.34, P<0.01) and opioid use (OR 3.39; 95% CI: 1.07–10.70, P=0.03) were identified as significant predictive factors for ACEOL (Table 2). As a sensitivity analysis, a multivariate analysis was performed with the additional factors of Charlson Comorbidity index (median), primary cancer site and marital status. Younger age was still significantly associated with ACEOL (OR 2.22; 95% CI: 1.28–3.86, P<0.01), whereas opioid use was not significant but tended to be highly associated (OR 3.16; 95% CI: 0.98–10.20, P=0.06) (Table S1).

Discussion

In this study, it was revealed that 57.8% of patients with advanced gastrointestinal cancer received at least one indicator of ACEOL, such as acute care hospital death or prolonged hospitalization. Younger age and opioid use at the start of first palliative chemotherapy were independently associated with an increased likelihood of ACEOL. In addition, OS was significantly shorter among patients who received ACEOL than in those who did not.

ACEOL for cancer patients is common, with studies reporting 59.3% to 71% of patients experiencing at least one indicator of aggressive care (13,20). Recent trends show an increase in high-intensity interventions, including ICU admissions and ER visits near death (21-23). Factors associated with more aggressive care include younger age, male sex, higher comorbidity index, and certain cancer types such as gastrointestinal and hematologic malignancies (13,24,25). Conversely, older age, metastatic disease, and breast cancer are associated with less aggressive care (13). Community health services, especially palliative care, significantly reduce the risk of ACEOL (20). ACEOL has a significant economic impact, with higher costs for patients who receive aggressive care compared with those who do not (24).

Our findings are consistent with the high prevalence of ACEOL reported in previous studies, which also highlight the influence of younger age (13,20). Possible explanations include greater physical reserve, emotional unreadiness for EOL, and family responsibilities. Oncologists may also feel more compelled to pursue intensive treatments in younger patients. Notably, our study highlights opioid use at the time of initial palliative chemotherapy as a novel predictive factor, suggesting that greater symptom burden or need for pain management may lead to more intensive interventions as patients approach EOL. This aligns with recent prospective findings that greater symptom burden, including pain, is independently associated with the receipt of intensive EOL care (26). Contrary to previous literature suggesting that palliative care involvement reduces aggressive care, patients receiving ACEOL in our study were more frequently referred to palliative care physicians. One possible explanation is that the role of palliative care physicians may be different at our institution, where they are consulted primarily to manage refractory symptoms such as severe pain and delirium rather than to guide treatment decisions. These findings extend the existing literature by highlighting the need to identify opioid-using patients with advanced gastrointestinal cancer who may be particularly vulnerable to overly aggressive care.

A key strength of this study is its focus on a homogeneous population of gastrointestinal cancer patients, allowing for an in-depth examination of disease-specific factors that may increase the likelihood of ACEOL. In addition, the single-institution design ensured consistent clinical protocols, reducing variability due to differing institutional practices. Our comprehensive data collection from the start of initial chemotherapy until death also provides a clear temporal framework for the assessment of ACEOL.

The single-institution, retrospective design may limit the generalizability of our findings because treatment approaches and referral patterns differ between hospitals and regions. We also did not assess patient-reported goals of care, which could clarify whether ACEOL was goal-concordant for some individuals. For patients who prioritize life prolongation, aggressive interventions may align with their values and preferences.

Conclusions

In conclusion, our results indicate that more than half of patients with advanced gastrointestinal cancer receive ACEOL. Younger age and opioid use at the start of palliative chemotherapy emerged as significant predictors of such interventions. These findings highlight the importance of early identification of high-risk patients and the involvement of specialized palliative care services to reduce ACEOL.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-25-56/rc

Data Sharing Statement: Available at https://apm.amegroups.com/article/view/10.21037/apm-25-56/dss

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-25-56/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-25-56/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of the Osaka Medical and Pharmaceutical University (approval No. 2023-154) and patient consent was obtained using the opt-out method.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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