Challenges and innovations in adjuvant therapy for gallbladder cancer: a meta-analytic perspective

Although gallbladder cancer (GBC) is considered a rare cancer, it is the sixth most common cancer of the gastrointestinal tract in the US and accounts for nearly 2% of all cancer-related deaths worldwide with high incidence rates in Eastern Europe, East Asia and Latin America. It is more common in women and nutrition, infection with bacteria like Salmonella typhi or Helicobacter pylori and the presence of gallstones are potential risk factors (1), hinting at a contribution of host immunological factors in its pathogenesis. Treatment options, especially for advanced stages, are still limited and the overall prognosis remains poor. While surgical resection is a curative option, less than 50% of patients are eligible for surgery due to extensive locoregional disease, liver and/or distant metastases and the long-term survival is given with 5–12% only (2). High recurrence rates mandate further treatment but, surprisingly, the data on adjuvant chemotherapy, radiotherapy or radio-chemotherapy is not unanimously clear and the benefits of adjuvant chemotherapy remain under debate. Current guidelines recommend adjuvant therapy for selected high-risk patients, e.g., at T2 stage or higher, positive resection margins or positive lymph nodes (3,4).

Adjuvant chemotherapy is associated with modest survival benefits in patients with GBC. The BILCAP trial investigated adjuvant capecitabine and showed a survival benefit in the per-protocol analysis (which was not significant in the intention-to-treat analysis). The study enrolled various biliary tract cancers (n=223 in the capecitabine arm and n=224 in the control arm), including 39 GBC in the capecitabine arm and 40 GBC in the control arm indicating the heterogeneity of study data and the usually small numbers of GBC in such clinical trials (5). Nonetheless, these data are a strong basis to support adjuvant chemotherapy in resected GBC.

Adjuvant radiotherapy may provide a survival benefit in patients with R1 resection margins or advanced T stages, although its benefit in node-negative disease is less clear (6,7). Radiotherapy is limited by toxicity but is also explored in combination with chemotherapy using e.g., fluoropyrimidines as radiosensitizers. Yet, results for GBC are scarce but various studies demonstrated a (non-significant) trend to prolong overall survival (OS) for selected (node positive, higher stages, non-adenocarcinoma) patients (8,9).

The comprehensive meta-analysis by Zeng et al. is therefore of great value to understand the role of adjuvant therapies in resected GBC (10). Based on intensive database query of PubMed, Embase, and Web of Science until April 2024 in total 23 studies with 36,214 patients with GBC, with adjuvant therapy and with known clinical endpoints (such as OS, disease-free survival, and progression-free survival) and with reported hazard ratios were included in the meta-analysis containing real relevant data of evaluating the possible role adjuvant setting in GBC. The statistical analysis of this meta-analysis could demonstrate that adjuvant therapy could improve the OS depending on the specific type of adjuvant therapy, too. The subgroup analysis indicates more clinical benefit for high risk patients, especially with advanced disease stage regarding TNM-staging, microscopic cancer residuals after surgery (R1-situation) and older age. Looking in more detail of this meta-analysis revealed some kind of critical points regarding the investigated clinical trials, which are definitively realized and mentioned by the authors of this meta-analysis: (I) firstly, most of the included studies were retrospective rather than randomized controlled trials, which impacts the overall quality of the evidence. (II) Secondly, the heterogeneous nature of these studies, especially the variety in adjuvant therapy regimens, hindered the standardization of specific treatment protocols, such as chemotherapy. (III) Additionally, the presence of publication bias in studies examining the relationship between adjuvant therapy and OS suggests that the conclusions of the meta-analysis of Zeng et al. may need further scrutiny (10). (IV) Finally, although an influence of high-risk factors on the efficacy of adjuvant therapy was found, the recent meta-analysis by Zeng et al. was limited by the small number of original studies, necessitating a generalised classification under “high-risk features” (10). This variability highlights the need for more consistent trials to draw more robust conclusions.

As this review and meta-analysis by Zeng et al. is not the first attempt to evaluate the role of adjuvant therapeutic strategies in GBC and the associated influencing parameters, as shown in Table 1.

A search for meta-analyses on adjuvant therapy for GBC in PubMed reveals a total of 19 meta-analyses. However, only nine of these studies assess the impact of clinico-pathological characteristics on patient outcomes in relation to adjuvant treatment strategies. A common feature of all these meta-analyses is that they primarily include retrospective clinical studies with heterogeneous patient cohorts related to clinico-pathological characteristics and with heterogeneous therapy protocols. Nevertheless, all of them clearly identify possible clinico-pathological characteristics that necessitate adjuvant treatment which are lymph node-positivity, R1-resection status and American Joint Committee on Cancer (AJCC)-stage ≥ II, as shown in Table 1.

Besides larger studies, also novel therapeutic approaches like immunotherapy or targeted therapies must be explored in the adjuvant setting of GBC. Individual cases with GBC from studies enrolling other biliary tract cancers indicate that immune checkpoint inhibitors may also lead to a survival benefit. Yet, those studies (e.g., TOPAZ 1 or KEYNOTE-966) were usually not placed in the adjuvant setting (18-20). Several genetic alterations like IDH2 or FGFR2 alterations were described as oncogenic drivers in biliary tract cancers (21). GBC patients who harbor such actionable alterations (e.g., also NTRK fusions, Her2 amplifications or EGFR mutations) can be identified by the broad and routine use of next-generation sequencing technologies during diagnostic procedures and then receive the optimal treatment for the genetic profile of their respective tumor. Her2-targeting antibody-drug conjugates have achieved major breakthroughs in other cancer types. Considering an amplification rate of up 17% in GBC (22), studies with such agents are urgently needed. First case reports in advanced GBC patients support this hypothesis (23,24). Prospective studies are needed to confirm this novel treatment paradigm also in the adjuvant setting.

In conclusion, the comprehensive meta-analysis by Zeng et al. (10) fully supports the use of adjuvant therapies in resectable GBC, although there is still a bias towards so-called high-risk GBC patients with advanced disease stage in terms of TNM staging (including nodal positivity), microscopic cancer residuals after surgery (R1-sitution) and older age, which warrants additional studies, best as prospective randomised controlled trials. Due to the rarity of GBC, larger international collaborations are urgently needed to gain more insight into which patients with GBC are at higher risk of relapse or progression and which therapeutic regimen is best in each situation.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2024-725/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.

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