As the most familiar cancer from biliary tract, GBC ranks 23rd among all tumors and 6th among digestive system tumors (1). The global morbidity and mortality of GBC have been increasing annually, Eastern Asia, South America, and Melanesia were the regions with highest ranking (2, 3), the latest global incidence and mortality data for GBC are visualized in Supplementary Figure 1 . Moreover, the etiology of GBC varies across different countries (4). GBC is one of the few cancers that shows a gender difference (5), with the morbidity in females nearly three times that of males (6), and is the only digestive system tumor that is predominantly female (7). As early symptoms are rare and lymph nodes and distant metastases often occur early, three-quarters of GBC patients are diagnosed with advanced stages or metastases, which results in poor prognoses (5, 8). In fact, symptomatic gallstones lead to cholecystectomy in most cases of GBC (9, 10). Additionally, among the biliary tract cancers, GBC has the shortest median survival rate. Despite improvements in diagnosis and treatment over the years, its 5-year survival rate remains lower than 20% (3). Therefore, addressing the treatment of GBC, a highly lethal tumor, is a significant challenge worldwide, and there is still considerable controversy surrounding the treatment of advanced GBC patients. Given that adenocarcinoma is the most prevalent and representative pathological type of GBC (11), and that treatment research has primarily centered on gallbladder adenocarcinoma (GBAC) (12, 13), the present study specifically addresses GBAC to ensure homogeneity, as other histological types exhibit different biological behaviors and treatment responses (14). Currently, among all treatment options for gallbladder cancer (GBC), only surgical intervention has demonstrated clear effectiveness, while other options, including radiotherapy, chemotherapy, and immunotherapy, remain in the exploratory stage (15). In the present article the SEER database, departmental cohort and the PubMed database were utilized to investigate treatment models for patients with advanced GBC, while also summarizing alternative treatment options.

Currently, treatment options for advanced GBC patients remain uncertain. Surgery continues to be the preferred treatment option for advanced GBC. Radical surgical is the only potential curative method for advanced GBC patients. Unfortunately, due to lymph node and distant metastases in advanced GBC, which limit the opportunity for radical surgery, non-radical surgery, as an alternative, including procedures aimed at relieving jaundice or pain, simple cholecystectomy, and tumor debulking surgeries, are often adopted. However, the efficacy of single surgical treatment is unsatisfactory. Therefore, adjuvant therapies, including chemotherapy and radiotherapy, as well as more advanced immunotherapy and targeted therapy, are also frequently used in the comprehensive management of advanced GBC patients to improve their survival time (17).

There is currently a controversy regarding whether radical surgery should be performed for advanced GBC patients. The scope of radical surgery for advanced GBC typically includes the removal of the gallbladder, adjacent liver tissue, lymph node(s), and affected organ(s). More aggressive procedures involve pancreaticoduodenectomy (PD) and hepatopancreaticoduodenectomy (HPD) (18, 19). Some scholars argue that aggressive surgery is beneficial for patient survival (10, 20–24). A multicenter cohort study analyzed the effects of extended resection surgery on locally advanced GBC patients, confirming the role of radical resection, resulting in some patients achieving a survival time of over two years (25). Even in AJCC stage IV GBC patients, the survival rate after radical surgery has been shown to be significantly higher than that of no surgery (26, 27). Conversely, some physicians question the benefits of radical surgery, considering routine or prophylactic extended surgery to have no significant survival advantage, and non-radical surgery is more recommended (18, 28). In one report, although HPD could eradicate locally advanced GBC, it did not show superiority over non-radical surgery in terms of overall survival, complication morbidity, and mortality (28–30). Therefore, in light of the above perspectives and the findings of this study, as an alternative, non-radical surgery is adopted, as it has also been proven effective for survival in advanced GBC (19, 28, 29).

Chemotherapy is widely used in gastrointestinal tumors, and although the progression-free survival of advanced GBC is relatively short due to its particularity, it still has a positive impact (31). Currently, the gemcitabine and cisplatin (GS) regimen is the most widely accepted chemotherapy regimen for GBC (32–35). With the emergence of neoadjuvant chemotherapy, it has also created opportunities for radical surgery and longer survival time (36–40). Recently, with the use of new drugs and the conduct of more clinical trials, more chemotherapy regimens have emerged, such as FOLFOX, modified FOLFIRINOX (mFOLFIRINOX), and GEMOX regimens (35, 41). Additionally, hepatic arterial infusion chemotherapy (HAIC) is also a choice (36, 42). It is worth mentioning that even without surgery, palliative chemotherapy is beneficial for the survival of advanced GBC (43, 44).

Radiotherapy, as a treatment option, is not widely used in advanced GBC, but still has a positive role (45). Currently, radiotherapy mainly includes four forms: preoperative radiotherapy (neoadjuvant radiotherapy), intraoperative radiotherapy, postoperative radiotherapy (adjuvant radiotherapy), and palliative radiotherapy, with doses mostly concentrated in the range of 45-54 Gy (46, 47). Some scholars have pointed out that after surgery for advanced GBC, not using radiotherapy or chemoradiotherapy can increase the risk of local recurrence (47, 48). In advanced GBC, radiotherapy is usually jointly used with chemotherapy for effect enhancement, including adjuvant chemoradiotherapy and neoadjuvant chemoradiotherapy (49, 50). It is worth mentioning that for unresectable advanced GBC, both radiotherapy and chemoradiotherapy can bring survival benefits to patients and create opportunities for radical surgery (50, 51).

Immunotherapy and targeted therapy also boost the survival of advanced GBC patients (34, 52). The term immunotherapy refers mainly to immune checkpoint inhibitors, such as PD-1, PD-L1, TMB-H, and MSI/MMRd (53–56). In the phase III TOPAZ-1 trial in 2022 and the KEYNOTE-966 trial in 2023, the combination of durvalumab or pembrolizumab with gemcitabine-cisplatin demonstrated improved survival compared to treatment with gemcitabine-cisplatin alone (57–59). Additionally, several phase II clinical trials have provided evidence supporting the effectiveness of other immunotherapy regimens, such as stereotactic body radiotherapy (SBRT) combined with nivolumab and ipilimumab, camrelizumab plus FOLFOX4 or GEMOX, and nab-paclitaxel combined with sintilimab (60–64). Targeted drugs include trastuzumab, erdafitinib, lenvatinib, and so on, mainly targeting specific molecular pathways such as Hedgehog, PI3K/AKT/mTOR, Notch, ErbB, MAPK/ERK, and Angiogenesis (53, 65–67). Additionally, patient-derived tumor organoid and patient-derived tumor xenograft models can facilitate personalized treatment for patients with advanced GBC (68).

The SEER database was utilized to compare treatment models for advanced GBC patients in this study. Among all patients, through Cox regression analyses, it was observed that the “RSCR” model exhibited the most significant improvement in CSS compared to the “NSNCNR” model, with other models also showing varying degrees of improvement. After excluding treatment models with insufficient sample sizes and analyzing the post-PSM data, or after conducting analysis using only cases with complete data, the results remained robust. These results consistent with the current understanding. After subgroup analysis by AJCC stage, the efficacy of the “RSCR” model remained significant. Some discordant results observed in subgroup analyses may stem from variations in the underlying patient profiles at each AJCC stage, or from the relatively small sample sizes in certain treatment models and stage categories. It is noteworthy that the extension effect of the “NrSCR” model on CSS was also considerable, often ranking second only to the “RSCR” model. Considering the difficulty of achieving radical surgery in advanced GBC, non-radical surgery is also a treatment option for patients who cannot undergo radical surgery, of course, in conjunction with other treatment options as much as possible. Additionally, it was found that the use of radical or non-radical surgery, chemotherapy, and radiotherapy provided significant benefits to patients compared to no surgery, no chemotherapy, and no radiotherapy, and the survival time was prolonged to varying degrees after the combination of treatment options.

In our departmental cohort analysis, the absence of significant differences in clinical and demographic characteristics between the two groups (p > 0.05) indicates that the patients were comparable in terms of baseline factors at the time of treatment assignment. This comparability is crucial as it reduces the likelihood of confounding bias, allowing any observed differences in survival outcomes to be more confidently attributed to the effect of immunotherapy rather than baseline imbalances. In the KM analysis, the lack of statistical significance (p = 0.23) may be attributed to the limited sample size in our cohort, particularly with only 5 patients receiving immunotherapy. Small sample sizes often reduce the power of statistical tests, making it more difficult to detect significant differences even if a true effect exists. While the trend observed in the Kaplan-Meier curves suggests a potential benefit of immunotherapy, further studies with larger patient cohorts are needed to confirm this finding and achieve adequate statistical power. It is believed that these results can provide new insights to clinicians, indicating that when conditions permit, comprehensive treatment including surgery, chemotherapy, radiotherapy, as well as immunotherapy and targeted therapy should be provided to patients with advanced GBC, rather than limiting treatment to one or two options.

However, several limitations still exist in this innovative study. Firstly, the SEER database is a retrospective database, and data such as vital signs, nutritional status, underlying diseases of patients are not reflected in the database. Secondly, the specific location of the tumor, tumor burden, and surgical procedures were not mentioned. Additionally, the specific modes, doses, and durations of chemotherapy and radiotherapy, as well as the sequence and intervals of surgery, chemotherapy, and radiotherapy, were not within the scope of the study, and treatment options such as targeted therapy and immunotherapy were not embraced. Despite these limitations, the SEER database is still useful in terms of providing the most comprehensive data on treatment patterns and survival status in the United States to date. Additionally, to address the limitations of the database, we conducted a review of our departmental cohort and literature from the PubMed database to enhance our understanding of immunotherapy and related treatments. Based on our knowledge, a comprehensive study of all twelve treatment models selected from the SEER database is being conducted for the first time, while several studies have utilized the database to analyze GBC, none have combined such a broad range of treatment models and ranked them accordingly (69). Additionally, this study is one of the few that focuses on advanced GBC. Previous researchers have often overlooked this patient group, as advanced GBC has traditionally been considered unsuitable for surgical intervention (70). Given that the SEER database analysis is retrospective in nature, future research should incorporate more detailed clinical data, including specific surgical approaches, chemotherapy regimens, radiation doses, and the sequencing of various treatment options. Moreover, larger departmental cohorts should be established to enhance the reliability of the findings. Furthermore, we recommend that prospective studies explore these aspects in greater depth and assess their applications in clinical practice.

For the SEER database, the “Radical surgery + Chemotherapy + Radiotherapy” models provide the greatest survival benefit for advanced GBC patients. At the same time, the departmental cohort analysis suggests that incorporating immunotherapy may offer further advantages to patients. Providing patients with the most comprehensive treatment possible, even if the optimal treatment effect is not achieved, is a way to extend the survival of patients. As long as treatment options are taken, it is always beneficial for patient survival. This innovative finding requires more comprehensive data and prospective studies for validation.