Survival gap in gallbladder cancer: Bridging tumor biology and healthcare system logistics

Abstract

Gallbladder cancer (GBC) remains one of the most lethal gastrointestinal malignancies, characterized by aggressive biology and poor survival. Despite advances in molecular profiling and systemic therapies, innovations have not translated into proportional survival gains in many regions, suggesting underrecognized determinants of prognosis. In this opinion review, we argue that healthcare system logistics represent a critical, modifiable factor influencing GBC outcomes. In intermediate-incidence settings, such as Latin America, many cases are diagnosed incidentally following cholecystectomy. In this context, timely referral for radical re-resection represents a critical component of curative-intent management; however, delays in diagnosis and staging frequently compromise this therapeutic window. Emerging evidence indicates that system-level inefficiencies may impact survival more than traditional clinical variables. We explore the interplay between tumor biology and healthcare delivery, highlighting molecular stratification, surgical centralization, and multidisciplinary coordination. Additionally, we address controversies in incidental GBC, including optimal timing of re-resection and perioperative systemic therapy. We propose that healthcare logistics be formally recognized as a prognostic factor. Bridging the survival gap requires both oncologic advances and structural optimization of care pathways to ensure timely access to curative treatment.

Key Words: Gallbladder carcinoma; Incidental gallbladder cancer; Healthcare logistics; Referral pathways; Radical re-resection; Molecular stratification; Neoadjuvant therapy; Real-world evidence; Therapeutic window; Hepatobiliary surgery

Core Tip: Gallbladder cancer (GBC) prognosis is traditionally viewed through the lens of aggressive tumor biology. However, in intermediate-incidence regions like Brazil, systemic fragmentation often prevents curative intent. This opinion review proposes a paradigm shift: Classifying healthcare logistics as a modifiable prognostic factor. By integrating molecular stratification, focusing on TP53 and HER2, with logistical “auto-alerts” and neoadjuvant “biological filters”, we can bridge the survival gap. Optimizing the “therapeutic window” between incidental diagnosis and radical surgery is as crucial as the surgical technique itself in transforming GBC outcomes.

INTRODUCTION

Gallbladder carcinoma (GBC) remains one of the most aggressive and lethal malignancies of the gastrointestinal tract. Contemporary global epidemiological data continue to demonstrate marked geographic disparities, with disproportionately high incidence rates observed in specific regions of Asia and South America[1,2]. However, GBC should not be regarded solely as a disease confined to high-incidence areas. Evidence from Latin America further reinforces the existence of regional inequalities in incidence and mortality[3], while population-based analyses suggest that healthcare system performance may significantly influence outcomes across different settings[4].

The aggressive nature of GBC is further compounded by its typically late diagnosis, contributing to poor survival outcomes across different healthcare systems[1,2]. Although the international literature has extensively focused on molecular characterization and the development of targeted therapies, real-world clinical practice often reveals a different reality. In many settings, the therapeutic “window of opportunity” is frequently missed, not due to lack of technological resources, but rather as a consequence of inefficiencies in referral pathways between the initial cholecystectomy, commonly performed for presumed benign disease, and the timely completion of radical re-resection required to achieve oncological adequacy[3,4]. This issue is particularly relevant in the context of incidental GBC (iGBC), in which early-stage disease is unexpectedly identified after cholecystectomy and outcomes are critically dependent on timely and appropriate surgical management.

In this opinion review, we propose that, beyond surgical and oncological advances, healthcare system logistics should be recognized as a critical and modifiable prognostic factor in the management of iGBC.

GLOBAL TRENDS AND DEMOGRAPHIC PROFILE OF GALLBLADDER CANCER

GBC exhibits a striking geographic heterogeneity, with a 100-fold variation in incidence rates across populations worldwide[5]. In 2022, an estimated 122491 new cases and 89055 deaths occurred globally, with projections indicating a 65% increase in incidence by 2042[6].

Geographic distribution: Global hotspots

The highest age-standardized incidence rates (ASR) are concentrated in two distinct geographic clusters: The Andean region of South America and the “Gangetic belt” of Northern India[5,6]. Among females, the highest recorded rates are observed in Southern Chile (ASR: 15.4-27 per 100000) and Northeastern India (ASR: 14.9-21.5 per 100000), followed by Poland (14 per 100000), South Pakistan (11.3 per 100000), and Japan (7 per 100000)[5,7]. Bolivia exhibits the highest national ASR globally (21.0 per 100000 in females)[5,6]. In contrast, the lowest incidence rates are reported in Sub-Saharan Africa, with ASR as low as 0.14-0.21 per 100000 in Uganda and South Africa[5].

In absolute numbers, Asia carries the greatest burden, with India and China contributing the majority of global cases[6]. However, national averages often mask substantial subnational heterogeneity. In India, 84.6% of cases are concentrated among residents or migrants from the Gangetic belt, where geographic origin itself constitutes an independent risk factor (odds ratio: 3.3)[7,8]. Similarly, in Chile, elevated incidence is strongly associated with Mapuche ancestry, and multifactorial risk models incorporating genetic markers have been shown to refine selection for prophylactic cholecystectomy[9].

Demographic profile: Age and gender

GBC is one of the few malignancies with a marked female predominance. Globally, 64.5% of new cases and 64.7% of deaths occur in women[5]. This female predilection is particularly pronounced in high-incidence regions, where rates in women are approximately two to three times higher than in men[5,7]. In the United States, Hispanic women have the second highest incidence after American Indian/Alaska Native women, with rates double those of non-Hispanic White women (2.5 vs 1.1 per 100000)[10].

The disease predominantly affects older adults, with over half of cases and deaths occurring in individuals aged 50-74 years[6]. The incidence rises progressively with age, and population aging is a major driver of the increasing absolute burden, particularly in low- and middle-SDI regions[6]. Notably, an increasing incidence trend has been observed among males and younger individuals (< 50 years) in some populations, warranting enhanced surveillance[6].

Incidental vs non-iGBC

Approximately 50%-70% of GBC cases in high-income settings are diagnosed incidentally following cholecystectomy for presumed benign disease[11,12]. The incidence of iGBC ranges from 0.19%-1% of all cholecystectomies, depending on the population and indication[13,14]. Patients with iGBC tend to present at earlier stages and have significantly better survival outcomes compared to those with non-incidental (symptomatic) disease[7,12]. In a large cohort from Chile and Argentina, median survival was 32.3 months for iGBC vs 5.8 months for suspected GBC[7].

However, the survival advantage of iGBC is not solely attributable to earlier stage at diagnosis. Lead-time bias and the opportunity for radical re-resection play critical roles[7,11]. Importantly, up to 60% of iGBC cases are pT2 tumors, and the presence of residual disease at re-exploration, identified in 35%-53% of patients, remains the strongest predictor of poor outcomes[7,15-17].

Socio-demographic inequalities and healthcare system performance

Beyond biologic and geographic factors, socio-demographic inequalities profoundly influence GBC outcomes. The mortality-to-incidence ratio (MIR) serves as a surrogate of healthcare system effectiveness: While North America reports a favorable MIR of 0.40, Africa approaches 1.00, reflecting near-universal mortality due to late diagnosis and limited surgical access[16]. Countries with higher Human Development Index and lower corruption indices demonstrate more favorable MIRs[16].

In middle-incidence settings such as Brazil, these disparities are reflected in clinical outcomes. A recent study from a high-volume center reported that 72.3% of patients present with stage IV disease, only 13.5% are eligible for radical surgery, and median survival for non-iGBC is just 7 months[18]. In India, 60% of patients present with metastatic disease, and socioeconomic factors, such as unemployment, are significantly associated with treatment discontinuation[7].

These findings underscore that survival in GBC is not determined solely by tumor biology, but by the ability of healthcare systems to deliver timely, specialized, and oncologically adequate care.

LATIN AMERICAN SCENARIO AND THE “MORTALITY PARADOX

Latin America exhibits a distinct epidemiological profile for GBC when compared with high-income regions. Contemporary global analyses indicate that several countries in this region present disproportionately elevated mortality rates relative to incidence, highlighting an unfavorable mortality-to-incidence ratio that contrasts with patterns observed in more developed healthcare systems[5,6]. This heterogeneity across Latin America and the Caribbean reflects not only potential biological and environmental differences, but more critically, substantial disparities in access to specialized oncological care.

This regional landscape is characterized by what may be conceptualized as a “mortality paradox”. Despite the progressive expansion of knowledge regarding GBC biology and management, the translation of this evidence into improved clinical outcomes remains inconsistent. In practical terms, advances in diagnosis and surgical strategy have not been uniformly incorporated into routine care, particularly in resource-constrained settings[6].

For GBC, a disease in which curative intent is highly dependent on the timely performance of radical re-resection, this gap becomes especially consequential. Emerging data from Brazil reinforce that delays in referral and the fragmentation of perioperative care pathways are central determinants of suboptimal outcomes, even in the presence of potentially curable disease[18]. In this context, analyzing patient flow and healthcare system logistics is not merely a local concern, but rather a critical step toward understanding why Latin America continues to struggle in converting early or incidental diagnoses into meaningful long-term survival.

MOLECULAR LANDSCAPE: FROM DRIVER MUTATIONS TO THERAPEUTIC TARGETS

The biological behavior of GBC is driven by a complex and heterogeneous genomic landscape. Over the past decade, molecular characterization has evolved from the mere identification of genetic alterations to a more integrated understanding of pathogenic mechanisms with direct clinical relevance. GBC is consistently associated with a high prevalence of TP53 mutations, frequently linked to chromosomal instability and aggressive tumor phenotypes[19,20].

More recently, advances in whole-exome sequencing and integrative multi-omic analyses have expanded this framework, revealing a broader spectrum of actionable molecular targets. In addition to TP53, recurrent alterations in genes such as ERBB2 (HER2), PIK3CA, and ARID1A have emerged as critical drivers with therapeutic implications[21,22]. Furthermore, integrative genomic and transcriptomic studies suggest that GBC is not defined solely by isolated mutations, but by complex molecular subtypes shaped by tumor microenvironment interactions and dysregulated signaling pathways[23-25].

From our perspective, this growing molecular clarity must be incorporated into clinical decision-making beyond systemic therapy. In the setting of iGBC, specific genomic alterations may function as a surrogate of tumor kinetics—a “biological clock” reflecting the likelihood of early systemic dissemination.

HER2-targeted therapies: A new paradigm in precision oncology

The therapeutic landscape of biliary tract cancers, particularly GBC, has undergone a significant transformation with the validation of human epidermal growth factor receptor 2 (HER2) as a clinically actionable target. Historically, systemic treatment was largely limited to gemcitabine-based chemotherapy, with modest survival benefits. However, recent advances in targeted therapy have redefined treatment possibilities in this setting[26].

A major milestone in this evolution was the demonstration of clinically meaningful activity of antibody-drug conjugates in HER2-expressing disease. The HERB trial established trastuzumab deruxtecan as a highly active agent in previously treated biliary tract cancers, including GBC, with durable responses observed even in heavily pretreated patients[27].

In our view, these developments necessitate a paradigm shift in the management of iGBC. Traditionally, treatment strategies have focused predominantly on surgical parameters, such as margin status and lymphadenectomy. However, in the era of precision oncology, molecular characterization, particularly HER2 status, should be incorporated into the initial pathological assessment following cholecystectomy. In intermediate-incidence settings, early identification of HER2-positive tumors may facilitate access to clinical trials or neoadjuvant strategies, potentially converting patients at risk of progression during referral delays into candidates for curative-intent treatment with improved systemic control.

TP53 mutations and the biological clock of GBC progression

Despite the emergence of targeted therapies, TP53 remains the most prevalent genomic alteration in GBC and a key determinant of tumor aggressiveness[19]. Increasing evidence suggests that TP53 mutations occur early in the carcinogenic process, with a stepwise accumulation from pre-malignant conditions to invasive carcinoma[28].

This progressive acquisition of genomic instability implies that, by the time GBC becomes clinically apparent, or is incidentally detected during cholecystectomy, the tumor may already harbor advanced molecular alterations associated with rapid progression. In addition, genomic profiling studies indicate that these alterations extend beyond single-gene mutations, involving key pathways related to DNA repair, apoptosis, and cell cycle control[29].

From a clinical standpoint, TP53 mutations may reflect a more aggressive tumor phenotype and could serve as a surrogate of tumor kinetics. In patients with iGBC, particularly in healthcare systems with known logistical delays, the presence of such alterations may indicate a significantly reduced window for curative intervention. Consequently, delays in referral and re-resection should not be viewed merely as administrative inefficiencies, but as factors that directly interact with tumor biology, potentially leading to irreversible disease progression.

Immunotherapy era: Insights from TOPAZ-1 and KEYNOTE-966

The integration of immune checkpoint inhibitors has marked a new era in the systemic treatment of biliary tract cancers. Two landmark phase III trials have established chemoimmunotherapy as the new first-line standard of care for advanced disease.

The TOPAZ-1 trial, demonstrated that durvalumab combined with gemcitabine and cisplatin significantly improved overall survival compared to chemotherapy alone, with a median overall survival (OS) of 12.9 months vs 11.3 months [hazard ratio (HR): 0.76; 95%CI: 0.64-0.91]. At the 3-year follow-up update, the 24-month OS rate was 23.6% vs 11.5%, and the 36-month OS rate was 14.6% vs 6.9%, with 17.0% of patients in the durvalumab arm qualifying as extended long-term survivors (≥ 30 months) compared to 8.7% in the placebo arm[30].

Similarly, the KEYNOTE-966 trial, confirmed these findings with pembrolizumab plus gemcitabine and cisplatin, demonstrating a median OS of 12.7 months vs 10.9 months (HR: 0.83; 95%CI: 0.72-0.95; P = 0.0034). At the 3-year follow-up (median 36.6 months), the OS benefit was maintained (HR: 0.86; 95%CI: 0.75-0.98), with 24-month OS rates of 24.6% vs 19.2% and a median duration of response of 8.3 months vs 6.9 months[31].

These advances have effectively redefined the first-line treatment paradigm, moving beyond the long-standing reliance on cytotoxic regimens alone. Importantly, as highlighted in translational analyses from these and other studies, the benefit of chemoimmunotherapy appears to be influenced by tumor biology, including factors such as tumor mutational burden and immune microenvironment characteristics, which are closely associated with the genomic instability and molecular subtypes previously described in GBC[23-25].

In our perspective, the emergence of effective immunotherapy has important implications for iGBC. While these therapies offer new opportunities for systemic disease control, their optimal impact is highly dependent on appropriate timing within the disease course. In healthcare systems characterized by delays in surgical referral, patients may progress beyond the curative setting before receiving definitive treatment.

Therefore, rather than compensating for systemic inefficiencies, the immunotherapy revolution arguably amplifies the need for optimized care pathways. Ensuring rapid coordination between initial diagnosis, molecular characterization, and definitive surgical management is essential to maintain patients within a potentially curative window, where both surgical and systemic therapies can be effectively integrated.

EMERGING STRATEGIES FOR EARLY DETECTION

Recent advances in GBC detection have increasingly focused on innovative diagnostic technologies aimed at improving early-stage identification. In particular, radiomics and artificial intelligence (AI)-based imaging analysis have emerged as promising tools to enhance the diagnostic accuracy of conventional imaging modalities. By extracting high-dimensional quantitative features from standard computed tomography (CT) scans, radiomics has demonstrated the ability to significantly improve lesion characterization when combined with traditional radiological assessment, with reported area under the curve values approaching 0.98 in differentiating malignant from benign gallbladder lesions in selected cohorts[32].

In parallel, deep learning models applied to contrast-enhanced CT imaging have shown robust performance in distinguishing GBC from benign conditions, in some cases reaching diagnostic accuracies comparable to or exceeding expert radiologists[33]. Similarly, AI-enabled ultrasound platforms evaluated in prospective cohorts have demonstrated sensitivities exceeding 90%, highlighting their potential as accessible and non-invasive tools for early detection, particularly in high-risk populations[34].

These technological advances represent a paradigm shift in the diagnostic approach to GBC, with the potential to move beyond subjective image interpretation toward more standardized and reproducible frameworks. In theory, such tools could facilitate earlier detection, improve risk stratification, and support clinical decision-making prior to surgical intervention.

However, from a pragmatic perspective, important limitations must be acknowledged. In middle-income healthcare systems, including Brazil, the implementation of AI-driven imaging and radiomics is constrained by cost, limited infrastructure, and lack of standardization. Moreover, the inherently aggressive biology of GBC means that even with improved diagnostic tools, a substantial proportion of patients will still present with advanced disease.

Therefore, while these emerging technologies hold significant promise, their current impact remains largely restricted to specialized centers. In contrast, the most immediately actionable strategy for improving outcomes continues to be the systematic identification of iGBC through routine histopathological evaluation and the timely execution of radical re-resection when indicated, given its well-established association with survival outcomes[17].

SURGICAL MANAGEMENT AND THE DILEMMA OF NODAL STAGING

The adequacy of lymphadenectomy remains one of the most debated technical aspects in the surgical management of GBC. Current international guidelines recommend the evaluation of at least six lymph nodes to ensure accurate pathological staging[35]. However, a substantial discrepancy persists between these recommendations and real-world practice, particularly in non-specialized centers.

Quantitative threshold: Is six always the magic number?

Available evidence suggests that the recommended threshold of ≥ 6 lymph nodes is infrequently achieved in routine clinical practice. Large database analyses have demonstrated that only a minority of patients undergo adequate lymphadenectomy, despite its clear association with improved survival outcomes[36]. Importantly, achieving this threshold has been linked to significant survival benefits in both node-negative and node-positive disease.

Nevertheless, the universal applicability of this benchmark remains controversial. In a large National Cancer Database analysis of 6531 patients, demonstrated that the median number of lymph nodes evaluated was only 2 (interquartile range: 1-5), and that merely 21.1% of patients achieved the American Joint Committee on Cancer recommended threshold of ≥ 6 nodes. Using a machine-learning approach, the authors identified that evaluation of fewer than 4 lymph nodes was associated with a significantly higher hazard of death compared to the 4-7 node group (HR: 1.27; 95%CI: 1.16-1.40; P < 0.001), whereas patients with 4-7 and > 7 nodes evaluated had comparable long-term mortality (HR: 1.10; 95%CI: 0.98-1.24; P = 0.11). These findings suggest that while obtaining ≥ 6 nodes may be challenging in routine practice, evaluation of at least 4 lymph nodes represents a more pragmatic and achievable threshold associated with optimal staging accuracy and survival outcomes[37].

These findings raise a critical question: Should surgical quality be defined by rigid numerical targets, or by context-adapted standards that better reflect real-world constraints?

Incidental GBC: Staging vs therapeutic benefit

The management of iGBC introduces additional complexity to the role of lymphadenectomy. While lymph node dissection is traditionally considered essential for staging, its direct therapeutic benefit remains a matter of debate, particularly in early-stage disease.

Evidence from population-based and registry studies supports the role of radical re-resection in improving survival, especially in patients with T2 or more advanced disease[38,39]. This benefit is closely tied to the identification of nodal disease, which would otherwise remain undetected in patients undergoing simple cholecystectomy.

Furthermore, tumor-specific factors such as location within the gallbladder have been shown to influence both lymphatic spread and prognosis, reinforcing the importance of tailored surgical strategies[40]. Similarly, the role of extended procedures, such as extra-hepatic bile duct resection, remains controversial; with current evidence suggesting that its routine use may not provide additional survival benefit and should be selectively applied[41].

Beyond the extent of lymphadenectomy, appropriate patient selection for surgical exploration remains equally critical. Emerging evidence supports the role of staging laparoscopy as a valuable tool to detect occult metastatic disease and avoid non-therapeutic laparotomies in patients with GBC[42,43]. Similarly, functional imaging with 18F-fluorodeoxyglucose positron emission tomography has demonstrated additional diagnostic value in identifying distant disease not detected on conventional imaging, potentially refining preoperative staging and surgical decision-making[44].

Taken together, these findings reinforce that optimal management of iGBC depends not only on the adequacy of nodal dissection, but also on accurate preoperative staging strategies that guide appropriate patient selection for surgery.

Qualitative refinements: Lymph node ratio and nodal stations

Beyond the absolute number of retrieved lymph nodes, qualitative metrics have emerged as more refined prognostic indicators. The lymph node ratio (LNR), defined as the proportion of metastatic to examined nodes, has been shown to provide superior prognostic stratification compared to nodal count alone. Recent analyses indicate that an LNR ≥ 30% is strongly associated with significantly worse survival outcomes[45].

In addition, the anatomical distribution of nodal involvement appears to play a critical role. Multi-station lymph node metastasis has been identified as an independent predictor of recurrence and reduced disease-free survival, suggesting that the pattern of dissemination may carry greater prognostic weight than the total number of positive nodes[46].

These observations reinforce that nodal staging in GBC is not merely quantitative, but fundamentally biological.

From our perspective, these surgical nuances reinforce the importance of centralization in the management of GBC. Higher lymph node yields and adherence to oncologic principles are consistently associated with improved survival outcomes[47].

We argue that lymphadenectomy should not be viewed solely as a technical component of surgery, but rather as a measurable indicator of quality within an integrated oncologic care pathway. This perspective aligns with expert consensus recommendations emphasizing standardized surgical strategies and multidisciplinary management in GBC[48].

CONTROVERSIES IN INCIDENTAL GBC MANAGEMENT: TIMING, BIAS AND CENTRALIZATION

The clinical management of iGBC is defined by three interrelated controversies: The influence of lead-time bias, the optimal timing of radical re-resection, and the impact of surgical centralization[11,16]. Rather than isolated technical debates, these axes collectively challenge traditional surgical dogma and highlight the need for a more biologically and system-oriented approach to care.

Lead-time bias: Staging vs therapeutic intervention

The improved survival observed in iGBC compared to primary GBC is, at least in part, attributable to lead-time bias. Earlier diagnosis at the time of elective cholecystectomy advances the point of detection without necessarily modifying the underlying tumor biology[11,16].

In this context, the role of re-resection extends beyond a purely therapeutic intervention. We argue that revision surgery functions primarily as the most accurate staging tool available, identifying patients with occult advanced disease who are unlikely to benefit from aggressive surgical strategies. Conversely, it enables appropriate selection of patients who may derive benefit from multimodal treatment approaches, including systemic therapy.

This perspective reframes re-resection not simply as a standard step, but as a biological filter—distinguishing indolent from aggressive disease.

Timing of re-resection: Challenging the 4-8 weeks window

The optimal interval between index cholecystectomy and re-resection remains one of the most debated issues in GBC management. A landmark multi-institutional analysis established the widely adopted paradigm that reoperation between 4 weeks and 8 weeks is associated with the most favorable survival outcomes[49].

However, more recent evidence has challenged this rigid timeframe. Data suggest that extended intervals, particularly when utilized for patient optimization or neoadjuvant therapy, may be associated with improved oncologic outcomes in selected patients[50]. This is further supported by a recent meta-analysis demonstrating no significant survival difference between early and delayed re-resection strategies[51].

The ongoing OPT-IN (EA2197) trial is expected to redefine this paradigm by evaluating the role of neoadjuvant systemic therapy in this setting, potentially transforming what has traditionally been viewed as a “waiting period” into a “therapeutic window”[52].

Importantly, additional technical dogmas have also been questioned. For example, routine port-site excision has not demonstrated a survival benefit and should no longer be considered standard practice[53].

Collectively, these findings suggest that timing should not be dictated by arbitrary intervals, but rather individualized based on tumor biology, patient condition, and systemic treatment strategy.

Centralization: The most impactful modifiable factor

Among all variables in iGBC management, centralization emerges as the most impactful and modifiable determinant of outcomes. High-quality surgery (HQS), defined as adequate hepatic resection, proper lymphadenectomy (≥ 6 nodes), and negative margins, is achieved in only 9.6% of patients, yet is associated with a median overall survival more than double that of low-quality surgery (55.1 months vs 25.5 months, P < 0.001). Importantly, adjuvant chemotherapy cannot rescue the survival deficit caused by inadequate surgery (27.9 months vs 55.1 months, P < 0.001), reinforcing that the index surgical strategy remains the cornerstone of curative intent[54].

Healthcare system factors play a decisive role in this context. In a propensity-matched analysis of 7967 patients from the National Cancer Database (NCDB), treatment at academic cancer centers (ACCs) was independently associated with improved overall survival compared to community cancer centers (median OS 20.99 months vs 17.68 months; adjusted HR: 0.876, 95%CI: 0.801-0.958, P = 0.004), with high-volume ACCs demonstrating the greatest benefit[55]. Furthermore, Melillo et al[56] demonstrated that patients treated at ACCs had significantly lower 30-day mortality (4.1% vs 6.9%), 90-day mortality (13.2% vs 18.5%), and improved 5-year overall survival (26.2% vs 22.4%, P < 0.01) compared to community centers.

The volume-outcome relationship was further quantified in a study of 10174 patients, showing that treatment at the highest-volume hospitals was independently associated with a decreased hazard of death (HR: 0.835, 95%CI: 0.753-0.925, P < 0.001), and that the apparent benefit of traveling longer distances was entirely mediated through hospital volume rather than distance itself. Conversely, patients managed in non-specialized settings are significantly less likely to receive adequate oncologic resection, with Surveillance, Epidemiology, and End Results-Medicare data confirming that management by general surgeons at non-academic hospitals is strongly associated with receipt of cholecystectomy alone rather than oncologic resection[57,58].

Furthermore, large population-based analyses continue to demonstrate persistent undertreatment of GBC, with only 7.6% of patients undergoing appropriate re-resection after incidental diagnosis. Canadian data further reinforce that 55% of GBC patients are never referred to a cancer center, an omission that independently increases the hazard of death by 2.64-fold (HR: 2.64, 95%CI: 1.51-4.62)[59,60].

These findings align with current guideline recommendations emphasizing that, in the absence of hepatobiliary expertise, initial surgical procedures should be limited and patients promptly referred to specialized centers.

In our view, the management of iGBC should move beyond rigid surgical algorithms toward a more integrated framework that incorporates tumor biology, timing strategy, and healthcare system capacity. Lead-time bias, variable re-resection intervals, and disparities in surgical quality are not independent phenomena, but interconnected reflections of how care is delivered.

Ultimately, improving outcomes in iGBC will depend less on refining isolated technical steps and more on ensuring that the right patient is treated, at the right time, in the right center. This paradigm shift—from procedure-centered to system-centered care, may represent the most meaningful opportunity to impact survival in this challenging disease.

SURVIVAL GAP: TUMOR BIOLOGY VS HEALTHCARE SYSTEM LOGISTICS

The prognosis of GBC is dictated by a complex interplay between intrinsic tumor biology, which defines the theoretical survival ceiling, and healthcare system logistics, which determine whether a patient can actually reach that ceiling. In middle-incidence regions, this “survival gap” is primarily driven by modifiable systemic factors rather than biological fatalism.

Tumor biology: Beyond anatomical staging

The heterogeneity of GBC extends far beyond conventional TNM staging, encompassing distinct molecular, proteogenomic, and tumor microenvironment (TME) profiles that directly influence prognosis and therapeutic response. Integrative analyses have demonstrated substantial intertumoral variability, including alterations in cell cycle regulation, metabolic pathways, and immune signaling[20,24].

More importantly, emerging classifications based on the TME have identified biologically distinct subgroups with clear clinical implications. Studies have described immune-enriched and immune-depleted phenotypes associated with markedly different survival outcomes[23], while other analyses have further reinforced the prognostic relevance of stromal and immune interactions[25].

Collectively, these findings suggest that tumor biology, not merely anatomical extent, should play a central role in guiding therapeutic strategies.

Even within the same T stage, significant biological heterogeneity can be observed. T2b tumors (hepatic side) exhibit more aggressive behavior and worse oncologic outcomes compared to T2a lesions, suggesting that anatomical subclassification may, at least in part, reflect underlying tumor biology. These observations further support a paradigm shift toward biologically informed decision-making in iGBC[61].

Healthcare system logistics: The hidden determinant of outcomes

Beyond tumor biology, healthcare system factors represent a critical yet underappreciated determinant of outcomes in iGBC. Global disparities in incidence and mortality reflect not only geographic variation but also profound inequities in access to specialized oncologic care[5].

One of the most impactful observations in this domain is the remarkably low rate of HQS, defined as liver resection with adequate lymphadenectomy (≥ 6 nodes) and negative margins. Only 9.6% of patients with GBC undergo such optimal surgical management, and, importantly, adjuvant chemotherapy does not compensate for inadequate resection, reinforcing that surgical quality remains the primary driver of survival[54].

This gap is further compounded by failures in referral systems. A substantial proportion of patients in high-income settings are never referred to hepatobiliary centers after incidental diagnosis, significantly reducing the likelihood of appropriate re-resection[60]. In parallel, real-world data highlight how systemic limitations, including delayed referrals and resource constraints, directly impact treatment timelines and outcomes[7].

Taken together, these findings emphasize that survival in iGBC is not determined solely by tumor characteristics, but by the ability of healthcare systems to deliver timely, specialized, and oncologically adequate care.

Convergence: Neoadjuvant therapy as a bridge

The role of neoadjuvant therapy (NAT) in iGBC represents a paradigm shift from a purely surgical model to a biology-driven, multimodal strategy. The GAIN trial demonstrated that perioperative gemcitabine plus cisplatin nearly doubled median overall survival compared to upfront surgery (27.8 months vs 14.6 months; HR: 0.46, P = 0.04), while also improving R0 resection rates (62.5% vs 33.3%) and reducing 30-day (4.2% vs 24%) and 90-day postoperative mortality (4.2% vs 28%)[62]. The POLCAGB trial further showed that neoadjuvant chemoradiation was superior to neoadjuvant chemotherapy alone in locally advanced GBC, with a median OS of 21.8 months vs 10.1 months (P = 0.006) and higher R0 resection rates (51.6% vs 29.7%, P = 0.01)[63].

In parallel, a meta-analysis encompassing over 6000 patients confirmed a significant survival benefit with NAT (HR: 0.54; 95%CI: 0.47-0.62), while also demonstrating reduced surgical futility (16% vs 27% unable to proceed to surgery) without an increase in postoperative morbidity[64].

These findings reinforce the concept that the interval between index cholecystectomy and re-resection should not be viewed as a passive waiting period, but rather as a critical window to assess tumor biology and treatment responsiveness.

Importantly, NAT may help avoid non-beneficial surgery in patients with rapidly progressive disease while optimizing outcomes in biologically favorable tumors. As such, integrating systemic therapy into the preoperative pathway represents a key step toward personalized and biology-driven care in iGBC.

CRITICAL WINDOW: TIMING OF REFERRAL AND CASCADE OF CARE

The management of iGBC is defined by a race against biological progression. Despite universal recommendations for radical re-resection in stage ≥ T1b, real-world data reveal an alarming magnitude of undertreatment. Papageorge et al[59] demonstrated that only 7.6% of patients in the NCDB underwent oncological re-resection, while Romatoski et al[58] confirmed that 73.5% received only simple cholecystectomy, resulting in a survival deficit of over 20%.

Cascade of failures in the critical window

The interval between index cholecystectomy and definitive surgery can be decomposed into four sequential stages, each serving as a potential bottleneck.

Pathological alert (days 0-14): Delays in pathology reporting and communication to the primary surgeon consume precious time. Modern protocols, as suggested by the NCCN Guidelines[35], advocate for automated institutional alerts for incidental malignancy to trigger immediate referral.

Staging and imaging (weeks 2-4): Multiphase CT or magnetic resonance imaging is mandatory to determine resectability. While positron emission tomography CT remains selective, staging laparoscopy identifies occult distant disease in 20%-23% of cases, particularly in T3 tumors or those with positive margins[42,43].

Referral bottleneck (weeks 2-6): This remains the most significant modifiable factor. Canadian data indicate that 55% of GBC patients are never referred to an oncology center, a failure that independently increases the hazard of death by 2.64-fold[60].

Therapeutic decision (weeks 4-12): The choice between immediate surgery and NAT defines the use of the temporal window. NAT is increasingly recommended for locoregionally advanced disease to exclude rapid progressors and avoid futile surgery[35]. The GAIN and POLCAGB trials demonstrated improved survival with perioperative systemic therapy, while a 2025 meta-analysis confirmed that NAT reduces surgical futility (16% vs 27%) and improves overall survival (HR: 0.54)[62-64]. Propensity score analyses have shown that NAT allows selection of favorable disease biology and improves R0 resection rates, particularly benefiting patients with node-positive disease[65,66].

A structured, time-optimized management algorithm designed to overcome these bottlenecks is presented in Figure 1.

Figure 1 Integrated management framework for incidentally diagnosed gallbladder cancer. This infographic illustrates a multi-level strategy designed to optimize outcomes in regions of intermediate incidence. The framework transitions from identifying systemic and biological factors to a specialized care pathway. Key logistical interventions, marked as (LOGISTICAL GAPS/AUTO-ALERTS), include synchronized pathology reporting and the implementation of institutional automatic triggers for multidisciplinary team referral. The therapeutic decision relies on molecular stratification to guide the use of neoadjuvant chemotherapy as a biological sieve, followed by standardized radical re-resection and targeted systemic therapy. GBC: Gallbladder cancer; MRI: Magnetic resonance imaging; PET-CT: Positron emission tomography-computed tomography; HER2: Human epidermal growth factor receptor 2; NAT: Neoadjuvant therapy; .

Timing debate: Chronological vs biological windows

The controversy surrounding the “optimal” interval for re-resection reflects a paradigm shift from rigid chronological targets toward biologically informed decision-making. In a landmark multi-institutional analysis of 207 patients, demonstrated that reoperation between 4 weeks and 8 weeks was associated with the longest median overall survival (40.4 months), compared with < 4 weeks (17.4 months; HR: 2.63, 95%CI: 1.25-5.54) and > 8 weeks (22.4 months; HR: 2.07, 95%CI: 1.17-3.66; log-rank P = 0.03). This survival advantage persisted after excluding aborted procedures and R2 resections, and when recalculating survival from the date of initial cholecystectomy to account for lead-time bias[49].

However, this paradigm has been challenged by data from high-volume centers in endemic regions. In a large cohort of patients with iGBC, propensity score-matched analyses demonstrated that surgery performed between 10 weeks and 14 weeks was associated with superior OS (P = 0.049) and disease-free survival (P = 0.006) compared to earlier intervals. Notably, patients with locally advanced disease who received neoadjuvant therapy prior to revision surgery achieved a 3-year OS of 59.9%, compared to 32.3% in those undergoing upfront surgery (P = 0.001). These findings suggest that revision surgery may function not only as a therapeutic intervention but also as the most accurate staging procedure, and should be considered whenever the patient remains non-metastatic[50].

A subsequent meta-analysis including 2067 patients from 12 studies found no significant difference in overall survival between re-resection performed at ≤ 4 weeks vs > 4 weeks (HR: 1.29; 95%CI: 0.79-2.10), while also highlighting the lack of standardized definitions for timing intervals across studies, which limits direct comparisons[51]. Importantly, the presence of residual disease, identified in 35%-53% of patients at re-exploration, remains the strongest predictor of survival. Median survival has been reported as 19.6 months in patients with residual disease vs 62.7 months in those without (P < 0.001), findings that have been consistently reproduced across independent cohorts[17,67,68].

The ongoing OPT-IN trial (EA2197) is expected to further clarify this debate by prospectively evaluating perioperative gemcitabine-cisplatin vs adjuvant therapy alone in T2/T3 iGBC, with randomization permitted within 12 weeks of index cholecystectomy, effectively transforming what has traditionally been viewed as a “waiting period” into a therapeutic window[52].

The consistent observation that a substantial proportion of patients never reach specialized centers, and consequently never receive indicated oncologic treatment, suggests that survival is, to a significant extent, a function of system performance. Therefore, iGBC should be understood not only as a biologically aggressive disease, but also as a condition highly susceptible to system-level failure, where optimizing care pathways may yield survival gains comparable to advances in systemic therapy.

MODIFIABLE RISK FACTORS AND PREVENTIVE STRATEGIES

Modifiable risk factors: Beyond genetics

Recent large-scale analyses estimate that up to 74.6% of global GBC cases are attributable to modifiable risk factors, including central obesity (29.7%), gallstones (27.9%), and physical inactivity (20.5%)[69]. A comprehensive field-wide systematic review further supports strong associations for obesity, chronic biliary infection, and physical inactivity, while emphasizing the need for higher-quality evidence regarding additional environmental exposures[70].

Emerging data also highlight the role of environmental and infectious contributors. Elevated serum levels of aflatoxin B1-lysine have been associated with a 6.8-fold increase in GBC risk[71]. In parallel, chronic Salmonella Typhimurium infection has been shown to promote carcinogenesis through activation of the host epigenetic modulator KDM6B, establishing a direct mechanistic link between persistent biliary inflammation and malignant transformation[72].

Prophylactic strategies and surgical indications

Given the substantial population-attributable risk, prophylactic cholecystectomy remains a key preventive strategy in selected high-risk populations. While not indicated for asymptomatic gallstones in the general population, it is recommended in the presence of well-established risk factors, including: Porcelain gallbladder and anomalous pancreaticobiliary junction[35]; gallstones ≥ 3 cm or gallbladder polyps > 8 mm[35]; primary sclerosing cholangitis with gallbladder polyps > 8 mm, with close surveillance (every 6 months) for smaller lesions[73].

ACTIONABLE STRATEGIES FOR HEALTH SYSTEM OPTIMIZATION

The persistently high mortality rates observed in middle-incidence regions, such as Brazil, are not inevitable consequences of tumor biology, but rather the result of fragmented healthcare delivery. Bridging this survival gap requires a coordinated, system-level response centered on pragmatic, low-cost, and high-impact logistical interventions.

Surgical centralization and structured referral

Among all modifiable factors, surgical centralization remains the most impactful determinant of outcomes in GBC. Real-world data consistently demonstrate that academic centers achieve significantly higher rates of high-quality oncologic surgery compared to community hospitals (14.9% vs 6.1%), while failure to refer patients to specialized centers increases the hazard of death by 2.64-fold[54,60].

Two immediately actionable strategies emerge: The “halt and refer” protocol: In accordance with NCCN 2026 recommendations, surgeons operating in non-specialized settings should be trained to interrupt the procedure when malignancy is suspected intraoperatively, ensuring appropriate documentation and immediate referral to hepatobiliary centers[35]. Institutional auto-alert systems: Pathology departments should implement automated “critical diagnosis” alerts for iGBC, triggering expedited referral pathways to hepatobiliary multidisciplinary teams (MDT) and thereby minimizing delays within the critical window.

Universal molecular testing and MDT integration

Mandatory discussion within a MDT is essential to ensure that therapeutic decisions, particularly the choice between immediate re-resection and neoadjuvant therapy, are guided by tumor biology rather than logistical constraints.

In parallel, universal molecular profiling has become a key component of contemporary management in advanced or recurrent disease (category 2A recommendation). Routine testing for HER2 (ERBB2), MSI-H/dMMR, BRAF V600E, and NTRK fusions is critical, as targeted therapies directed at these alterations have transitioned from investigational strategies to components of standard care[35].

THERAPEUTIC VANGUARD: TOWARD A PERIOPERATIVE PARADIGM

The management of GBC has evolved from a surgery-first approach to a perioperative, biology-driven model. As discussed in previous sections, neoadjuvant chemotherapy has demonstrated meaningful survival benefits while functioning as a biological filter to optimize patient selection. In parallel, chemoimmunotherapy has become the standard of care for advanced disease, and HER2-targeted therapies have emerged as the first major breakthrough in precision oncology for this setting.

HER2-targeted therapy: The HERIZON-BTC-01 milestone

The identification of HER2 amplification as a therapeutically actionable target has opened a new chapter in the management of biliary tract cancers, including GBC. The HERIZON-BTC-01 trial evaluated zanidatamab, a bispecific anti-HER2 antibody, in patients with HER2-amplified, unresectable, locally advanced or metastatic BTC who had progressed on prior gemcitabine-based chemotherapy. In the initial phase 2b analysis, zanidatamab demonstrated a confirmed objective response rate of 41.3%, a disease control rate of 68.8%, a median duration of response of 12.9 months, and a median progression-free survival of 5.5 months[74].

The final analysis confirmed the durability of these responses, with a median overall survival of 15.5 months in a heavily pretreated population. These results supported the accelerated regulatory approval of zanidatamab in November 2024 for HER2-positive (immunohistochemistry 3+) BTC, establishing the first effective anti-HER2 strategy in this disease and reinforcing the importance of routine HER2 testing in patients with advanced GBC[75].

Adjuvant immunotherapy: The ACCORD trial

While most advances have focused on the neoadjuvant and palliative settings, emerging evidence now supports the integration of immunotherapy into adjuvant treatment. The ACCORD trial demonstrated that the addition of camrelizumab (anti-programmed death 1) to adjuvant chemoradiation significantly improved overall survival in resected extrahepatic cholangiocarcinoma and GBC (HR: 0.43; P = 0.004), with 3-year OS rates of 85% vs 67% in the control arm. These findings suggest a potential expansion of the therapeutic paradigm, positioning immunotherapy as a component of curative-intent multimodal strategies[76].

Future directions: Dynamic biomarkers and predictive modeling

Future advances in GBC management will likely be driven by the integration of dynamic biomarkers and advanced risk modeling.

Circulating tumor DNA: Liquid biopsy platforms may enable real-time monitoring of treatment response during the perioperative window and facilitate earlier detection of minimal residual disease, potentially guiding adjuvant therapy decisions[29].

AI-driven risk stratification: Integrated predictive models incorporating genetic susceptibility markers, ancestry-related risk factors, and environmental exposures may refine patient selection for both preventive cholecystectomy and personalized therapeutic strategies[9].

CONCLUSION

GBC management is at a critical inflection point, where poor outcomes can no longer be attributed to tumor biology alone. Contemporary evidence demonstrates that the survival gap observed in real-world practice is largely driven by systemic fragmentation, particularly within the “critical window” following index cholecystectomy. Healthcare logistics must therefore be recognized as a modifiable prognostic factor, directly influencing oncologic outcomes. Bridging this gap requires the integration of centralized referral pathways, neoadjuvant-driven biological selection, and universal molecular profiling. Ultimately, improving survival in GBC will depend not only on therapeutic innovation, but on the ability of health systems to deliver timely, coordinated, and biology-informed care.