Impact of adjuvant therapy on survival outcomes in resected gallbladder cancer: a systematic review and meta-analysis

Introduction

Gallbladder cancer (GBC) is the most prevalent malignancy of the biliary tract and ranks as the fifth most common cancer originating from the digestive system (1). Unfortunately, GBC has a particularly grim prognosis (2). Surgery is currently the only accepted curative treatment for GBC, but it is only viable if the disease is resectable. Despite attempts to cure the disease through surgical intervention, the 5-year overall survival (OS) rate remains discouragingly low, ranging from 17% to 45%, in relation to primary tumor stage (3). Additionally, even after complete resection, the high recurrence rates are associated with a poor prognosis (4).

It is noteworthy that the standard of care for patients with unresectable biliary tract cancer (BTC) has been established as cisplatin and gemcitabine, suggesting that BTCs are chemosensitive malignancies (5). This has been corroborated by meta-analyses with higher levels of evidence (6). Therefore, we believe it is necessary to investigate whether adjuvant therapy for resectable GBC improves prognosis after surgery. Given the high relapse rate and poor prognosis of GBC, adjuvant therapy is considered a rational strategy following surgical resection. However, its role remains controversial. Until recently, adjuvant treatment strategies were primarily informed by a meta-analysis that included heterogeneous retrospective studies, which demonstrated a survival benefit for selected populations of resected BTC patients, specifically those with node-positive disease and/or R1 resection (7).

Some studies suggest that adjuvant therapy, including chemotherapy (CT), radiotherapy (RT), or chemoradiotherapy (CRT), may benefit certain GBC patients. Additionally, while immune checkpoint inhibitors have shown potential in treating various cancers (8), reports suggest that their adverse effects may negatively impact patient prognosis (9). Retrospective studies have indicated that patients might experience a survival benefit from adjuvant CRT or RT (10,11). Nonetheless, other retrospective studies have reported conflicting results regarding the effectiveness of adjuvant therapy in GBC (12,13). The survival benefit of adjuvant therapy is influenced by factors such as the status of surgical margins, tumor-node-metastasis (TNM) stage, and lymph node involvement. Specifically, the clarity of surgical margins, the severity of the TNM stage, and the presence of cancer cells in lymph nodes can all impact the effectiveness of adjuvant therapy. Due to limited clinical evidence, no specific adjuvant therapy is universally recommended for GBC, and the National Comprehensive Cancer Network (NCCN) has not endorsed a preferred treatment option (14). Recent advancements in adjuvant systemic therapy for resected BTC have sparked significant discussion, especially following major trials like BILCAP, BCAT, and PRODIGE-12/ACCORD-18 (15). Simultaneously, recent studies highlight the importance of identifying broadly applicable prognostic tools across cancers (16). Such approaches may also improve the prognosis of GBC patients.

A systematic review and meta-analysis focusing on adjuvant therapy regimens for resectable GBC has not been conducted to date, and specific outcomes for resectable GBC remain poorly defined. Therefore, this meta-analysis aims to examine the outcomes from adjuvant therapy regimens, including adjuvant CT, adjuvant RT, and adjuvant CRT, reported in the literature for resectable GBC. By deriving pooled outcomes, this analysis seeks to establish a benchmark for future GBC-specific clinical trials and provide insights that could help improve prognosis for these patients. We present this article in accordance with the PRISMA reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-433/rc).

Methods

Literature search

This systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the ID CRD42024571075. The literature search was performed by two independent reviewers (D.Z. and N.W.) across PubMed, Embase, and Web of Science databases from their inception up to April 2024, with the search restricted to English-language publications. In the event of discrepancies between the reviewers, a third reviewer (Y.W.), was consulted to achieve consensus.

Inclusion and exclusion criteria

Inclusion criteria: (I) studies involving patients with GBC diagnosed through pathological examination. (II) Studies that evaluated the impact of adjuvant therapies (CT, RT, or CRT) on patient outcomes, including OS, disease-free survival (DFS), and progression-free survival (PFS). (III) Studies that reported survival outcomes with hazard ratios (HRs) and 95% confidence intervals (CIs) for the efficacy of adjuvant therapies in resectable GBC.

Exclusion criteria: (I) studies focusing on patients with benign or borderline gallbladder conditions, or other types of BTCs. (II) Studies that did not specifically assess the effectiveness of adjuvant therapies (CT, RT, or CRT) for resectable GBC. (III) Studies lacking sufficient data, such as those without reported survival outcomes or essential statistics [e.g., HR, odds ratios (ORs), or relative risks (RRs)]. (IV) Studies that included tumors other than GBC. Studies that did not involve surgical treatment or focused solely on non-surgical interventions.

Statistical analysis

Survival data were analyzed utilizing HRs along with their corresponding 95% CIs through multivariate regression techniques. Categorical variables were evaluated using ORs. The presence of statistical heterogeneity among studies was assessed with Cochrane’s Q-test and I² statistics, with thresholds for low, moderate, and high heterogeneity set at 25%, 50%, and 75%, respectively. To account for potential variability across studies, a random-effect model was employed consistently, irrespective of the level of heterogeneity.

Subsequent subgroup analyses were performed to explore potential sources of heterogeneity, including the types of adjuvant therapy (CT, RT, or CRT). We also conducted a subgroup analysis to assess the effectiveness of adjuvant therapy in patients with universally recognized high-risk factors post-surgery, including R1 resection, non-textbook outcomes, and advanced TNM stages. Statistical significance was set at a threshold of P<0.05. Publication bias was assessed using funnel plots and Egger’s test. All statistical analyses were carried out using STATA 17.0 software.

Quality assessment of studies

Two independent investigators (D.Z. and N.W.) assessed the quality of the included studies using the Newcastle-Ottawa Scale (NOS). This scale evaluates aspects such as study design, selection of study groups, comparability, and outcome assessment. Studies with a NOS score of six or higher were deemed eligible for inclusion in the final meta-analysis.

Results

Literature search

We initially identified 966 articles from electronic databases including PubMed, Embase, and Web of Science. After removing duplicates and irrelevant studies, 310 full-text articles were assessed for eligibility. Following a thorough examination of these articles, 23 studies met the inclusion criteria and were included in the qualitative synthesis (4,12,17-37). The article selection process is illustrated in the PRISMA diagram (Figure 1).

Figure 1 The article selection process illustrated in the PRISMA diagram. HR, hazard ratio; OR, odds ratio; RR, relative risk; CI, confidence interval.

Study characteristics and quality assessment

This meta-analysis included a total of 36,214 patients diagnosed with resectable GBC from studies published between 2015 and 2024. Of the 23 studies included, 19 investigated adjuvant CT, 8 examined CRT, and 6 focused on adjuvant RT alone. Quality assessment using the NOS indicated that most studies were of high quality, with 23 scoring 7 or higher (details of NOS are provided in Table S1). The PRISMA diagram illustrating the study selection process is shown in Figure 1, and detailed study characteristics are summarized in Table 1.

Association of adjuvant therapy (CT, RT, CRT) with OS in post-surgery GBC patients

Twenty-three studies examined the correlation between adjuvant therapy (including CT, RT, and CRT) and prognosis in resected GBC. The pooled analysis of all included studies revealed that adjuvant therapy was associated with improved OS (HR, 0.72; 95% CI: 0.66–0.78; P<0.001) (Figure 2).

Figure 2 Forest plot of the association between adjuvant therapy (CT, RT, CRT) and OS in resected GBC patients. HR, hazard ratio; CI, confidence interval; CRT, chemoradiotherapy; CT, chemotherapy; RT, radiotherapy; OS, overall survival; GBC, gallbladder cancer.

Association of adjuvant therapy (CT, RT, CRT) with DFS in post-surgery GBC patients

Five included studies comprising 9 comparative analyses examined the correlation between adjuvant therapy (including CT, RT, and CRT) and prognosis in resected GBC. A pooled analysis of all included studies indicated that adjuvant therapy was associated with improved DFS (HR, 0.55; 95% CI: 0.40–0.75; P<0.001) (Figure 3).

Figure 3 Forest plot of the association between adjuvant therapy (CT, RT, CRT) and DFS in resected GBC patients. HR, hazard ratio; CI, confidence interval; CT, chemotherapy; RT, radiotherapy; CRT, chemoradiotherapy; DFS, disease-free survival; GBC, gallbladder cancer.

Correlation between adjuvant CT and OS in GBC patients after surgery

Nine studies examined the correlation between adjuvant CT and prognosis in resected GBC. In 11 studies, adjuvant CT emerged as a protective predictor of improved OS among patients with GBC. Conversely, in eight studies, the impact of adjuvant CT on OS did not achieve statistical significance. The pooled analysis of all included studies revealed that adjuvant CT was associated with improved OS (HR, 0.80; 95% CI: 0.72–0.88; P<0.001), despite high heterogeneity (Figure 4).

Figure 4 Forest plot of the correlation between adjuvant CT and OS in resected GBC patients. HR, hazard ratio; CI, confidence interval; CT, chemotherapy; OS, overall survival; GBC, gallbladder cancer.

Correlation between adjuvant RT and OS in GBC patients after surgery

Six studies examined the correlation between adjuvant RT and prognosis in resected GBC. In four studies, adjuvant RT emerged as a protective predictor of improved OS among patients with GBC. Conversely, in two studies, the impact of adjuvant RT on OS did not achieve statistical significance. The pooled analysis of all included studies revealed that adjuvant RT was associated with improved OS (HR, 0.76; 95% CI: 0.65–0.88; P<0.001), despite high heterogeneity (Figure 5).

Figure 5 Forest plot of the correlation between adjuvant RT and OS in resected GBC patients. HR, hazard ratio; CI, confidence interval; RT, radiotherapy; OS, overall survival; GBC, gallbladder cancer.

Correlation between adjuvant CRT and OS in GBC patients after surgery

Eight studies examined the correlation between adjuvant CRT and prognosis in resected GBC. Notably, in all eight studies, CRT emerged as a protective predictor of improved OS among patients with GBC. The pooled analysis of all included studies revealed that adjuvant CRT was associated with improved OS (HR, 0.56; 95% CI: 0.47–0.67; P<0.001), despite high heterogeneity (Figure 6).

Figure 6 Forest plot of the correlation between adjuvant CRT and OS in resected GBC patients. HR, hazard ratio; CI, confidence interval; CRT, chemoradiotherapy; OS, overall survival; GBC, gallbladder cancer.

Correlation between adjuvant therapy and OS in GBC patients with poor postoperative prognostic factors

Nine studies examined the correlation between adjuvant therapy (CT, RT, and CRT) and OS in resected GBC patients with poor postoperative prognostic factors. Specifically, these factors include: R1 resection (2 studies), T stage ≥3 (1 study), T stage ≥2 (1 study), T stage ≥2 with N stage ≥1 (2 studies), non-textbook outcomes (1 study), N stage ≥1 (1 study), and age ≥70 years (1 study). In seven studies, adjuvant therapy emerged as a protective predictor of improved OS among these patients. Conversely, in two studies, the impact of adjuvant therapy on OS did not achieve statistical significance. The pooled analysis of all included studies revealed that adjuvant therapy was associated with improved OS (HR, 0.62; 95% CI: 0.50–0.76; P<0.001), despite high heterogeneity (Figure 7). Additionally, we have summarized the most important conclusion of this study in Figure 8.

Figure 7 Forest plot of the correlation between adjuvant therapy (CT, RT, or CRT) and OS in resected GBC patients with poor postoperative prognostic factors. Specifically, these factors include: R1 resection (2 studies), T stage ≥3 (1 study), T stage ≥2 (1 study), T stage ≥2 with N stage ≥1 (2 studies), non-textbook outcomes (1 study), N stage ≥1 (1 study), and age ≥70 years (1 study). HR, hazard ratio; CI, confidence interval; CT, chemotherapy; CRT, chemoradiotherapy; RT, radiotherapy; OS, overall survival; GBC, gallbladder cancer.

Figure 8 Key findings overview of this study. CT, chemotherapy; RT, radiotherapy; CRT, chemoradiotherapy; HR, hazard ratio; CI, confidence interval; GBC, gallbladder cancer.

Sensitivity analyses

In the sensitivity analyses, we employed a random-effect model, systematically excluding each study in turn, to assess the robustness of the prognostic role of adjuvant CT, adjuvant RT, and adjuvant CRT in the OS of GBC. These sensitivity analyses were conducted using StataMP 17 software (StataCorp. 2022; Stata Statistical Software: Release 17.). The results reaffirmed the reliability of our findings. Detailed sensitivity analyses for each type of adjuvant therapy can be found in the supplementary materials (see Figures S1-S6, which correspond sequentially to Figures 2-7).

Publication bias

In studies examining the correlation between adjuvant therapy and OS, despite the asymmetrical distribution of funnel plots indicating the presence of publication bias, Egger’s regression test confirmed this, revealing a P value of 0.03. However, subsequent subgroup analyses successfully eliminated this publication bias. This suggests that the initial findings were influenced by certain confounding factors. The refined analysis provides a more accurate assessment of the true impact of adjuvant therapy on OS (Figure S7A,S7B).

In studies examining the correlation between adjuvant therapy and DFS, the symmetrical distribution of funnel plots indicated no significant risk of publication bias. Furthermore, Egger’s regression test confirmed this, revealing an insignificant presence of publication bias with a P value of 0.14 (Figure S8A,S8B).

In studies examining the correlation between adjuvant CT and OS, the symmetrical distribution of funnel plots indicated no significant risk of publication bias. Furthermore, Egger’s regression test confirmed this, revealing an insignificant presence of publication bias with a P value of 0.15 (Figure S9A,S9B).

Similarly, in studies investigating the correlation between adjuvant RT and OS, the symmetrical distribution of funnel plots suggested no notable risk of publication bias. Egger’s regression test supported this finding, with a P value of 0.20 (Figure S10A,S10B).

For studies exploring the correlation between adjuvant CRT and OS, the symmetrical distribution of funnel plots indicated no significant risk of publication bias. This was further corroborated by Egger’s regression test, which showed an insignificant presence of publication bias with a P value of 0.12 (Figure S11A,S11B).

Lastly, in studies focusing on GBC patients with poor postoperative prognostic factors, the symmetrical distribution of funnel plots suggested no notable risk of publication bias. Egger’s regression test confirmed this with a P value of 0.10 (Figure S12A,S12B).

Discussion

GBC is a frequently encountered malignancy of the biliary tract. The primary curative approach remains radical resection; however, the prognosis remains bleak. Although safe gallbladder resection has emerged as a promising treatment option, high recurrence rates significantly impact long-term survival (38). To enhance outcomes, various therapeutic strategies combining surgery with adjuvant therapy have been investigated. Based on previous literature, there has been ongoing debate regarding the efficacy of adjuvant therapies following surgery for GBC. While some studies, including those by major institutions worldwide (39,40), have suggested potential benefits of AT, contrasting findings also exist. For instance, Kim et al. reported that adjuvant RT, CT, or CRT did not significantly impact DFS following appropriate surgery (41). Similarly, another study involving 279 GBC patients who underwent R0 resection found that neither adjuvant CT nor RT improved OS. These conflicting results highlight the need for a comprehensive meta-analysis to evaluate the role of adjuvant therapies in improving outcomes specifically for resectable GBC cases (3). Therefore, our study aims to conduct a meta-analysis to assess the impact of adjuvant therapy on postoperative outcomes in resectable GBC cases.

In our comprehensive review of nineteen studies investigating the impact of adjuvant CT on GBC patients post-surgery, the pooled analysis consistently demonstrated a significant association between adjuvant CT and improved OS. This consensus is in line with findings reported across numerous other studies in the field. For example, some studies have suggested a role for adjuvant CT in the setting of positive surgical margins (42,43). Previous studies have reported high rates of disease recurrence in patients with resected GBC, ranging from 31.9% to 66.3%. Recurrence occurred at locoregional sites (33.9% to 79.2%), distant sites (52.6% to 79.8%), and both (18.9% to 50%) (6). The most frequent sites of recurrence were regional lymph nodes (27.8% to 47.3%), liver (22.2% to 36.8%), and the local area (20.8% to 28.3%) (41,44,45). These findings underscore the common occurrence of both locoregional and distant recurrences post-surgery in GBC patients, highlighting the potential benefit of adjuvant treatments in reducing recurrence rates. However, many studies still contend that CT has limited impact on the prognosis of resectable GBC. Notably, two influential randomized controlled trials (RCTs) have been negative in this regard. Both the French PRODIGE-12 study comparing gemcitabine plus oxaliplatin versus surveillance and a Japanese study comparing gemcitabine versus observation failed to demonstrate improvements in recurrence-free survival or OS after resection (46,47). In addition, other studies also suggest that CT has limited impact on the prognosis of resectable GBC (48). Therefore, whether adjuvant CT is necessary for resectable GBC remains a topic of debate, highlighting the urgent need for further high-quality research.

As for RT, our comprehensive review of six studies examining the impact of adjuvant RT on GBC patients post-surgery, the pooled analysis consistently showed a significant association between adjuvant RT and improved OS. Adjuvant RT is an indispensable component of adjuvant therapy for resected GBA. A study by Kamarajah et al. demonstrated that adjuvant RT significantly extended the survival of GBA patients after propensity score matching (PSM), even for those with negative margins and node metastasis (49). Furthermore, a meta-analysis of 21 clinical trials indicated that adjuvant RT not only improved OS but also reduced local recurrence rates in resected GBA patients (50). However, there are differing opinions. For example, the Itoh study analyzed the 5-year survival of 21 patients who underwent combination resection-RT versus resection alone and found no significant improvement in survival (51). This indicates that the effectiveness of RT for resectable GBC remains uncertain and requires further high-quality research to explore its potential benefits.

Regarding CRT, our study found that CRT is beneficial for the prognosis of patients with resectable GBC. This aligns with existing research findings. For example, Gold et al. reported that adjuvant CRT reduced the risk of death by 70% compared with surgery alone in stage I–II GBC patients who had undergone R0 resection (52). Similarly, Cho et al. found that adjuvant CRT after surgical resection (R0 and R1 resection in 38 and 2 patients, respectively) is beneficial for node-positive T2/T3 GBC patients (53). Furthermore, our study indicates that CRT provides better prognosis for GBC compared to CT or RT alone. RT is typically administered concurrently with CT, and most studies demonstrating the benefit of adjuvant RT have included patients treated with concurrent CT (54). Other researchers have also argued that adjuvant concurrent CRT provides an additional survival benefit over CT alone (24). Similarly, a study found that their current work confirms and expands on these findings in a more contemporary patient cohort. It goes beyond the existing literature by demonstrating that resection is associated with a survival benefit in lymph node-positive GBC (and immunohistochemistry), and that adjuvant CRT provides a survival benefit even after margin-negative resection for these patients (12). Therefore, we believe it is worthwhile to study the following question: Should resectable GBC suitable for CT be supplemented with RT to achieve comprehensive CRT as adjuvant therapy? To address whether resectable GBC suitable for CT should be supplemented with RT for comprehensive CRT, we propose a RCT. This trial would compare outcomes between two groups: one receiving adjuvant CRT and the other receiving CT alone. Key endpoints would include OS, DFS, and quality of life. Stratification by tumor stage and lymph node involvement would provide additional insights into the benefits of adding RT. This approach aims to offer robust evidence for optimizing adjuvant treatment strategies in resectable GBC.

Our subgroup analysis revealed that patients with high-risk factors, including but not limited to high TNM stage, R1 resection, absence of textbook outcome, and positive lymph nodes, showed more pronounced benefits when receiving adjuvant therapy (AT). This is consistent with previous findings. For instance, a meta-analysis conducted in 2012 by Horgan suggested that adjuvant CT or CRT indeed provided a survival benefit, particularly for patients with positive margins or nodes (55). Similarly, an article from 2022 found that stage II resected GBC patients with these high-risk features could be potential candidates for adjuvant treatment (19). This finding is highly significant because it could influence doctors’ treatment choices regarding adjuvant therapy for patients with high-risk factors. Reflecting on the potential of our study, it highlights the urgent need to refine treatment protocols for resectable GBC and informs clinical practice in optimizing adjuvant therapy strategies. While clear knowledge gaps remain regarding the optimal use of these therapies, our findings underscore their promise in improving patient outcomes. As researchers continue to explore these treatments, addressing these gaps through prospective, multi-center trials will be crucial. We anticipate that the next 5 years will witness significant advancements in understanding the molecular underpinnings of GBC and the integration of biomarkers, paving the way for more tailored therapeutic approaches. This evolving landscape may lead to improved survival rates and a better quality of life for patients, ultimately transforming the management of this challenging disease.

This study represents the first meta-analysis to investigate the prognostic effects of adjuvant therapy, including CT, RT, and CRT, on resectable GBC. However, it must be acknowledged that our study has some limitations. First, the majority of included studies were retrospective rather than RCTs, which affects the overall quality of evidence. Second, the heterogeneous nature of these studies, particularly the diversity in adjuvant therapy regimens, prevented standardization of specific treatment protocols, such as CT. Additionally, the presence of publication bias in studies examining the relationship between adjuvant therapy and OS suggests that our conclusions may require further scrutiny. Lastly, while we recognize the influence of high-risk factors on the efficacy of adjuvant therapy, our study was constrained by the limited number of original studies, necessitating a generalized classification under “high-risk features”. This variability underscores the need for more uniform studies to draw more robust conclusions.

Conclusions

Adjuvant therapy, including CT, RT, and CRT, significantly improves OS in patients with resected GBC. Despite high heterogeneity, pooled analyses show that CRT offers the greatest benefit, followed by RT and CT. Additionally, adjuvant therapy is particularly beneficial for GBC patients with poor postoperative prognostic factors.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-433/rc

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-433/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82002578), the Sichuan Science and Technology Program (Nos. 2022YSF0060, 2022YSF0114, 2022NSFSC0680, and 2023YFS0094), the 1·3·5 Project for Disciplines of Excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University (No. 20HXFH021), and the 1·3·5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. ZYJC21049).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-433/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.

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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