Challenges identified from trends in mortality among patients with gastrointestinal cancer in the United States

The outcomes of cancer treatments were evaluated by 5-year survival rates or the median survival time based on the Kaplan-Meier method. However, the number of cancer survivors who die from other causes, including cardiovascular disease, diabetes mellitus, stroke, chronic renal disease, and pulmonary disease, has been increasing, while the number of cancer-related deaths has decreased (1). This could be attributed to recent advances in cancer treatment, such as early diagnosis of cancer, improvements in surgical techniques, and advances in chemotherapy. Most patients who are diagnosed at an early stage through widespread access to routine physical examinations can be completely cured and live until death from other causes. The development of minimally invasive surgery and advances in perioperative management has enabled patients with comorbidities to undergo major surgery. Immune checkpoint inhibitors, molecular targeted therapies, and anticancer drugs based on genome panels have contributed to the cure of patients after radical surgery, as well as to sustaining the lives of patients with inoperable disease. Consequently, the occurrence of competing mortality risks in patients after cancer treatment has increased, and cancer death rates are often overestimated if the heterogeneity of death is not considered in the survival analysis. To evaluate the clinical utility of specific cancer treatments, each death certificate is reviewed using competing risk survival analysis (2). If the patient died of diseases other than cancer, the patient is labeled as censored at the time of death rather than classified as having died. To identify patients with cancer who may be long-term survivors without recurrence, cure models that focus on the plateau of survival curves at the end of the study are a useful and straightforward approach to characterizing survival outcomes (3).

For understanding the epidemiology of each type of cancer, it is beneficial to classify patients with cancer into the following categories: patients who died of cancer and those who died of non-neoplasm causes with or without recurrence of cancer. In an observational retrospective cohort study based on the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, “Incidence-Based Mortality”, Hua et al. analyzed trends in cause-specific mortality among patients in the United States who were diagnosed with malignant neoplasms of the digestive system (MNDS) in 2000–2021 and died in 2007–2021 (4). The cohorts were stratified based on tumor site, sex, age at death, race, and tumor stage, and trends in overall, cancer-related, and non-cancer mortality were investigated in each group.

The overall mortality rate of the cohort increased during the observation period, during which MNDS-related deaths decreased and deaths from other causes increased rapidly. Intriguingly, the non-neoplasm mortality rate at all tumor sites significantly increased. Conversely, cancer-specific mortality rates increased only in the pancreas, anus, and biliary tract, decreased in the esophagus, stomach, and colon, and remained unchanged in the small intestine and liver. This trend in colorectal, esophageal, and gastric cancers is attributable to the remarkable development of chemotherapies. Colorectal cancer is the most representative disease that can be treated with neoadjuvant and adjuvant chemotherapy, such as FOLFOX and FOLFIRI, along with molecular targeted therapies, including anti-vascular endothelial growth factor and anti-epidermal growth factor receptor, which contribute to prolonged survival without recurrence after surgery (5). Patients with esophageal cancer and gastric cancer also benefit from the development of anticancer therapies, such as cisplatin, S-1, paclitaxel, and immune checkpoint inhibitors (6). In addition, these types of cancers are the most screening-friendly MNDS and are increasingly being detected at early and/or curable stages (7). In addition to gastrointestinal endoscopy, which allows direct visualization and biopsy, an annual stool test is easy to perform and can identify individuals at high risk for colon cancer, allowing broader access to screening for these cancers.

Chemotherapies for pancreatic cancer and biliary tract cancer have also been developed, such as gemcitabine, S-1, and nab-paclitaxel (8); however, these two cancers are highly malignant and difficult to detect at an early stage, even with advances in imaging modalities, such as ultrasonography. Therefore, only a few patients with these types of cancers are cured, and cancer-related mortality rates remain high or may even increase.

Recent advances in chemotherapy using immune checkpoint inhibitors with anti-vascular endothelial growth factor agents (atezolizumab with bevacizumab) or multikinase inhibitors (lenvatinib) have contributed remarkably to the prolongation of survival in patients with hepatocellular carcinoma (9). However, hepatocellular carcinoma originating from chronic liver diseases, such as hepatitis B or C infection, alcoholic hepatitis, and metabolic dysfunction-associated steatohepatitis, is difficult to cure even after locoregional therapies, which may underlie the trend of cancer-related mortality in liver cancer.

Along with the improved cure rate for cancer, non-neoplasm mortality has increased, except for infectious diseases, whose mortality rate has rapidly increased since the outbreak of coronavirus disease 2019 (COVID-19) in 2020 (10). Other chronic diseases, such as cardiovascular disease, chronic obstructive pulmonary disease, chronic kidney disease, and stroke-related mortality, could be associated with increased morbidity from diabetes mellitus (11).

The trend of a decline in MNDS-related mortality rates and an increase in non-neoplastic causes of death did not differ between men and women. This tendency is similar across all generations; however, overall and non-neoplasm mortality increased quite rapidly in older adults, especially in patients aged >85 years. Despite reports that older patients can be safely treated for MNDS (12), clinicians should keep in mind whether older patients can benefit from treatment or palliation of cancer and carefully select candidates.

The mortality trend differed remarkably among races, reflecting social constructs and structural social factors. Non-cancer mortality increased across all races, whereas cancer-specific mortality decreased in White, Black, and Asian Pacific Islander patients and increased only in American Indian and Alaska Native patients. This trend can be attributed to disparities in lifestyle factors, environmental exposure, and socioeconomic barriers that affect healthcare access and utilization (13). Similarly, it was previously believed that African Americans had a high cancer burden and faced greater obstacles in cancer prevention, diagnosis, treatment, and survival (14). However, this study showed the opposite result: a rapid decline in MNDS-related deaths in the Black patient group. Nevertheless, African Americans are the only group in which overall mortality has not improved, suggesting that medical access for non-malignant diseases in Black individuals has yet to improve.

The number of cancer-related deaths in patients with localized and regional MNDS increased slowly and did not change, respectively, whereas the non-cancer-related and overall mortality rates of these patients increased very rapidly. Conversely, cancer-related and non-cancer-related mortality in patients with distant-stage MNDS increased very slowly. This trend by cancer stage suggests that the diagnosis of cancer at an early stage greatly contributes to the cure of the disease, while patients with cancer at advanced stages may experience prolonged survival but are unlikely to be cured despite advances in anticancer treatments.

One category was excluded in this study. Marital status is associated with both overall and cancer-specific survival in men and women (15). Married patients with cancer had better survival rates than those of single patients, and this tendency was stronger in men, especially among widowed patients. This can be explained by the fact that women are more likely to encourage their spouses to have a health-promoting lifestyle than vice versa. Through data from a nationwide cohort, clinicians can benefit from increased awareness of the effects of marital status on cancer treatment.

This study showed a remarkable development in cancer treatments; that is, a high cure rate of MNDS has led to an increase in non-cancer-related deaths. However, it also highlighted some concerns in the public health of cancer in the United States. First, there was a significant difference in the progress of MNDS treatment among cancer sites. Most patients with highly malignant MNDS, such as pancreatic, anal, and bile duct cancers, cannot be completely cured, even if diagnosed at an early stage. Given that cancer treatments using only surgery or chemotherapy have limitations, multidisciplinary treatments should be developed. Second, there is a medical disparity among races. In particular, many American Indian and Alaska Native and Black individuals receive suboptimal cancer treatment, which could be attributed to the health insurance system in the United States. Finally, the prevalence of chronic conditions, such as heart disease, stroke, and diabetes mellitus, continues to worsen, despite the decline in cancer-related deaths (16). Given the mortality trends among patients with MNDS elucidated in this study, the development of cancer treatments may be less effective without concurrent improvements in lifestyle-related diseases.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0387/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is 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.

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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