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. Author manuscript; available in PMC: 2025 Feb 16.
Published in final edited form as: Ann Surg Oncol. 2023 May 6;30(8):4904–4911. doi: 10.1245/s10434-023-13531-2

Benchmarks and Geographic Differences in Gallbladder Cancer Surgery: an International Multi-Center Study

Eduardo A Vega 1,2,*, Timothy E Newhook 1, Sebastian Mellado 2,4, Andrea Ruzzenente 5, Masayuki Okuno 6,7, Mario De Bellis 5, Elena Panettieri 8, M Usman Ahmad 13, Ignacio Merlo 11, Jesus Rojas 15, Agostino M De Rose 8, Hiroto Nishino 7, Andrew J Sinnamon 9, Matteo Donadon 14, Marit S Hauger 12, Oscar A Guevara 10, Cesar Munoz 15, Jason W Denbo 9, Yun Shin Chun 1, Hop S Tran Cao 1, Rodrigo Sanchez Claria 11, Ching-Wei D Tzeng 1, Xabier de Aretxabala 3, Marcelo Vivanco 3, Kristoffer W Brudvik 12, Satoru Seo 7, Juan Pekolj 11, George A Poultsides 13, Guido Torzilli 14, Felice Giuliante 8, Daniel A Anaya 9, Alfredo Guglielmi 5, Eduardo Vinuela 3, Jean-Nicolas Vauthey 1,*
PMCID: PMC11830408  NIHMSID: NIHMS2051908  PMID: 37149547

Abstract

Background:

High-quality surgery plays a central role in the delivery of excellent oncologic care. Benchmark values indicate the best achievable results. We aimed to define benchmark values for gallbladder cancer (GBC) surgery across an international population.

Methods:

This study included consecutive patients with GBC who underwent curative-intent surgery during 2000-2021 at 13 centers, across seven countries and four continents. Patients operated on at high-volume centers without the need for vascular and/or bile duct reconstruction and without significant comorbidities were chosen as the benchmark group.

Results:

Of 906 patients who underwent curative-intent GBC surgery during the study period, 245 (27%) were included in the benchmark group. These were predominantly women (n=174, 71%) and had a median age of 64 years (interquartile range 57–70). In the benchmark group, 50 patients (20%) experienced complications within 90 days after surgery, with 20 patients (8%) developing major complications (Clavien-Dindo grade ≥IIIa). Median length of postoperative hospital stay was 6 days (interquartile range 4-8). Benchmark values included ≥4 lymph nodes retrieved, estimated intraoperative blood loss ≤350 mL, perioperative blood transfusion rate ≤13%, operative time ≤332 minutes, length of hospital stay ≤ 8 days, R1 margin rate ≤7%, complication rate ≤22%, and rate of grade ≥IIIa complications ≤11%.

Conclusion:

Surgery for GBC remains associated with significant morbidity. The availability of benchmark values may facilitate comparisons in future analyses between GBC patients, GBC surgical approaches, and centers performing GBC surgery.

Graphical Abstract

graphic file with name nihms-2051908-f0002.jpg

INTRODUCTION

High-quality surgery plays a central role in the delivery of excellent oncologic care. The quality of surgery can drastically influence both short- and long-term postoperative outcomes, and, thus, it is crucial to consider the quality of surgery in studies that assess surgical outcomes.1,2 Poor-quality surgery represents a failure to deliver intended treatment; failure to consider the quality of surgery can introduce bias in comparisons of oncologic surgery with other interventions or comparisons of surgical outcomes across institutions.3 Hence, there is a need for accurate measures for the quality of oncologic surgery.

An approach for developing accurate quality measures is benchmarking, a quality-improvement process in which the best possible outcomes are identified to serve as a point of reference against which performance can be compared. In the field of hepatobiliary surgery, a landmark study by Rössler et al. defined benchmarks for major hepatectomy to facilitate evaluation of surgical performance across multiple centers and patient populations.4 These authors analyzed outcomes in low-risk patients because outcomes in such patients would be expected to represent the best achievable results of the respective operations.

Oncologic extended resection (OER) for gallbladder cancer (GBC) is technically challenging and requires considerable expertise to meet high-quality operative standards.5,6 Features of high-quality OER for GBC have been identified and include adequate lymphadenectomy, R0 margins, and minimizing blood loss and operative time. A recent study showed that the quality of GBC surgery in the United States differs by insurance status, income, geographic location, education level, and other characteristics, showing that high-quality surgery was rare and that low-quality surgery is significantly associated with decreased survival.3 Although general characteristics of high-quality OER for GBC are understood, low-quality surgery remains common, urging the need for specific benchmarks.

Defining benchmark values for GBC surgery will create a reference that institutions can use to assess their surgical performance, improve surgical outcomes, and help move centers that currently perform lower-quality GBC surgery toward performing higher-quality surgery. In the present study, we aimed to strictly define benchmarks in GBC surgery, and we also evaluated geographic differences in GBC surgery across multiple continents.

METHODS

Patient Selection

We retrospectively identified all consecutive patients who underwent curative-intent surgery for GBC during 2000-2021 at 13 centers across seven countries and four continents (Table 1). All the centers are high-volume centers with prospectively compiled patient care databases and are heavily involved in research, frequently conducting studies on biliary tract cancer.7–16 Patients were identified from the surgical oncology liver resection database at MD Anderson Cancer Center (RCR01-116) and from anonymized databases at all other institutions. This database protocol (PA18-0311) was approved by the institutional review boards of the participating institutions. The cloud-based all-in-one (registry and statistical analysis) package Ledidi Core (Ledidi, Oslo, Norway) was used to collect and collaborate on encrypted data.

Table 1.

Participating institutions and locations

Institution Location
The University of Texas MD Anderson Cancer Center Houston, Texas, USA
Sotero del Rio Hospital & Pontificia Universidad Catolica de Chile Santiago, Chile
Clinica Alemana de Santiago Santiago, Chile
Verona University Hospital Verona, Italy
Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore Rome, Italy
Kyoto University Kyoto, Japan
H. Lee Moffitt Cancer Center & Research Institute Tampa, FL, USA
Instituto Nacional de Cancerologia Bogota, Colombia
Hospital Italiano de Buenos Aires Buenos Aires, Argentina
Oslo University Hospital Oslo, Norway
Department of Surgery, Stanford University Stanford, CA, USA
Humanitas University Milan, Italy
Universidad Catolica del Maule Talca, Chile
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Data Collection and Outcomes of Interest

The following data was collected from patient medical records: baseline demographic and clinical characteristics; details of the OER, including type of resection; use of perioperative chemotherapy and radiation therapy; postoperative complications; pathologic characteristics, including T category, N category, tumor size and number, and margin status; and data on recurrence and survival.

Surgical Technique

All participating centers used the same, previously described, standardized surgical technique, with some technical modifications made over the study period.17,18 OER was designed to achieve an R0 resection and allow appropriate staging at all institutions. Intraoperative ultrasonography was used to evaluate tumor location and liver metastases.

During the initial study period, common bile duct (CBD) resection was part of the standardized operative technique; later, however, CBD resection was performed only in patients with a positive cystic duct stump margin after OER or with macroscopic tumor invasion. Combined resection of adjacent organs was performed as needed to achieve R0 resection. Port site resection was performed in rare cases, according to surgeon preference and clinical indication.

Definitions

GBC staging is based on The Eighth Edition AJCC Cancer Staging Manual.19 Recurrence-free (RFS) and overall survival (OS) are defined as time between surgery and first detected recurrence and time between surgery and death, respectively. Type of resection (major vs. minor) is based on the Brisbane classification.20 R0 resection is defined by a surgical margin > 1 mm. Estimated intraoperative blood loss (EBL) was noted in the surgical report at all institutions. Perioperative transfusion rate was defined as any blood product given in the intraoperative or postoperative hospital stay. Complications are described according to the Clavien-Dindo classification, with complications grade ≥IIIa considered as major.21

Benchmark Analysis

Guided by the approach used in the seminal study of benchmark analysis in liver surgery,22 we identified a cohort of patients with a low risk of complications to be used as the benchmark group. Specifically, in the benchmark group, we included only patients with (1) surgery with or without intraoperative frozen section analysis of aortocaval lymph nodes, (2) limited resection of the liver bed or anatomic resection of liver segments IVb-V, and (3) dissection of the hepatoduodenal ligament, common hepatic artery, and retropancreatic lymph nodes as a standard approach for GBC. Patients were excluded if they had major liver resection or pancreatoduodenectomy, or liver resection combined with vascular, adjacent organ, or CBD resection, no lymph nodes retrieved, an American Society of Anesthesiologists physical status classification score (ASA score) ≥3, a body mass index (BMI) ≥35 kg/m2, and jaundice at the time of GBC discovery or surgery (Table 2).

Table 2.

Inclusion and exclusion criteria for the benchmark cohort of GBC patients

Inclusion criteria
 Age ≥18 and ≤ 75 years
 Resectable GBC
 Liver bed resection or resection of liver segments IVb and V with lymphadenectomy
Surgical exclusion criteria
 Major liver resection and/or pancreatoduodenectomy
 Common bile duct resection
 Vascular resection
 Adjacent organ resection
 No lymph nodes retrieved
Medical exclusion criteria
 American Society of Anesthesiologists physical status classification score ≥3
 Body mass index ≥35 kg/m2
 Jaundice at time of GBC discovery or surgery
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Abbreviation: GBC, gallbladder cancer

On the basis of review of previously published benchmark analyses4,23,24 and author discussion, we defined 8 parameters to be used for benchmarking: number of lymph nodes retrieved, EBL, perioperative blood transfusion rate, R1 surgical margins, length of postoperative hospital stay, operative time, complication, and major complications.

For each center, we first calculated the median values for number of lymph nodes retrieved, EBL, perioperative blood transfusion rate, length of hospital stay, operative time, the proportion of patients with R1 margins, any complication and grade ≥IIIa complications. We then calculated the median of these values across the centers and defined the benchmark range as the range from the 25th to 75th percentile.

All statistical tests were two-sided, and p<0.05 was considered statistically significant in all analyses. Variables were presented as median (interquartile range) or frequency (percentage), as appropriate. Continuous variables were compared using the Kruskal-Wallis test or Mann-Whitney test, as appropriate, and categorical variables were compared using the χ2 test. Survival curves were generated using the Kaplan-Meier method. Results were reported in terms of hazard ratio (HR) and confidence interval (CI).

Analysis of Geographic Differences in Practice Patterns

To understand geographic differences in practice patterns, we divided the study cohort by continent (Asia, Europe, North America, and South America) and compared clinicopathologic characteristics, preoperative and postoperative treatment, and type of surgical procedure between continents.

RESULTS

Basic Characteristics of Patients in the Benchmark Group

Of 906 patients who underwent curative-intent GBC surgery during the study period, 245 (27%) met the criteria for inclusion in the low-risk benchmark group. Patients in the benchmark group were predominantly female (n=174, 71%) and had a median age of 64 years (interquartile range 57–70) (Supplementary Table 1). The proportion of benchmark patients among all patients at the participating institutions ranged from 4% to 16%. Most tumors in the benchmark group were discovered incidentally (n=165, 67%). Sixteen patients (7%) received neoadjuvant treatment, either chemotherapy alone (n=15) or chemoradiation (n=1).

Postoperative Outcomes of Patients in the Benchmark Group

In the benchmark group, 50 patients (20%) experienced complications within 90 days, and 20 patients (8%) experienced Clavien-Dindo grade ≥IIIa complications (Tables 3). Five patients (2%) died within 90 days of surgery. The median length of postoperative hospital stay was 5 days (interquartile range 4-8). Perioperative blood transfusions were administered in 17 patients (7%). The median OS of the benchmark group was 65 months (95% CI 42-89), and the median RFS was 33 months (95% CI 25-45). The 1-, 3-, and 5-year actuarial OS rates were 86%, 63%, and 52%, respectively, and the RFS rates were 70%, 51%, and 42%, respectively (Figure 1).

Table 3.

Benchmark values

Parameter 25th percentile 50th percentile 75th percentile
Number of lymph nodes retrieved 4 6 8
Estimated intraoperative blood loss, ml 131 300 350
Perioperative blood transfusion, % 0 7 13
Operative time, min 215 233 332
Any complication, % 10 17 22
Clavien-Dindo grade ≥IIIa complication, % 0 6 11
Postoperative hospital stay, median, days 4 5 8
R1 surgical margin status, % 1 3 7
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Bold = benchmark values

Figure 1.

Figure 1.

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Recurrence-free survival (A) and overall survival (B) in the benchmark group. The survival analysis included 210 patients for recurrence-free survival and 230 patients for overall survival because survival data were not available for all patients.

Comparison of Patients in the Benchmark and Non-Benchmark Groups

As expected, patients in the benchmark and non-benchmark groups differed significantly with respect to age, BMI, and ASA score. However, patients in the two groups did not differ significantly with regarding incidental GBC, preoperative acute cholecystitis, chronic cholecystitis, or cholelithiasis at surgery. Furthermore, patients in the two groups were similar with respect to histologic type, tumor differentiation, and perineural and/or lymphovascular invasion. Patients in the non-benchmark group had a higher rate of stage III or IV disease. Patients in the non-benchmark group also had higher rates of overall complications and major complications. Finally, surgical approach differed significantly between the two groups (Supplementary Table 1). The survival outcomes of the benchmark group were compared to those of the non-benchmark group, revealing that the benchmark group had a significantly better OS with a HR of 0.78 (95% CI [0.62 – 0.98]; p = 0.040). However, no significant difference was observed between the two groups in regard to RFS (HR 0.95, 95% CI [0.76 – 1.22]; p = 0.796).

Benchmark Values

Benchmark values for selected parameters are shown in Table 3. The intraoperative benchmark values were ≥4 lymph nodes retrieved, EBL ≤350 mL, perioperative blood transfusion rate ≤13%, and operative time ≤332 min. The postoperative benchmark values were hospital stay ≤8, complication rate ≤22%, rate of major complications ≤11%, and rate of R1 margins ≤7%.

Major liver resection in GBC

Overall, 60 (6%) patients underwent major hepatectomy (excluding 28 patients who also underwent pancreatoduodenectomy). Of these 60 patients, 77% (43/60) of patients had CBD resection, 17% (14/60) of patients had adjacent organ resection, and 15% (9/60) of patients had vascular inflow resection. Compared to the gallbladder bed or bysegmentectomy group, the major liver resection group had significantly more CBD, adjacent organ, and vascular inflow resection (p < 0.001).

Patients who underwent major hepatectomy had a rate of overall morbidity of 68%, severe morbidity of 35%, and 90-days mortality of 9.6%. In addition, patients who underwent major hepatectomy had a median survival of 16 months and a predicted 5-year OS of 20%, compared with 58 months and 50% for patients who did not undergo major hepatic resection (p < 0.001).

Practice Patterns by Continent in the Entire Study Population

In all four continents, there were more females than males with GBC, although the female preponderance was lower in Asia. The youngest median age at GBC presentation was in South America (62 years), and the oldest was in Asia (71 years). In North America 80% of the GBC cases were detected as incidental findings, whereas in Asia, only 10% were. Preoperative chemotherapy for GBC was given to 19% of the patients in North America but was rarely (1% to 4% of patients) given to patients in other continents. In contrast, postoperative chemotherapy was administered to almost 50% of patients in North America, Europe, and Asia, and to 24% of those in South America. Minimally invasive OER was performed more frequently in South America (25% of cases) and Europe (21% of cases) than in North America or Asia. However, major liver resection, CBD resection, and the use of Pringle maneuver during liver resection were performed more frequently in Asia than in any other continent. In all four continents, adenocarcinoma was the most frequent histologic type of GBC, and half or more of patients were diagnosed with stage ≥ III disease (Table 4).

Table 4.

Patterns of practice by continent

Characteristic Asia Europe North America  South America
All patients 52 (6) 254 (28) 266 (29) 334 (37)
Female, % 29 (56) 154 (61) 180 (68) 262 (78)
Age, median (IQR), years 71 (63-76) 66 (59-72) 65 (57-72) 62 (53-69)
Body mass index, median (IQR), kg/m2 21 (19-23) 25 (23-29) 28 (24-31) 27 (24-31)
Incidental gallbladder cancer, yes 5 (10) 134 (53) 214 (80) 223 (67)
Acute cholecystitis, yes 7 (13) 25 (10) 108 (41) 130 (39)
Cholelithiasis at surgery, yes 21 (40) 144 (57) 151 (57) 273 (82)
Oncologic extended resection (OER)
 Preoperative chemotherapy or chemoradiation, yes 1 (2) 9 (4) 50 (19) 2 (1)
 Minimally invasive OER, yes 3 (6) 54 (21) 20 (8) 84 (25)
 Major liver resection, yes 23 (44) 30 (12) 14 (5) 21 (6)
 Pringle maneuver, yes 39 (75) 143 (56) 125 (47) 74 (22)
 Common bile duct resection, yes 32 (62) 32 (13) 56 (21) 69 (21)
 Postoperative hospital stay, median (IQR), days 31 (17-43) 8 (6-11) 6 (4-7) 5 (4-7)
 Histologic type
  Adenocarcinoma, yes 46 (88) 217 (85) 253 (95) 317 (95)
 AJCC 7th edition staging system, stage III/IV, yes 42 (81) 152 (60) 126 (47) 192 (57)
 Postoperative chemotherapy or chemoradiation, yes 23 (44) 108 (43) 148 (56) 80 (24)
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Abbreviation: AJCC, American Joint Committee on Cancer; IQR, interquartile range.

DISCUSSION

In this international multicenter study, we found that benchmark values for GBC surgery include ≥4 lymph nodes retrieved, EBL ≤350 mL, perioperative blood transfusion rate ≤13%, operative time ≤332 min, postoperative hospital stay ≤8, R1 margin rate ≤7%, complication rate ≤22%, and rate of major complications ≤11%. In addition, we found that surgery for GBC remains associated with significant morbidity: in the benchmark group, the 90-day complication rate was 20%, with 20 patients (8%) experiencing major complications. To our knowledge, this is the first study to identify benchmark values for OER in GBC.

Although GBC is the most common type of biliary tract cancer worldwide, our knowledge of new treatments and surgical standards is limited. Hence, GBC is usually portrayed as an “orphan cancer” because it is rare in regions of the world where most medical research is funded and performed.25 The benchmark values presented here will allow surgeons and institutions to a) define the best resection, not only in terms of patient survival, but also by various outcome indicators in “ideal” GBC patients and b) enable comparisons with other GBC patient groups, increasing the quality of research collaboration. In addition, the benchmark values may help to safely decide when a center should incorporate minimally-invasive surgery in the treatment of GBC.

The importance of optimal lymphadenectomy for GBC is widely supported by evidence: lymph node dissection and higher number of lymph nodes retrieved are associated with better survival,26–30 even in node-negative patients.5 In our study, the median number of lymph nodes retrieved ranged from four to nine, and the benchmark value was removal of ≥4 nodes. Removal of six lymph nodes is recommended in the eighth edition of the AJCC Cancer Staging Manual, but may be challenging.31 However, studies have shown that lymph node yield following portal lymphadenectomy, even when standardized surgical technique is followed, can often be below this standard.32 Evaluation of ≥4 lymph nodes may be a more appropriate threshold as this cut-off value was associated with optimal short- and long-term outcomes among patients undergoing surgery for GBC.33 The latter study validates our benchmark value of ≥4 lymph nodes retrieved.

Interestingly, median values for blood loss and operative time in the Tokyo minor hepatectomy cohort of Kawaguchi et al. were almost double the values included in our analysis of GBC resection.34–37 This further suggests that blood loss and operative time should not be contextualized as an index for morbidity associated with GBC resection, as it is in minor hepatectomy. Instead, morbidity in GBC resection needs to be correlated to different intraoperative metrics specific to GBC, such as extension of the lymphadenectomy.6,37–39

The rate of postoperative complications of GBC surgery in the benchmark group in our current study, 20%, was comparable to previously reported rates of postoperative complications for major hepato-pancreato-biliary procedures. Pancreaticoduodenectomy is widely understood as a morbid procedure with a considerable rate of postoperative morbidity, with some studies reporting postoperative morbidity rates of 30% to 60%.40–42 Similarly, major hepatectomy and surgical resection for cholangiocarcinoma are associated with high rates of morbidity.43–45 Ziogas et al., in a meta-analysis and systematic review, reported that the complication rate for major hepatectomy ranged from 18.4% with a robotic approach to 28.3% with a laparoscopic approach.44 In an analysis of surgical resection of hilar cholangiocarcinoma, Hasegawa et al. found that 32.8% of patients experienced a postoperative complication.46 Our finding regarding the rate of postoperative complication after GBC surgery suggests that GBC resection, similar to the hepato-pancreato-biliary procedures mentioned above, should be performed at high-volume, specialized centers that are capable of handling high rates of postoperative complications while maintaining high-quality surgery.47

Regarding our findings of geographic differences in patterns of practice, consistent with previously reported observations, female predominance was less marked in Asia, and major hepatectomy, Pringle maneuver, and CBD resection were performed more frequently in Asia.48 Also, the rate of preoperative therapy, but not postoperative therapy, was considerably higher in North America than in the other continents. Another interesting finding was the adoption of minimally invasive surgery for GBC in South America and Europe, which was likely influenced by the high incidence of GBC in those regions and the availability of expertise in minimally invasive techniques among the centers included in our study. We did not analyze differences in survival by continent because our study included only one center from Asia.

This study has several limitations. First, complications were classified using the Clavien-Dindo classification. A more granular analysis of complications, using the comprehensive complication index, for example, might have allowed us to better assess the precise weight of major and minor complications.49 Second, although we included a high number of centers, inclusion of more centers, specifically centers from Asia and other areas where GBC is endemic, would have allowed for a more robust analysis. Third, future benchmark analyses should stratify not only according to low-risk and high-risk surgery, but also according to low-risk and high-risk patients. For instance, analyzing according to Charlson Comobidity Index or the presence of cirrhosis can better define, not only benchmark values, but also lower-risk patients. Finally, the challenges of accurately estimating blood loss in a retrospective study should be mentioned. However, it is important to note that despite the limitations of estimating blood loss, it remains a clinically relevant and commonly used metric in surgical practice, and we have incorporated blood transfusion rate in our results to provide a more complete picture of our results.

CONCLUSION

We identified benchmark values for OER of GBC that can serve as key references for quality improvement efforts and for future comparisons between GBC patients, GBC surgical approaches, and centers performing GBC surgery. In particular, the availability of these benchmarks can guide surgical teams to strive for optimal outcomes in GBC surgery, benefiting their patients and better contextualizing GBC resection as a complex surgery that requires specialized care.

Supplementary Material

Supplemental

SYNOPSIS.

Surgery for GBC is complex, requiring expertise, and associated with significant morbidity. The present study defines benchmark values, which represent the best achievable results in patients with GBC. Such values may help promote high-quality surgery and reach excellent oncologic care.

ACKNOWLEDGMENTS

The authors thank Stephanie Deming, Research Medical Library, MD Anderson Cancer Center for valuable editorial support and recognize Ms. Ruth Haynes for administrative support in the preparation of this manuscript

Financial Support:

This study was supported by the National Cancer Institute under award number P30CA016672, which supports the MD Anderson Cancer Center Clinical Trials Support Resource.

Footnotes

Conflicts of Interest and Source of Funding: None of the authors declare any conflict of interest.

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