No survival benefit from adjuvant chemotherapy in high-risk stage II small intestinal adenocarcinoma after surgery: a population-based long-term survival analysis

Introduction

Small intestinal adenocarcinoma (SA) is a rare yet aggressive malignancy, accounting for less than 3% of all gastrointestinal tumors (1,2). Among its histological subtypes, primary adenocarcinoma is the most common, comprising approximately 30% to 40% of all SA cases (2,3). The prognosis of SA remains generally poor compared to other gastrointestinal malignancies such as colorectal cancer, with reported 5-year overall survival (OS) rates ranging from 30.0% to 79.0% for localized disease and 3.0% to 19.0% for metastatic disease (4,5). Surgical resection is the only potentially curative treatment for localized SA. However, approximately 40% of patients experience recurrence after primary tumor resection (6), with metastasis being a primary factor limiting long-term survival.

Adjuvant chemotherapy is well established in the management of several gastrointestinal malignancies, where it aims to eradicate micrometastases and reduce postoperative recurrence (7-9). However, due to the low incidence of SA and the consequent lack of randomized controlled trials, high-quality evidence supporting the benefit of adjuvant chemotherapy in this setting remains limited (10). The first clinical guidelines for the systemic treatment of SA were not published until 2018 by a French intergroup (6). The updated 2022 French guidelines recommend—with a low level of evidence—adjuvant chemotherapy for stage III disease and for stage II tumors classified as T4 (6,11). Similarly, the 2020 National Comprehensive Cancer Network (NCCN) guidelines recommend fluoropyrimidine- and oxaliplatin-based adjuvant chemotherapy for stage III SA, and suggest considering it for stage II patients with high-risk features (2). However, a nationwide Dutch cohort study indicated a survival benefit with adjuvant chemotherapy in stage III SA (12). Currently, adjuvant strategies for SA are largely extrapolated from protocols established for colorectal cancer, and it remains unclear which SA patients are most likely to benefit from adjuvant chemotherapy based on specific clinicopathological characteristics (13,14). Furthermore, the molecular characteristics of SA show significant differences from colorectal cancer, which may affect the adjuvant chemotherapy response (15-20). Therefore, there is a pressing need for more robust evidence regarding the efficacy of adjuvant chemotherapy specifically for SA based on different risk stratification.

In this study, using population-based data, we aim to evaluate the long-term survival benefit of adjuvant chemotherapy with pathological stages I–III jejunum and ileum adenocarcinoma following surgical resection and to provide further evidence to support clinical adjuvant chemotherapy decision-making. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-875/rc).

Methods

Study participants

The patients’ data were extracted from the Surveillance, Epidemiology, and End Results (SEER) Program {SEER Research Data, 17 Registries, Nov 2024 Sub [2000–2022]}. We identified patients with malignant pathologies of the primary jejunum and ileum diagnosed between 2004 and 2022. The study cohort was limited to patients who underwent curative surgery for pathologically confirmed stages I–III adenocarcinoma. In addition, the following clinical and pathological variables were extracted from the SEER database for analysis: demographic factors (age at diagnosis, sex, race, marital status, and median household income by county); tumor characteristics [primary site, histological grade, and tumor-node-metastasis (TNM) stage]; treatment information [surgical procedure and receipt of adjuvant chemotherapy (yes/no)]; and pathological factors (number of regional lymph nodes examined). The detailed screening process is shown in Figure 1. For the purpose of subgroup analysis, patients with stage II disease were categorized as “high-risk” if they exhibited at least one of the following established pathological features associated with worse prognosis: T4 stage, examination of <8 regional lymph nodes, or poor tumor differentiation (grades III–IV) (2,6). Patients not meeting any of these criteria were considered “low-risk”.

Figure 1 Flowchart of study cohort selection. SA, small intestinal adenocarcinoma.

Ethical statement

The use of de-identified data from the public SEER database exempted this study from informed consent in compliance with the SEER Data Use Agreement. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Statistical analyses

All statistical analyses and data visualization were performed using R software (version 4.5.1). Data cleaning, transformation, and management were conducted using the dplyr (1.1.4) and tidyverse (2.0.0) packages. Categorical variables were compared between groups using Pearson’s Chi-squared test. To control for potential confounding factors, propensity score matching (PSM) was performed to balance baseline characteristics between the adjuvant chemotherapy (+) and (−) groups [MatchIt package (version 4.7.2) and tableone package (version 0.13.2)]. Matching was conducted separately for the stages I–II and stage III cohorts. For the stages I–II cohort, a 1:2 nearest-neighbor matching algorithm was used to maximize statistical power. For the stage III cohort, a 1:1 nearest-neighbor matching algorithm was applied to achieve precise balance. A caliper width of 0.1 of the standard deviation of the logit of the propensity score was enforced in both cases to ensure match quality. Survival analyses were conducted using the survival package (version 3.8.3). Kaplan-Meier curves were generated to visualize survival probabilities, and between-group differences were compared using the log-rank test. The survminer package (version 0.5.1) was used to create publication-quality survival plots. Variables that showed a statistically significant association with survival (P<0.05) in the univariable analysis were then entered into the initial multivariable Cox proportional hazards model. Results were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). All graphical outputs were refined and consolidated using the ggpubr package (version 0.6.1). P value <0.05 was considered statistically significant.

Results

Patients’ characteristics

Between 2004 and 2022, 16,971 patients were diagnosed with primary SA. Among them, 896 patients with stages I–III SA were included in the study. The final cohort comprised 896 patients with stages I–III SA. This patient group was categorized according to adjuvant chemotherapy status into: the adjuvant chemotherapy (−) group (n=501) and the adjuvant chemotherapy (+) group (n=395). Clinicopathological characteristics of the two groups are shown in Table 1. Patients who received adjuvant chemotherapy were more likely to be younger (<60 years: 51.4% vs. 26.1%, P<0.001) and to present with features indicative of more advanced disease. These features included a higher proportion of poorly differentiated tumors (grades III–IV: 36.5% vs. 26.3%, P=0.001), deeper tumor invasion (T4 stage: 46.8% vs. 26.5%, P<0.001), greater lymph node invasion (N1/N2: 63.0% vs. 21.0%, P<0.001), and consequently a more advanced TNM stage (stage III: 63.0% vs. 21.0%, P<0.001). These marked disparities reflect the clinical selection criteria for adjuvant chemotherapy (confounding by indication), where treatment is preferentially administered to patients with higher-risk pathological features. In contrast, no significant differences were observed in any demographic variables, including sex, race, area, marital status, income, or primary tumor site between the two groups (all P>0.05).

Survival outcomes

Among the entire cohort, which was followed for a median of 61.5 months. The 5-year OS rates were 53.3% and 52.1% for the adjuvant chemotherapy (+) and (−) groups, respectively. Although the absolute difference in 5-year OS between the adjuvant chemotherapy (+) and adjuvant chemotherapy (−) groups was minimal, it remained statistically significant (P=0.02; Figure 2A). However, no significant statistical difference in the 5-year cancer-specific survival (CSS) rate was observed between the adjuvant chemotherapy (+) and adjuvant chemotherapy (−) groups (64.0% vs. 56.5%, P=0.10; Figure S1A).

Figure 2 Kaplan-Meier curves for OS between the adjuvant chemotherapy (+) and adjuvant chemotherapy (−) groups were compared in SA: (A) overall patients; (B) stage I patients; (C) stage II patients; (D) stage III patients. OS, overall survival; SA, small intestinal adenocarcinoma.

As summarized in Table 2, the multivariate analysis demonstrated that age ≥60 years, poor tumor grade (III–IV), and advanced T and N stages were all independently associated with worse OS and CSS (all P<0.05; Table 2). Higher income (≥$70,000), jejunal primary tumor site, and more than 8 lymph nodes examined were associated with better survival outcomes (all P<0.05; Table 2). Furthermore, adjuvant chemotherapy was an independent prognostic factor for OS (HR =0.56; 95% CI: 0.45–0.69; P<0.001; Table 2) but not for CSS (HR =1.18; 95% CI: 0.97–1.45; P=0.10; Table 2).

However, when stratified by TNM stage, the benefit of adjuvant chemotherapy exhibited distinct patterns. In patients with stages I and II SA, no significant survival benefit from adjuvant chemotherapy was observed (all P>0.05; Figure 2B,2C and Figure S1B,S1C). Notably, stage III SA patients receiving adjuvant chemotherapy demonstrated a significant improvement in both OS and CSS (all P<0.001; Figure 2D and Figure S1D).

Subgroup analysis of patients based on the primary tumor site of the tumor and high-risk factors

Subsequent subgroup analyses stratified by primary tumor site (ileum vs. jejunum) were performed. In the jejunum subgroup, adjuvant chemotherapy was associated with an improvement in the 5-year OS rate (58.7% vs. 56.3%, P=0.047; Figure 3A). However, no statistically significant difference in CSS was observed in this subgroup (P=0.48; Figure S2A). Similarly, no significant survival benefit was identified in the ileum group (P=0.28, Figure 3B; P=0.43, Figure S2B). Tables S1,S2 present the results of multivariate Cox proportional hazards analyses, which are consistent with the Kaplan-Meier survival outcomes based on primary tumor site. In the jejunum cohort, adjuvant chemotherapy is an independent favorable prognostic factor for OS, with significantly improved outcomes (HR =0.64; 95% CI: 0.48–0.85; P=0.002). Additionally, age ≥60 years, T4 stage, and lymph node invasion are key determinants of poor prognosis between the jejunum and ileum groups.

Figure 3 Kaplan-Meier curves of subgroups for OS between the adjuvant chemotherapy (+) and adjuvant chemotherapy (−) groups were compared in SA: (A) jejunum; (B) ileum; (C) low-risk group; (D) high-risk group. OS, overall survival; SA, small intestinal adenocarcinoma.

The categorization of high-risk status for subgroup analysis was based on established pathological features in stage II SA: the number of lymph nodes <8, grade III/IV tumor, or T4 stage (2,6), which typically guide recommendations for adjuvant chemotherapy. Patients meeting at least one criterion were assigned to the high-risk group; all others were considered low-risk. In the low-risk group, although Kaplan-Meier analysis suggested an improvement in 5-year OS with adjuvant chemotherapy (P=0.02, Figure 3C; P=0.23, Figure S2C), subsequent Cox regression analysis indicated that adjuvant chemotherapy was not an independent prognostic factor for OS (HR =0.65; 95% CI: 0.29–1.46; P=0.43; Table S3). In the high-risk group, adjuvant chemotherapy did not significantly improve either 5-year OS or CSS (Table S4; P=0.24, Figure 3D; P=0.23, Figure S2D).

Survival prognostic factors after PSM

To precisely evaluate the survival benefit of adjuvant chemotherapy in SA, PSM was performed to balance clinicopathological characteristics between the adjuvant chemotherapy (+) and adjuvant chemotherapy (–) groups. After PSM, the clinicopathological characteristics of the two groups were well-balanced for both stages I–II and stage III patients, with no significant differences found across all variables (Table S5 and Table 3; all P>0.50, Figure S3).

Similar to the results before PSM, Kaplan-Meier analysis showed that the adjuvant chemotherapy demonstrated a significant survival benefit only in stage III SA, with no statistically advantage observed in stages I–II SA (Figure 4). Univariable and multivariable Cox regression analyses were performed to identify factors associated with OS and CSS in stages I–II and stage III SA after PSM (Tables S6,S7). For stages I–II patients, older age (≥60 years) and T4 stage were independently associated with worse OS and CSS (all P<0.05; Table S6). Additionally, the jejunum primary tumor site was associated with better survival outcomes. For stage III patients, adjuvant chemotherapy was independently associated with significantly improved OS (HR =0.46; 95% CI: 0.33–0.64; P<0.001; Table S7) and CSS (HR =0.54; 95% CI: 0.37–0.78; P<0.001; Table S7). Other factors associated with improved survival included the jejunum primary tumor site and the number of lymph nodes examined more than 8 (Table S7). Stage T4 and higher tumor grade (III–IV) were associated with worse outcomes (Table S7).

Figure 4 Kaplan-Meier curves for OS and CSS were compared between the adjuvant chemotherapy (+) and adjuvant chemotherapy (−) groups after PSM. (A,C) stages I–II patients; (B,D) stage III patients. CSS, cancer-specific survival; OS, overall survival; PSM, propensity score matching.

Discussion

The findings of this large, population-based cohort study provide critical evidence that adjuvant chemotherapy was associated with a significant survival benefit specifically in patients with stage III jejunal and ileal adenocarcinoma, while demonstrating no comparable advantage for those with stages I–II disease. These results suggest that a lymph node status-driven approach may be appropriate for adjuvant treatment decisions in this rare malignancy.

The high rate of disease recurrence, occurring in approximately 40% of patients with localized SA following primary tumor resection, is the major challenge in disease management (2,6). Adjuvant chemotherapy is designed to eradicate residual circulating tumor cells and micrometetastatic deposits, aims to reduce this risk (7-9). A noteworthy aspect of our findings is the divergence between OS and CSS outcomes in the unadjusted overall cohort. The presence of a statistically significant yet minimal OS benefit, concurrent with the absence of a CSS benefit. Patients who received adjuvant chemotherapy were systematically younger at baseline. These differences could introduce biases that affect OS estimates through various pathways, including both cancer progression and competing risks from non-cancer mortality. Although models such as the Fine-Gray competing risk model are designed for such analyses (21), they were not applied in our study due to the lack of granular data on specific non-cancer causes of death and patient comorbidity burden in the SEER registry. To address these potential biases, we therefore relied on our stage-stratified and PSM analyses. In our study, the significant improvement in both 5-year OS and CSS observed in stage III patients receiving adjuvant chemotherapy underscores its efficacy in controlling micrometastatic disease. Notably, this survival benefit was consistently confirmed as an independent favorable prognostic factor for stage III disease even after PSM was employed to balance baseline characteristics, thus substantially strengthening the reliability of our conclusion. Our results are consistent with a growing body of evidence from previous studies. de Back et al. recently reported that adjuvant chemotherapy improved OS compared to surgery alone in stage III SA (12). Similarly, a large retrospective analysis from the National Cancer Database (NCDB) also endorsed the use of adjuvant chemotherapy for resected stage III SA (22). This converging evidence collectively builds a solid foundation for advocating a lymph node status-driven strategy for adjuvant therapy in clinical practice.

In contrast, the role of adjuvant chemotherapy remains controversial for patients without lymph node metastasis (10,11,23-25). Although a study based on the NCDB database suggested a trend towards improved OS with adjuvant chemotherapy in patients with stage II T4 tumors (11,22), our study did not demonstrate a survival benefit for patients with stages I–II disease. Furthermore, subgroup analyses revealed that even patients with stage II high-risk features (such as pT4 stage, examination of <8 lymph nodes, or poor tumor differentiation) did not appear to provide a significant benefit from adjuvant chemotherapy. These results are supported by data from previous studies, which often lacked thorough stratification based on clinicopathological factors or included heterogeneous tumor locations (23,26). The underlying biological rationale may be that the risk of occult micrometastasis is substantially lower in node-negative disease, potentially limiting the absolute benefit of systemic chemotherapy. Therefore, the evidence from our study is currently insufficient to advocate for the routine use of adjuvant chemotherapy in stage II high-risk SA. These findings highlight the need for further investigation and the importance of individualized decision-making in clinical practice. An interesting observation was that Kaplan-Meier analysis suggested a potential benefit of adjuvant chemotherapy in the stage II low-risk subgroup, whereas multivariable analysis did not confirm it as an independent favorable factor. This highlights that the apparent univariable association was likely influenced by confounding variables. Furthermore, the analysis in this and other subgroups may be underpowered due to the limited sample sizes after multiple stratifications [adjuvant chemotherapy (+): n=29; adjuvant chemotherapy (−): n=89].

Our study focused specifically on the jejunum and ileum adenocarcinoma, distinguishing it from many previous investigations that often combine these with duodenal tumors. This distinction is critical for several reasons. First, from a fundamental biological standpoint, duodenal adenocarcinoma originates from the foregut, whereas jejunal and ileal adenocarcinomas are midgut-derived. This difference in embryological origin is associated with distinct clinical and pathological profiles, warranting separate analysis (27,28). Second, the surgical management differs substantially. Duodenal adenocarcinoma frequently requires pancreaticoduodenectomy, whereas tumors of the jejunum and ileum are typically treated with segmental resection (2,6). Third, the definitions of established high-risk factors vary by tumor site. For example, the number of lymph nodes examined is commonly defined as fewer than 8 nodes for jejunal and ileal adenocarcinoma, compared to fewer than 5 for duodenal adenocarcinoma (2,29). These anatomical and procedural differences may significantly influence both prognosis and responses to adjuvant therapy (30,31). To address the heterogeneity introduced by including duodenal adenocarcinoma, our study was confined to jejunal and ileal origins. In this study, patients with tumors located in the ileum had relatively worse survival outcomes compared to those with tumors in the jejunum. After adjusting for potential confounding factors using PSM, the ileal tumor remained associated with poorer prognosis. This finding is consistent with most of the previous retrospective studies on SA (23,32). However, a large multicenter analysis of the Japanese Society for Cancer of the Colon and Rectum (JSCCR) database in Japan found that patients with the SA in the jejunum had a significantly lower 5-year DSS rate than those with the SA in the ileum (33). The underlying biological basis for this site-specific survival difference may involve anatomical, embryological, and molecular distinctions between jejunal and ileal adenocarcinomas, which could influence tumor behavior and treatment response (15,20). It should be noted that our study lacks detailed data on molecular profiles [e.g., microsatellite instability (MSI)/mismatch repair (MRR) status], surgical quality metrics (e.g., margin status, extent of mesenteric resection), and patient comorbidities. These unmeasured factors could confound the relationship between primary tumor location and survival.

The advantages of this study include a large amount of data derived from a population-based registry and the application of PSM to improve intergroup comparability. However, several limitations inherent to its retrospective design should be acknowledged. First, its retrospective and observational nature, using registry data and cannot fully account for unmeasured confounding factors, despite our use of PSM. Second, the SEER database lacks information on specific chemotherapy regimens, doses, and cycles, which limits our ability to assess the impact of treatment intensity or completeness. Furthermore, despite the use of PSM to balance measurable covariates, residual confounding cannot be fully ruled out—particularly confounding by indication related to unobserved treatment selection factors. Specifically, the absence of data on MSI/MMR status, tumor genomic characteristics, and surgical quality (e.g., resection margin status, extent of lymphadenectomy) limits our ability to fully adjust for confounding. This is particularly relevant when interpreting factors like primary tumor location as independent prognostic markers, as these unmeasured variables may be unevenly distributed between jejunal and ileal tumors and directly influence survival. Finally, the sample size, though substantial for this rare cancer, limited the statistical power for some subgroup analyses (e.g., within stage III by N substage). Nevertheless, our study still provides sufficient evidence to the survival benefits of adjuvant chemotherapy for patients with stages I–III SA. Future research should focus on prospective, multicenter cohort studies or pooled analyses with standardized data collection to validate these findings. Incorporating comprehensive molecular profiling and biomarker data (e.g., MSI, HER2, KRAS/NRAS) will be crucial to identify biologically distinct subgroups that may derive differential benefit from adjuvant chemotherapy.

Conclusions

Our study provides supporting evidence from a population-based analysis for the administration of adjuvant chemotherapy in patients with lymph node-positive jejunal and ileal adenocarcinoma after curative resection. However, our findings suggest that adjuvant chemotherapy may not be routinely indicated for patients with stages I–II disease, even in the presence of stage II high-risk pathological features.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-875/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-875/prf

Funding: This work was supported by the Jiangxi Provincial Health Commission Science and Technology Plan (General Program) (No. 202410524).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-875/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.

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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