Adjuvant chemotherapy for gallbladder cancer: Current evidence, controversies, and future directions

Abstract

Gallbladder cancer is an aggressive malignancy notorious for its poor prognosis and treatment challenges, even at early stages. In their recent work, Kim et al utilized data from the National Cancer Database to explore whether adding chemotherapy to surgical intervention could improve survival outcomes for patients diagnosed with stage II gallbladder cancer. The use of adjuvant chemotherapy following curative surgery in this patient population has been a long-standing source of debate. Historically, the lack of clear guidelines for managing stage II gallbladder cancer has resulted in inconsistent, sometimes contradictory findings from various studies regarding the effectiveness of postoperative chemotherapy. Consequently, many clinicians have relied on studies involving other biliary tract cancers to justify the routine use of prophylactic chemotherapy after surgery, aiming to minimize recurrence risk. Given the rarity, high mortality rate, and the small sample sizes typical in gallbladder cancer studies, Kim et al’s contribution represents a significant and commendable effort to address these challenges. Kim et al designed a retrospective cohort study with well-defined inclusion criteria and clear treatment classifications. Notably, their findings suggested that in stage II gallbladder cancer, adjuvant chemotherapy did not yield a meaningful survival benefit over surgery alone. These results therefore casted doubt on the routine practice of administering chemotherapy to all patients postoperatively, prompted clinicians to reconsider their approach. Furthermore, this controversy directly influences clinical decisionmaking and guideline recommendations, as uncertainty regarding the benefit of adjuvant chemotherapy may lead to heterogeneous practices across different institutions and regions. This article critically assessed the research design, methodology, and clinical implications of the study by Kim et al. It also provided an in-depth exploration of the broader question regarding the appropriateness of adjuvant chemotherapy following surgery for stage II gallbladder cancer, highlighting the necessity of rigorous study designs to produce reliable evidence.

Key Words: Gallbladder cancer; Adjuvant chemotherapy; National Cancer Database; Retrospective analysis; Cancer staging

Core Tip: Whether patients with stage II gallbladder cancer should routinely receive adjuvant chemotherapy after surgery remains uncertain. The analysis by Kim et al, based on National Cancer Database data, found no statistically significant survival benefit associated with chemotherapy in these patients. However, the results should not be hastily interpreted as evidence against chemotherapy altogether. Instead, clinicians must consider individualized treatment decisions based on pathological features and the patient’s overall health condition. This article further evaluated the strengths and weaknesses of Kim et al’s research design. It recommended conducting future studies, ideally prospective clinical trials or refined retrospective analyses, to better clarify chemotherapy’s role in this context.

TO THE EDITOR

Gallbladder cancer is a rare but highly lethal malignancy, with only a small proportion of patients diagnosed at an early stage. Although surgery remained the cornerstone of curative treatment, there was ongoing controversy regarding the use of adjuvant chemotherapy after surgery in patients with stage II gallbladder cancer. Previous studies have predominantly focused on advanced or unresectable cases, resulting in a lack of robust evidence concerning adjuvant therapy for early-stage gallbladder cancer. The high risk of recurrence after gallbladder cancer surgery poses a significant clinical challenge, as the 5-year survival rate following curative resection is less than 40%, with over two-thirds of patients experiencing recurrence within 5 years[1]. Consequently, considerable attention has long been devoted to exploring perioperative treatments aimed at reducing the risk of recurrence. The primary objective of adjuvant chemotherapy is to eradicate residual disease and thereby lower the risk of relapse[2]. However, current research on adjuvant therapy following gallbladder cancer surgery has produced conflicting results. Kim et al[3] conducted a retrospective analysis based on National Cancer Database (NCDB) data to determine whether adjuvant chemotherapy confers an additional survival benefit for patients with stage II disease. The significance of this study lies in its effort to fill the evidence gap regarding adjuvant treatment in the stage II population and in offering new conclusions on the efficacy of postoperative adjuvant chemotherapy in gallbladder cancer.

RECENT ADVANCES IN GALLBLADDER CANCER TREATMENT

In recent years, rapid advancements in molecular biology and precision medicine have continually updated the strategies for adjuvant treatment in gallbladder cancer. Currently, the main approaches for postoperative adjuvant therapy in gallbladder cancer include chemotherapy, radiotherapy (RT), and emerging monoclonal antibody-targeted therapies[4]. Traditionally, adjuvant chemotherapy often employed agents such as capecitabine, gemcitabine, and 5-fluorouracil, aiming to eliminate any microscopic residual disease following surgery and thereby reduce the risk of recurrence[5]. RT, on the other hand, was used in patients with a higher risk of local recurrence, employing high-energy radiation to destroy any remaining cancer cells. In recent years, the advent of immunotherapy has brought new hope to the adjuvant treatment of gallbladder cancer. Combination regimens such as pembrolizumab with gemcitabine and cisplatin, as well as durvalumab with gemcitabine and cisplatin, have been approved for the treatment of biliary tract cancers, demonstrating favorable clinical efficacy and tolerability, and providing patients with more therapeutic options[6]. However, some studies have also indicated that adjuvant chemotherapy alone may have a limited impact on improving the overall survival (OS) of gallbladder cancer patients, suggesting that a single treatment modality might not fully address the complex biological characteristics of the disease[6-9]. Furthermore, recent research has reported preliminary results on the use of photodynamic nanoparticles for targeted tumor therapy[8]. This novel nanotechnology aimed to enhance the precision of drug delivery and therapeutic efficacy, although it is still in the early stages of clinical exploration. Beyond these conventional modalities, novel approaches such as immunotherapy and nanotechnology are gaining attention as complementary adjuvant strategies. Despite the emergence of these innovative techniques, adjuvant chemotherapy remains the mainstream postoperative treatment approach in clinical practice, owing to its well-established clinical data and extensive experience[9].

DIFFERENT POSTOPERATIVE ADJUVANT TREATMENT APPROACHES

In adjuvant chemotherapy, the commonly used drugs and regimens were shown in Table 1. According to the clinical practice guidelines of the American Society of Clinical Oncology, it was recommended that patients receive 6 months of capecitabine adjuvant chemotherapy after surgery to reduce the risk of recurrence and improve survival[7]. A meta-analysis has demonstrated that fluoropyrimidine-based agents (such as capecitabine) may be the most effective adjuvant chemotherapy regimens, significantly improving OS and event-free survival[8]. An Indian phase I clinical trial (GECCOR-GB) evaluated the efficacy of gemcitabine combined with cisplatin (gemcitabine and cisplatin regimen) vs capecitabine combined with concurrent chemoradiotherapy in patients following gallbladder cancer surgery[10]. The results showed that both regimens had a certain degree of efficacy, but it was not clearly established which regimen was superior. In stage II gallbladder cancer, adjuvant chemotherapy, RT, immunotherapy, and targeted therapies each offer distinct evidence levels and toxicity profiles: Chemotherapy is supported by randomized trials, RT by retrospective series, immunotherapy by earlyphase studies (pembrolizumab plus gemcitabine/cisplatin), and targeted therapy data are emerging in molecularly selected subgroups (HER2amplified tumors)[11].

Table 1 Adjuvant chemotherapy regimens for gallbladder cancer.

Regimen	Composition	Ref.
Gemcitabine monotherapy	Gemcitabine	Lamarca et al[2], 2022
5-FU/LV	5-FU + LV	Shroff et al[8], 2019
Capecitabine monotherapy	Capecitabine	Shroff et al[8], 2019
Gemcitabine + cisplatin	Gemcitabine + cisplatin	Casak et al[5], 2024
Gemcitabine + oxaliplatin	Gemcitabine + oxaliplatin (GEMOX)	Sharma et al[6], 2025
S-1 monotherapy	Tegafur/gimeracil/oteracil (S-1)	Pavlidis et al[4], 2024

The choice of regimen depends on various factors, including patient tolerance, tumor characteristics, and regional treatment guidelines. 5-FU: 5-fluorouracil; LV: Leucovorin.

FUTURE RESEARCH DIRECTIONS

Although numerous prospective studies on adjuvant treatment for gallbladder cancer have been conducted, the final conclusions remain inconsistent. For future research, emphasis should be placed on the following directions. Firstly, to eliminate the inherent selection bias present in retrospective studies, it is imperative to design and conduct multicenter prospective randomized controlled trials to clarify the true benefit of adjuvant chemotherapy in patients with stage II gallbladder cancer. In particular, stratified designs that differentiate between low-risk and high-risk patients will help to accurately identify the subgroup that truly benefits from adjuvant therapy[6]. Additionally, stratification by pathological T3/T4 stage, N+ status, and resection margin involvement should be combined with liquid biopsy-based circulating tumor DNA and minimal residual disease monitoring to define highrisk cohorts for prospective trials[12]. Secondly, with advances in molecular biology and genomics, future studies should explore the molecular subtypes of gallbladder cancer and identify biomarkers related to prognosis and chemotherapy sensitivity[13]. Prospective biomarker studies focusing on excision repair cross-complementing group 1 low expression, ribonucleotide reductase M1 high expression, HER2 amplification, and isocitrate dehydrogenase 1/2 mutations are essential to personalize adjuvant regimens and avoid ineffective toxicity[14,15]. These findings could support more individualized treatment strategies that incorporate both pathological staging and tumor biology. Thirdly, the exploration of emerging therapies, such as immunotherapy and targeted therapy, should continue. For example, combining immune checkpoint inhibitors like pembrolizumab or durvalumab with standard chemotherapy, or evaluating their roles in neoadjuvant and adjuvant settings, may further improve survival and quality of life. Moreover, comparative studies of neoadjuvant vs adjuvant chemotherapy schedules in gallbladder cancer are warranted to determine optimal timing of systemic therapy and its relative impact on OS[16]. Lastly, before launching new prospective trials, researchers can make use of advanced statistical techniques - such as propensity score matching, multivariate regression, and machine learning - to conduct more refined analyses using existing large databases like NCDB and Surveillance, Epidemiology, and End Results. Leveraging complementary datasets and applying robust matching methods will further improve the causal inference from observational data. Integrating data from international multicenter studies will also be critical in validating the real-world effectiveness of different treatment strategies and bridging current evidence gaps.

LIMITATIONS AND CHALLENGES OF THE STUDY

Kim et al’s study provided a new perspective on the choice of adjuvant treatment following surgery for gallbladder cancer[3]. It demonstrated that adjuvant chemotherapy does not improve survival in patients with stage II gallbladder cancer. However, future research must acknowledge and address several apparent limitations. For instance, differences in patient performance status (e.g., American Society of Anesthesiologists scores) and timing of surgery (e.g., delays beyond six weeks) were not adjusted for and may have influenced outcomes; quantitative adjustment via hierarchical analysis or propensity score matching was not conducted. First, although the authors selected the large NCDB database and specifically focused on stage II patients, significant differences in baseline characteristics remained between the chemotherapy and non-chemotherapy groups. It was difficult to ascertain the impact of patients’ preoperative health status and the timing of surgery on prognosis.

Second, by nature, this study can only demonstrate associations rather than causation. Selection bias was a major concern because chemotherapy was not assigned randomly. Physicians may have favored treating patients considered high-risk. According to the statistical analysis section of Kim et al[3], only χ² tests for categorical variables and independentsample/paired t-tests for continuous variables were performed, with no multivariate regression analyses or propensity score matching applied to adjust for potential confounding factors[16]. Moreover, the study lacked detailed descriptions of the tumor biological characteristics and the specific chemotherapy regimens chosen for these patients.

Third, the NCDB reported OS rather than disease-free survival (DFS). Although chemotherapy may delay recurrence, exclusive reporting of OS fails to capture DFS benefits; incorporating DFS as a secondary endpoint would better assess early recurrences and the direct effects of adjuvant therapy[17]. Although chemotherapy may delay recurrence, it might not ultimately improve OS, especially if subsequent treatments compensate for initial differences, resulting in similar final OS between the two groups. This subtlety cannot be captured when only OS was analyzed. Finally, treatment approaches for gallbladder cancer vary across different countries and regions. It is difficult to discern the specific chemotherapy regimens selected by patients in this study. Consequently, the results may have had limited generalizability to other regions.

CONCLUSION

Kim et al’s study, through a large-scale retrospective analysis, provided a new perspective on the controversial issue of whether adjuvant chemotherapy should be administered following surgery for stage II gallbladder cancer[3]. The findings indicated that, overall, adjuvant chemotherapy did not significantly improve the OS of stage II patients, suggesting that for patients lacking high-risk features, surgery alone may be sufficient to achieve optimal outcomes. These studies highlighted the need for multidisciplinary consensus and timely guideline updates to inform clinical decision-making, ensuring that uncertainty around adjuvant chemotherapy does not result in inconsistent practices. However, due to limitations in the study design and the absence of critical clinical information in the data, the current evidence is insufficient to completely dismiss the potential value of adjuvant chemotherapy. Future research should employ high-quality prospective trials, molecular subtyping studies, and the integration of international multicenter data to further clarify which patients might benefit from adjuvant therapy, thereby advancing gallbladder cancer treatment toward a more precise and individualized approach. Additionally, future database studies can further enhance the level of evidence by utilizing methods such as propensity score matching, subgroup analyses, and molecular marker identification. For such a rare yet highly lethal cancer, individualized decision-making and multidisciplinary collaboration remain key to improving treatment outcomes.

ACKNOWLEDGEMENTS

We appreciate the constructive comments provided by the anonymous reviewers, which greatly improved the quality of this manuscript.