Performance of major liver resection for gallbladder cancer—a western retrospective single center cohort study

Introduction

Gallbladder carcinoma (GBCa) is predominant malignancy of biliary tract system and associated with a poor prognosis (1). Incidence rates exhibit substantial geographical heterogeneity, ranging from 2.5/100,000 individuals in western European countries to 21.5/100,000 individuals in India, suggesting a significant influence of socioeconomic, genetic and environmental factors (2,3). Unfortunately, early symptoms are typically absent. A large western population-based study found a 5-year overall survival of 18.0% for those patients undergoing surgery alone (4). In cases where gallbladder cancer (GBCa) is detected at an early stage (T2 or less), 5-year survival rates of 75% or higher have been achieved (5,6). Due to the rarity of the disease and a paucity of data, GBCa has only recently be acknowledged in the German guideline for hepatocellular and biliary tract cancer (7). The German and European Society for Medical Oncology (ESMO) guidelines recommend a resection, irrespective of the tumor staging, as long as distant metastases are absent and the tumor appears to be resectable (7-9). However, owing to the miscellaneous nature of the literature, the level of evidence supporting this recommendation is low.

Although data are scarce and heterogenous, evidence is slowly emerging challenging the current practice of extended resection in advanced GBCa. There are a few retrospective series supporting major hepatectomy (MaH), such as Shimada et al. where patients undergoing extended right hepatectomy (eRH) survived 2.2 years (10). In contrast, a recently published multicentric retrospective study by Balakrishnan et al. indicates that extensive upfront surgery may not necessarily confer a survival benefit, but being associated instead with increased mortality and unsatisfactory oncological outcome (11). However, prospective randomized trials or meta-analyses are lacking. The objective of our study was to analyze patient survival following resection based on the extent of surgery, and to compare these outcomes with patients being unresectable and treated with chemotherapy instead. We present this article in accordance with the STROCSS reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-440/rc).

Methods

We conducted a single center retrospective cohort study at a high-volume tertiary medical center. As exploratory study, all patients with GBCa who underwent either surgery or were treated by palliative chemotherapy between 2008–2023 were screened. Inclusion criteria were met, if the patients underwent surgery in our department for General, Visceral and Transplant Surgery and GBCa was histologically confirmed. Further included were patients with incidentally GBCa after index cholecystectomy undergoing re-operation and those receiving palliative chemotherapy either after surgical exploration or primarily if distant metastases were found radiographically. Exclusion criteria comprised inconclusive postoperative histological results indicative of a tumor origin discordant with GBCa (e.g., cholangiocarcinoma), as well as incomplete medical records. Patients receiving palliative chemotherapy at our center (University Medical Center Mainz) after prior resection at an alternate hospital were also excluded.

Preoperative work-up

Patients presenting with incidental (iGBCa) or suspected primary GBCa (pGBCa) were referred to our center for further staging and/or therapy. The computed tomography (CT)-scan was used as first line imaging technique. Magnetic resonance imaging was equally accepted, if of adequate quality. Palliative chemotherapy was initiated, if distant metastases were identified, or tumor was deemed unresectable during imaging work-up. In some cases, preoperative endoscopic retrograde cholangiopancreatography (ERCP) and insertion of a stent in the bile duct was required. All cases were reviewed by interdisciplinary tumor board involving hepatobiliary specialized surgeons, radiologists, pathologists and oncologists. Preoperative physical status was assessed using the Eastern Cooperative Oncology Group (ECOG) and American Society of Anesthesiologists (ASA) Classification (12,13).

Treatment procedures

Surgery was performed by a consistent team of experienced hepato-pancreato-biliary (HPB) surgeons. In cases of advanced tumor progression or discovery of peritoneal metastases, the procedure was terminated and classified as explorative laparotomy (EL). These patients were subsequently considered for secondary palliative chemotherapy (+EL/sPC). If patients were no candidates for surgery due to distant metastases, primary palliative chemotherapy was administered (−EL/pPC). In cases of recurring disease after surgical resection, patients were most often treated with palliative chemotherapy in accordance with our standard of care guidelines. A resection of up to two segments was defined as minor hepatectomy (MiH), including cholecystectomy and/or gallbladder bed resection, extended gallbladder bed resection (H45). Resections exceeding two segments were considered as MaH, containing right hepatectomy (RH), eRH, mesohepatectomy (MH) and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). A pringle maneuver was prepared in every major resection in case of major bleedings. Additional resection of hilar bifurcation (HB), or the common bile duct (CBD) was denoted as extrahepatic bile duct resection (EHBDR). Extrahepatic organ resection (EOR) was defined as resection of any extrahepatic organ such as pancreas, small bowel, or colon. Standard resection involved locoregional lymphadenectomy. If distant lymph nodes, such as those between vena cava and aorta, appeared to be invaded, a frozen section was performed. Proof of tumor invasion of distant lymph nodes was classified as distant metastases, leading to abortion of the operation.

Follow-up

Follow-up was conducted until February 2024. Patients were seen either at our center or by outpatient oncologists. Current survival status was determined by contacting patients’ physicians or oncologists.

Postoperative morbidity and mortality

Perioperative morbidity and mortality was classified according to the Clavien-Dindo classification (14). Postoperative mortality was defined as 90 days mortality. Additionally, complications were quantified by using the comprehensive complication index (CCI) scoring system (15). Median CCI was used to avoid statistical distortion by patients having no complications. Postoperative bile leakage and post hepatectomy liver failure (PHLF) were classified according to definitions of the International Study Group of Liver Surgery (ISGLS) (16,17).

Data analysis

Special interest of data analysis focused on demographic data, surgical procedure, extension of resection, postoperative outcome, morbidity and mortality, and overall survival. Histological results were classified according to the 8^th edition of the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) (18,19). Groups were categorized according to treatment procedure.

Data collection and statistical analysis

Patient data were collected from the institutional database and transferred to SPSS 29 (SPSS Inc., released 2014, IBM SPSS Statistics for Windows, Version 23.0, IBM Armonk, NY, USA). Treatment groups were compared for homogeneity and reduction of confounders using statistical tests such as analysis of variance (ANOVA), Kruskal-Wallis, Mann-Whitney U or T-test. Survival analysis was performed by Kaplan-Meier model and log rank test. Overall survival was defined as interval between the date of first cycle of palliative chemotherapy or surgery and decease. Recurrence-free survival (RFS) was defined as the interval between surgical resection and the detection of recurrent disease on a CT scan. Multivariate analysis was performed using cox regression model to identify independent risk factors for poor survival outcome. Patients with missing data were excluded in the analysis. Statistical significance was accepted by P<0.05.

Ethical considerations

All enrolled patients provided informed consent, authorizing the collection of data and anonymous utilization for potential scientific analysis. In compliance with the stipulations outlined in the state hospital (§36 & §37) of the federal state, and in accordance with the directives of the independent ethics committee of Rhineland-Palatinate, no ethical approval was necessary for this study. The study was performed in accordance with the Declaration of Helsinki and its subsequent amendments.

Results

Among 245 patients with GBCa during June 2008–December 2023, 167 met the inclusion criteria; 78 patients were excluded due to inconclusive histological results, or prior liver resection in different medical facilities (Figure 1).

Figure 1 Flow chart showing patients included for analysis. MaH, major hepatectomy; MiH, minor hepatectomy; +EL/sPC, palliative chemotherapy after explorative laparotomy; −EL/pPC, primary chemotherapy.

Demographic distribution was homogenous and did not differ between groups regarding sex (P=0.20), age (P=0.66) and physical status (P=0.50) (Table 1). Mean follow-up was 17.82 months.

Exploration and resection

Surgical exploration was indicated in 148 patients. Of those, 68 patients were deemed unresectable during intraoperative assessment and subsequently underwent palliative chemotherapy. Reasons for unresectability included hepatic artery invasion (n=12), advanced bile duct invasion (n=2), peritoneal carcinomatosis (n=29), interaortocaval lymph node invasion (n=6), which was classified as distant metastases, liver metastases (n=5), locally advanced disease (n=10), a small future liver remnant (n=1) or a combination of these (n=3). MiH was performed in 60 patients. Twenty patients required an MaH to achieve macroscopically tumor-free margins (Table 1). ALPPS was performed in two cases. The decision to perform ALPPS was based on a small future liver remnant in one patient (215 mL of segments 2/3), discussed and considered preoperatively. In the other case, the decision was made intraoperatively after tumor progression into the liver hilum was noted, necessitating an in situ split to achieve R0 resection.

Majority of tumors resected by MaH were T3 or higher (T3 =75%, T4 =10%). The median blood loss was 1,000 mL [95% confidence interval (CI): 646–1,354], and the median operation time 311 minutes (95% CI: 279.2–388.5) (Table 2). A Pringle maneuver was used when necessary to control bleeding.

In 23 cases EHBDRs was performed. Additionally, nine EORs (including stomach, duodenum and colon n=1; small bowel n=1; duodenum n=5; colon n=1; Whipple procedure n=1) were necessary to achieve a complete resection.

Morbidity and mortality

Of all patients who underwent surgical exploration, a total of 68 individuals encountered postoperative complications (Table 3). Notably, all patients with MaH manifested morbidity. After MaH five patients demised during the postoperative course, attributed to distinct etiologies: hemorrhagic shock (n=1), liver failure (n=1), septic shock (n=1), pneumonia (n=1), and cardiac low output failure (n=1). Major resections performed in those deceased patients included following procedures: right hepatectomy (n=1), extended right hepatectomy (n=2), mesohepatectomy (n=1), ALPPS (n=1). The median Charlson Comorbidity Index (20) within the MaH subgroup was 5, whereas among those who deceased it was 4. The median age for patients in this subgroup was 62.1 years.

Fifty patients after EL had no complication; However, three patients experienced mortality after surgery, primarily attributable to multi-organ failure (MOF) in the context of rapid tumor progression (MOF, n=2) and cholangiosepsis (n=1). The therapy was ceased in accordance with the patients or relatives will.

The median CCI demonstrated significant differences between MiH and MaH as well as between EL and MaH (P<0.001 and P<0.001, Kruskal-Wallis test, respectively).

Bile leakage occurred in nine patients after MiH (Type A, n=4; Type B, n=5), while four patients after MaH had a Type A bile leakage. Three patients after MaH had a postoperative liver failure.

Univariate analysis and survival

The median survival for patients receiving a MaH or MiH were 11.96 months (95% CI: 1.11–22.81) and 25.1 months (95% CI: 19.37–30.85), respectively (Figure 2). MiH was associated with statistically significant improved survival (MiH vs. +EL/sPC, P<0.001; MiH vs. MaH, P=0.004; MiH vs. −EL/pPC, P<0.001). Conversely, median survival in the +EL/sPC group was 10.32 months (95% CI: 7.74–12.9), and statistically non-inferior to MaH (P=0.052) Patients receiving primary palliative treatment (−EL/pPC) survived median 7.26 months (95% CI: 0.0–15.4), but the discrepancy to MaH was, however, not statistically significant either (P=0.24). A selective Kaplan-Meier survival analysis of patients with or without lymph node invasion (N0 vs. N1) undergoing MaH did not demonstrate a significant impact on survival outcome P=0.91). Nine patients who underwent MaH experienced recurrent disease, primarily in the liver (n=5), lymph nodes (n=3), and/or peritoneum (n=2). The median RFS for MaH was 8.0 months (95% CI: 3.0–26.0) (Table 2). These patients subsequently received palliative chemotherapy. Nine patients required extrahepatic organ resection (MiH EOR, n=6; MaH EOR, n=3) experiencing significantly poorer outcomes [EOR median 7.16 months (95% CI: 3.32–14.45) vs. no EOR median 25.11 months (95% CI: 17.56–32.66), P=0.004; Figure 3]. Survival rates of patients undergoing EOR for 1-, 3- and 5-year were 33%, 22% and 0% vs. 69%, 32% and 26% if no EOR was performed. Twenty-three patients received a EHBDR (MiH EHBDR, n=12; MaH EHBDR, n=11). EHBDR was associated with poor outcome [15.12 months (95% CI: 7.66–22.58) vs. 25.47 months (95% CI: 15.78–35.17), P=0.02; Figure 4]. The 1-, 3- and 5-year overall survival for EHBDR and no EHBDR was 55%, 5% and 5% vs. 69%, 39% and 31%, respectively.

Figure 2 Kaplan-Meier model of the different therapy modalities. MaH vs. MiH, P<0.001; MaH vs. +EL/PC, P=0.052; MaH vs. −EL/PC, P=0.25. Numbers at risk (lower left). Year survival rates (lower right): 1YS, 1-year survival; 3YS, 3-year survival; 5YS, 5-year survival. MiH, minor hepatectomy; MaH, major hepatectomy; +EL/PC, explorative laparotomy and subsequent palliative chemotherapy; −EL/PC, palliative chemotherapy only without explorative laparotomy.

Figure 3 Kaplan-Meier model: additional EOR during liver resection (n=9) vs. no EOR (n=70), P=0.004. Numbers at risk of patients receiving additional extrahepatic organ resection. EOR, extrahepatic organ resection.

Figure 4 Kaplan-Meier model: EHBDR (n=23) vs. no EHBDR (n=57), P=0.02. Numbers at risk of patients receiving extrahepatic bile duct resection. EHBDR, extrahepatic bile duct resection.

Multivariate analysis

A multivariate cox regression model was used to identify independent risk factors influencing survival (Table 4). Here, MaH was found to increase the risk of deceasing by 3.2 points [hazard ratio (HR) 3.186, 95% CI: 1.05–9.62, P=0.041]. Positive resection margins (>R1) increased the risk by 6.1 points (HR 6.079, 95% CI: 1.98–18.58, P=0.02).

Discussion

In this retrospective study performed at a high-volume western HPB center including 167 patients with GBCa, upfront MaH was not associated with a significant improvement of survival. The demographic distribution was homogenous regarding sex, age and physical status (ASA-Classification). Patients undergoing MaH had larger tumors in size (6.7±3.3 vs. 3.4±3.5 cm) and advanced T-stage compared to MiH.

While selected patients benefited from upfront major surgical resection, those patients with an additional extrahepatic bile duct or organ resection had a worse outcome in the Kaplan-Meier analysis. However, in the multivariate analysis, only MaH and positive resection margins were identified as independent factors supporting a poor survival outcome. We did not find a significant influence of nodal state on survival (P=0.91). Although the low patient numbers need to be considered, nodal state in MaH for GBCa seems to play a subordinate role.

More than half of patients (60.0%) after major resection had a complication ≥ Clavien-Dindo 3a, five patients demised during the postoperative course. However, two patients (10%) survived more than 3 years (36 and 64 months, respectively), indicating there might be a subgroup of patients who benefit from a major resection. But selection of those patients remains difficult, considering the aggressive and poorly understood tumor biology. Furthermore, often the necessity of major resection is determined while surgical exploration. So far, surgical resection is the only chance for long-term survival. Future neoadjuvant chemotherapy, molecular characterization and artificial intelligence for imaging analysis may offer chances to understand underlying tumor biology and select patients with favorable prognosis after resection (21,22).

A Swedish research group conducted a population-based survival outcome study spanning three distinct periods (2000–2004, 2005–2009, 2010–2014): survival of patients with low grade tumors receiving cholecystectomy or liver bed resection improved over time (P=0.02). According to the study, no patients with advanced disease were treated surgically, but given to palliative chemotherapy instead, resulting in a median of 6.2 months survival (23).

Diagnosis and consecutive therapy in early stage plays a pivotal role in improving survival rates. A Surveillance, Epidemiology, and End Results (SEER) based study found improved survival for radical resection of AJCC/UICC III and IV tumors in advanced GBCa (HR =0.29, 95% CI: 0.26–0.33, P<0.001) (24). However, current literature for radical surgical resection in advanced GBCa is heterogenous and conflicting. Interestingly, outcomes as well as surgical approaches differ between Asian and western cohorts. A study from the Netherlands performed by Kuipers and colleagues achieved a comparable survival outcome of 12.8 months (median) after major resection for 33 patients with GBCa (25); 58% had a Clavien-Dindo >3a, 16% demised as part of perioperative complications. However, the authors recommend an extensive resection if morbidity and mortality is acceptable. In contrast Mizuno and colleagues demonstrated a significant survival improvement of 79 patients undergoing MaH for advanced GBCa (T3 =62%, T4 =33%) compared to patients without resection (median 32 vs. 6 months, P<0.001) (26). Interestingly, almost 85% of those patients had a preoperative portal vein embolization, which is a standardized procedure in Japan (27). However, this might not explain these extraordinary results alone. Traditionally, there is a large discrepancy between western and Asian cohorts after liver resection for biliary tract cancer. Although being more aggressive during upfront surgery, even after combined liver and pancreas resection, Asian cohorts exceed the western cohorts in terms of survival rates and case numbers (28). In addition to the admittedly extremely high quality of HPB surgery in Asia also variations in surgical approaches as well as differences in the patient’s physique and comorbidities between Asian and Western cohorts could influence survival outcomes. Asian patients may have different baseline health statuses or genetic predispositions that contribute to better outcomes following liver resection. However, there is no clear explanation for this phenomenon. The largest series for GBCa, the recently published OMEGA trial including more than 3,000 patients around the globe, demonstrated no improved survival after MaH, but rather increased morbidity and mortality (HR 1.48, 95% CI: 1.16–1.88, P<0.002) (11).

In our cohort, additional EHBDRs was associated with a clearly worse outcome. Gavriilidis et al. compared patients with GBCa undergoing EHBDR with those without EHBDR. After excluding patients with cystic duct invasion and those with T1 tumor, 838 patients with R0-resection remained. No improvement in survival outcome was achieved by EHBDR (29). EHBDR should only be performed if frozen section or obvious intraoperative findings make it necessary for complete (R0) resection. If additional extrahepatic organ resection was necessary to obtain free margins, survival outcome was worse compared to the palliative chemotherapy group (5.8 vs. 7.26 months). However, in our multivariate cox regression analysis extrahepatic organ resection and EHBDR were not significantly influencing survival. This is explainable by the low patient numbers in the respective group. In contrast to our findings, Balakrishnan et al. demonstrated in their study, that extrahepatic organ resection was associated with a high rate of complications and mortality, most likely leading to the delayed induction of adjuvant chemotherapy (11). Studies, where a MaH and/or additional resection of the portal vein, pancreas or hepatic artery was performed, showed a similar or even worse survival outcome compared to chemotherapy after EL (+EL/sPC) in our study (30). However, there are authors reporting of patients achieving long term survival after extended liver and extrahepatic organ resection, suggesting that there might be a role for extensive surgery in a subgroup of well selected patients (31-33).

Nevertheless, the elevated risk of morbidity and mortality of extended surgery versus the potential adverse events induced by chemotherapy needs to be discussed with the patients beforehand.

As mentioned before, neoadjuvant chemotherapy might be a promising option to increase resectability and unfold underlying tumor biology. Currently there is no standardized neoadjuvant chemotherapy. Some authors demonstrated promising results of patients undergoing resection after neoadjuvant chemotherapy, if no tumor progress was noted (21). These outcomes are encouraging to further investigate new neoadjuvant concepts and the results are eagerly awaited (34,35).

In our cohort, approximately 50% (n=40) of patients undergoing resection received adjuvant chemotherapy postoperatively. The low utilization of adjuvant chemotherapy was due to patient refusal or non-prescription by physicians during a time, when pivotal studies, such as the BILCAP trial, providing support for adjuvant chemotherapy, were absent (36).

Just recently, the TOPAZ-1 phase-2-trial demonstrated efficacy and improved survival for patient with biliary tract cancer receiving gemcitabine/cisplatin and durvalumab as palliative chemotherapy. Objective response rates were up to 72%, median progression free survival was 12.1 months with an acceptable safety profile. There is currently a phase 3 clinical trial (NCT03875235) evaluating this triple combination as first line therapy for biliary tract cancer (37). The study is estimated to be finished in 2025. Depending on the result, this treatment combination could be a valid chemotherapy regime to investigate for neoadjuvant chemotherapy.

Of course, the retrospective study design and the small cohort limits the meaningfulness of this work, but this is owed to the rarity of the disease in western countries and the difficulty of performing randomized controlled trials in surgery. There are only few single center series with small cohorts concerning major resection in GBCa. As to our knowledge, there are currently no prospective studies investigating surgical strategies in GBCa. Since this is not a randomized trial, but real-world data, extend of resection was determined by the surgeon. The aim of this study was not to compare treatment procedures but to understand the underlying tumor biology by presenting data of a typical clinical setting. MaH is a well-established procedure, being safe and viable for many indications. However, in the context of GBCa, patients requiring MaH usually present with advanced tumor stages. Our data suggest that these patients might not necessarily benefit from upfront extensive surgery. To improve survival outcomes, further studies are needed investigating new neoadjuvant concepts to reduce preoperative tumor burden.

Conclusions

Currently, there is a poor understanding of GBCas tumor biology. MaH may improve survival outcome in selected patients but is still associated with a poor overall survival outcome. Therefore, early identification of advanced tumors, new neoadjuvant chemotherapy concepts, and prospective trials are needed to reduce preoperative tumor burden and select patients who truly benefit from resection.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROCSS reporting checklist. Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-440/rc

Data Sharing Statement: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-440/dss

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-440/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-440/coif). H.L. serves as an unpaid editorial board member of Hepatobiliary Surgery and Nutrition. A.W. reports honoraria for presentations from Leo Pharma, MSD, Eisai, Norgine, Ipsen and Alfasigma; travel support from Merck KGaA, Servier; participation on advisory board from Bayer, Roche, BMS, AstraZeneca, Sanofi, Servier, Taiho, MSD. F.F. has received honoraria for lectures from AstraZeneca, MSD, Pfizer, Roche and reimbursement of meeting attendance fees and travel expenses from Merck KGaA and Servier and he has served as an advisory board member for AstraZeneca, BMS, Eisai and Roche. The other 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. The study was conducted according to the guidelines of the Declaration of Helsinki and its subsequent amendments. In compliance with the stipulations outlined in the state hospital law (§36 415 & §37) of the federal state, and in accordance with the directives of the independent ethics committee 416 of Rhineland-Palatinate, no ethical approval was necessary for this study. All enrolled patients provided informed consent.

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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