Survival benefit of adjuvant radiotherapy for gallbladder cancer patients with stage IIIA: a population based, propensity score-matched study

Introduction

Gallbladder cancer (GBC) is the sixth most common gastrointestinal malignancy and the most prevalent biliary tract cancer, with an estimated 115,949 new cases and 84,695 deaths worldwide in 2020 (1). Due to non-specific early symptoms and lack of effective screening, most GBC patients are diagnosed at an advanced stage. The 5-year survival rates for T3 and T4 stages are only 23% and 12%, respectively (2). While a minority of patients with advanced disease may be cured with multimodality treatment, the majority remain incurable. Thus, improving survival for locally advanced GBC is a critical clinical need.

Surgical resection remains the mainstay of curative therapy for GBC (3,4). Nevertheless, even after complete resection, locoregional recurrence occurs in 15–59% of patients (5,6). Numerous studies have explored the benefits of adjuvant therapies, including chemotherapy (CT), radiotherapy (RT), and chemoradiotherapy (CRT). The BILCAP trial—a randomized phase III study—demonstrated that adjuvant capecitabine improves Overall survival (OS) and relapse-free survival (RFS) compared with observation in biliary tract cancer (7), and capecitabine is now recommended in ASCO guidelines (8). However, the role of adjuvant RT or CRT after surgery for advanced GBC remains unclear due to a lack of randomized trials. Given this knowledge gap, we aimed to evaluate the survival benefit of adjuvant radiotherapy (ART) or CRT in advanced GBC using a large, real-world population from the Surveillance, Epidemiology, and End Results (SEER) database and rigorous statistical adjustment via PSM. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2511/rc).

Methods

Study population and data sources

Data were extracted from the SEER database, which covers approximately 34.6% of the U.S. population and provides comprehensive clinical and demographic information (9). Patients were identified using SEER*Stat software (version 8.3.4). We identified patients diagnosed with pathologically confirmed GBC from January 2010 to December 2015. Eligible cases included those diagnosed with stage III or IV disease based on the American Joint Committee on Cancer (AJCC) 7th edition, who underwent surgery and had active follow-up. Only patients with complete information on age, marital status, race, sex, tumor grade, histology, AJCC stage, adjuvant chemotherapy (ACT), and liver metastasis at diagnosis were included in this study. According to the SEER classification, radical resection was defined as partial or total removal of the primary tumor, with or without en bloc resection of adjacent organs. Surgeries included in this study corresponded to SEER RX Summ--Surg Prim Site (1998+), codes 30, 40, 50, 60, and 90. Patients were divided into ART (n=430) and non-ART (n=1,582) groups (Figure 1). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Figure 1 The flowchart of study population selection. ART, adjuvant radiotherapy; N, node; SEER, Surveillance, Epidemiology, and End Results; T, tumor.

Propensity score matching (PSM)

To reduce selection bias, 1:1 nearest neighbor PSM with a caliper of 0.02 was performed (10). Covariates included in the logistic regression model were age, sex, race, marital status, grade, histology, AJCC stage, ACT, and liver metastasis. Covariate balance was assessed using Chi-squared tests.

Statistical analysis

Baseline characteristics were compared using Chi-squared tests. Univariate and multivariate Cox proportional hazards models were used to estimate hazard ratio (HR) with 95% confidence intervals (CIs) for OS and cancer-specific survival (CSS). Kaplan-Meier analysis and log-rank tests compared survival between groups. Subgroup analyses were also conducted according to disease stage. Survival curves were generated using GraphPad Prism 8. All statistical analyses were performed using SPSS 24.0 (IBM Corp., Armonk, NY, USA), and P<0.05 was considered significant.

Results

Patient characteristics

A total of 2,012 patients were included: 430 (21.4%) received ART and 1,582 (78.6%) did not. Prior to PSM, significant differences existed between groups in age, sex, marital status, tumor grade, stage, and receipt of ACT (Table 1). After PSM, 376 matched pairs were generated, and baseline characteristics were well balanced (Table 1).

Survival analysis

In the multivariate analysis after PSM, older age, higher tumor grade, advanced stage, and the absence of ACT or ART were all associated with poorer OS and CSS (Table 2). Conversely, receipt of ART was significantly associated with improved OS (HR =0.75, 95% CI: 0.64–0.89, P<0.001) and CSS (HR =0.73, 95% CI: 0.60–0.87, P<0.001) (Figure 2).

Figure 2 Kaplan-Meier survival cures of the effect of study groups after matching, SEER 2010–2015. ART, adjuvant radiotherapy; SEER, Surveillance, Epidemiology, and End Results.

Subgroup analysis

Table 3 presents the impact of ART on OS and CSS across different subgroups after PSM. Although the survival advantage of ART was evident in most subgroups, statistical significance was not achieved in all cases. ART was associated with significantly improved OS and CSS among patients who were older, female, had grade 3–4 tumors, adenocarcinoma histology, stage IIIA disease, received ACT, and lacked liver metastasis. Importantly, ART conferred a significant survival benefit specifically in patients with stage IIIA GBC [OS (HR =0.56, 95% CI: 0.41–0.77, P<0.001) and CSS (HR =0.54, 95% CI: 0.37–0.75, P<0.001)], whereas no significant benefit was observed for stages IIIB, IVA, or IVB (Figure 3).

Figure 3 Kaplan-Meier survival curves stratified by TNM stage after matching, SEER 2010–2015. ART, adjuvant radiotherapy; SEER, Surveillance, Epidemiology, and End Results; TNM, tumor-node-metastasis.

Discussion

To our knowledge, this is the first population-based study using PSM to assess the impact of ART for GBC. Our results indicate that ART, particularly when combined with ACT, provides a survival advantage for stage IIIA GBC, as demonstrated by both multivariate and PSM analyses.

Previous studies have indicated that the 5-year survival rate for advanced GBC is only 12–23% (2). Several retrospective analyses, including those utilizing the National Cancer Database (NCDB) and SEER databases, have demonstrated that adjuvant CRT offers a survival advantage compared to surgery alone or chemotherapy alone (11-13). Analyses of the NCDB by both Hoehn (11) and Mitin (12) found that adjuvant CRT was significantly associated with improved survival in stage II and III GBC patients compared with surgery alone. Zhu et al. reported that adjuvant CRT provided significantly greater survival benefits compared to chemotherapy alone, with a median OS of 25.0 vs. 19.0 months (P=0.003) (14). In that study, patients receiving adjuvant CRT had a higher median OS compared to those receiving CT alone (12.9 vs. 7.8 months, P=0.001). Consistent with these previous research, our study found that ART was significantly associated with improved survival among patients who also received ACT (HR for OS =0.74, 95% CI: 0.62–0.88, P=0.001; HR for CSS =0.72, 95% CI: 0.60–0.88, P=0.001). Interestingly, no significant survival benefit of ART was observed in patients who did not receive ACT (P=0.23 for OS; P=0.20 for CSS) (Table 3). These consistent findings further support the association between CRT and improved survival outcomes in patients with GBC. CRT has been recommended as an adjuvant treatment for GBC following resection, although this recommendation in the 2021 National Comprehensive Cancer Network (NCCN) guidelines is not yet based on high-quality evidence.

From a contemporary radiation oncology perspective, postoperative radiotherapy/CRT for GBC is generally delivered with external-beam techniques using conventional fractionation, with typical total doses in the range of approximately 45–50.4 Gy to the postoperative bed and regional lymphatics, and consideration of a boost to higher-risk areas (often to ~54–59.4 Gy) when organ-at-risk constraints permit (13). Target volumes commonly encompass the gallbladder fossa (liver resection bed) and relevant regional nodal basins (e.g., porta hepatis/hepatoduodenal ligament, peripancreatic and celiac nodes), tailored to the extent of resection and pathologic risk factors. In many institutions, radiotherapy is delivered concurrently with a fluoropyrimidine-based radiosensitizer (e.g., capecitabine or 5-fluorouracil) when patients are fit; however, radiotherapy alone may be considered for selected patients who cannot tolerate chemotherapy. Importantly, the SEER database does not capture radiotherapy details (dose, fractionation, technique, or target volumes), specific chemotherapy regimens/timing, surgical margin status, performance status, or comorbidities; therefore, reasons for omitting chemotherapy in some patients (e.g., frailty, comorbidity burden, postoperative complications, or patient preference) cannot be determined and may confound subgroup comparisons (particularly the ART-without-ACT subgroup)

In our study, after PSM, ART increased the median OS from 14.0 to 20.0 months and the median CSS from 17.0 to 23.0 months in patients with advanced GBC. We subsequently conducted stratified analyses according to different clinicopathological variables. Our results demonstrated that ART was associated with improved OS and CSS specifically in patients with stage IIIA disease. Notably, we did not observe a survival benefit from ART in patients with more advanced TNM stages. These findings suggest that patients with stage IIIA GBC may benefit from more aggressive treatments such as CRT or CT, whereas those with stage IIIB, IVA, or IVB disease may derive benefit primarily from chemotherapy alone, and the addition of CRT may not be necessary. This observation is consistent with the report by Cai et al., who found that postoperative radiotherapy did not improve OS, with or without chemotherapy, in stage IIIB GBC patients with one to three lymph node metastases (15). One possible explanation for the observed benefit being concentrated in stage IIIA is that this subgroup may have a relatively high risk of locoregional recurrence that remains amenable to improvement through enhanced local control. By contrast, more advanced stages (e.g., IIIB/IVA/IVB) may be more frequently dominated by occult or overt systemic dissemination, thereby diminishing the marginal impact of local therapy on OS. Notably, SEER does not provide data on recurrence patterns (locoregional vs. distant) or local control endpoints; therefore, this interpretation is hypothesis-generating and should be validated in datasets with recurrence information.

We acknowledged several limitations inherent to this study. As with any observational study, potential bias is always a concern. Using the PSM analyses, we could potentially eliminate the bias from the unbalanced distribution of measured factors. Nevertheless, bias from unmeasured covariates shall be inevitable. Randomized controlled trials remain the gold standard for causal inference. In contrast, SEER offers large, population-based real-world data that are broadly representative, but analyses are constrained by unmeasured confounding and the absence of key clinical and treatment details—such as GBC risk factors, performance status, comorbidities, and specific chemotherapy and radiotherapy information—which could influence survival. Multivariable analyses and PSM analyses were conducted, and OS and CSS results didn’t change significantly and therefore appeared valid and stable. Furthermore, randomized multicenter clinical trials are urgently needed to explore the effect of ART on GBC, and further, to clarify what kind of adjuvant treatment is most profitable.

Conclusions

In this large SEER-based study, ART, especially in combination with chemotherapy, was associated with improved survival for patients with stage IIIA GBC. For stages IIIB, IVA, and IVB, chemotherapy alone may be sufficient, and ART may not be necessary. Well-designed randomized controlled trials are warranted to further clarify the role of ART in advanced GBC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2511/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2511/prf

Funding: This work was supported by the Henan Province Medical Science and Technology Tackling Program Joint Co-Construction Project (Nos. LHGJ20230881 and LHGJ20221003).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2511/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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