Gallbladder cancer is a rare but highly lethal malignant disorder. Historically, it has been considered a terminal disease, with 5-year survival rates ranging from 0% to 12%, with a median survival of 6.4 months [1,2].
Surgery offers the only possibility of cure [3]. Although recent guidelines suggest that stage T2 and T3 gallbladder cancers should be treated by extended cholecystectomy, high-level evidence is lacking, because these guidelines are largely based on observational studies from isolated institutions [4]. Therefore, the extent of surgical resection for stage T2 and T3 gallbladder cancer remains an important field of study in hepatobiliary surgery.
The objective of the present study was to describe the association between the extent of surgical resection and overall survival in patients with stage T2 and T3 gallbladder cancer, in a large contemporary population-based cohort.
| Methods |
> Study design and setting
This was a retrospective, population-based cohort study of all gallbladder cancers resected in Ontario, Canada. Ontario has a population of about 13.5 million people, and a single-payer health insurance program, which provides coverage for doctors and hospital services.
> Study population and data sources
All incident gallbladder cancer cases from January 1, 2002, to March 31, 2012, were identified from the Ontario Cancer Registry (OCR), a passive, population-based cancer registry that captures diagnoses and information demographic of 98% of all incident cancer cases in Ontario [5].
OCR surgical pathology reports were obtained for all potentially eligible patients. All patients in whom T stage could not be determined, patients with gallbladder cancer with histologic findings of disease other than adenocarcinoma or adenosquamous carcinoma, and patients with metastatic gallbladder cancer at initial surgery were excluded.
Patients who had undergone cholecystectomy and subsequent re-resection were identified based on the presence of 2 separate pathological reports on different data, 1 for cholecystectomy, and the other for extended resection.
Simple cholecystectomy was defined as the removal of the gallbladder only, and extended resection was defined as cholecystectomy with initial or delayed partial resection of the liver or bile duct or both.
The OCR also provides information on vital status and cause of death. Complete information related to vital status was available until December 31, 2012, and information related to cause of death until December 31, 2010.
Per ICES ( International Credential Evaluation Service ) and Cancer Care Ontario policy , values for cells with fewer than 6 cases were suppressed; Results in these fields were reported as approximate values to ensure confidentiality. This study was approved by the General Research Ethics Board of Queen’s University , Kingston, Canada.
• Adjuvant treatment
The radiotherapy and chemotherapy databases are maintained by the Division of Cancer Care and Epidemiology at Queen’s University , with permission from the 14 cancer centers in Ontario. Using the unique identifier for each patient in the OCR, the Division links the OCR cancer diagnosis to cancer centers’ administrative chemotherapy and radiation therapy data. Only adjuvant treatment with curative intent was included in this study.
• Socioeconomic status
For the purpose of this study, socioeconomic status was estimated using an ecological measure: median household income in the patient’s neighborhood. Median household income at the broadcast area level was obtained from Statistics Canada .
Dissemination areas were grouped into quintiles according to average family income, with the fifth quintile constituting the richest 20%, and the first quintile constituting the poorest 20%.
> Primary and secondary result
The primary outcome was overall survival, and the secondary outcome was cancer-specific survival.
> Statistical analysis
All analyzes were performed using SAS 9.4 software (SAS Institute). Kaplan-Meier survival analysis was used to model time to death, with censoring occurring on December 31, 2012 for overall survival, and December 31, 2010 for cancer-specific survival. Factors associated with overall survival were evaluated using the Cox proportional hazards regression model.
Before constructing the Cox model, a bivariate analysis was performed on the following potential confounding variables: age, sex, socioeconomic status, presence or absence of lymphovascular invasion and perineural invasion, positive lymph nodes, and adjuvant treatment. In bivariate analysis, socioeconomic status and adjuvant treatment failed to reach p < 0.2 for stages T2 and T3 and were therefore excluded from the full Cox model.
Resection margin status was not included in the Cox model, because it caused a significant effect of multicollinearity in the model. There was a high Pearson correlation coefficient (r2 = 0.84) between margin status and type of resection (exposure variable).
When margin status was forced into the Cox model it led to large and erratic changes in the regression coefficient of the other predictor variables. Therefore, it can be conceptualized that margin status is simply a surrogate marker of surgery type, in that patients who underwent extended resection tended to have negative margins.
| Results |
Linkage to the administrative data set identified 1055 potentially eligible patients who underwent procedures for gallbladder cancer from January 1, 2002 to December 31, 2012, of whom 500 were excluded because they had only one biopsy procedure. Following all exclusion criteria, 370 patients constituted the study cohort, 232 with stage T2, and 138 with stage T3.
Of the 232 patients with T2, 176 (75.9%) had a simple cholecystectomy, and 56 (24.1%) had an extended resection. Patients who underwent simple cholecystectomy were, on average, older than those who had an extended resection (mean age 69.8 vs. 63.4 years).
In the group with extended resection, 23 (42.8%) had an advanced extended resection, and 33 (57.1%) had a delayed resection. Delayed resection procedures were performed on average 2.9 months (range: 1.0 to 5.0) after the initial cholecystectomy.
Of the 138 patients with T3 disease, 87 (63.0%) had a simple cholecystectomy, and 51 (37.0%) had an extended resection. As in the T2 group, patients who underwent a simple cholecystectomy were older than those who underwent an extended resection (mean age 70.0 vs. 66.3 years).
Thirty-six patients (72.5%) had an advanced resection and 15 (29.4%) had a delayed resection. Delayed resection procedures were performed on average at 2.2 months (range: 1.2 to 5.0).
> Survival
In the T2 group, the unadjusted 5-year overall survival rate, for those undergoing extended resection, was 49.5%, compared with 39.7% for those with simple cholecystectomy ( p = 0.03). . The 5-year cancer-specific survival rates were 49.9% and 41.3%, respectively ( p = 0.03).
Median overall survival was greater than 60 months for extended resection, compared with 23 months for simple resection ( p = 0.08). The 30-day postoperative mortality rate was 1.7% for both simple cholecystectomy and extended resection.
In T3 disease, the unadjusted 5-year overall survival rate for those undergoing extended resection was 22.8%, and 13.5% for those undergoing simple cholecystectomy ( p = 0.05). The corresponding 5-year cancer-specific survival rates were 24.4% and 17.0% ( p = 0.06).
Median 5-year overall survival was 21.5 months for extended resection, compared with 10.5 months for simple cholecystectomy ( p = 0.001). The 30-day postoperative mortality rate was 2.2% for the simple cholecystectomy group, and 0% for the extended resection group.
> Factors associated with survival
For T2 disease, in multivariate analysis, extended resection was associated with improved overall survival compared with simple resection (hazard ratio [HR] 0.51; 95% confidence interval (CI): 0.30 -0.97).
Patients with a high degree of differentiation (RR 3.42; 95% CI: 1.92-6.08), presence of lymphovascular invasion (RR 1.75; 95% CI: 1.16-2.64), and presence of positive lymph nodes (OR 1.78; 95% CI: 1.03-3.08), had a worse overall survival. Females showed a trend towards better overall survival compared to males (OR 0.70; 95% CI: 0.49-1.01).
In patients with stage T3 tumors, multivariate analysis showed no survival benefit for extended resection (OR 1.09; 95% CI: 0.62-1.92). In the full model, advanced age (RR 1.04; 95% CI: 1.02-1.06) showed a worse prognosis, but female sex was protective (RR 0.66; 95% CI: 0.43-1.06). 1.00).
When the interaction terms between the type of surgery (exposure variant) and the other potential confounding factors were tested, the results showed a trend towards a significant multiplicative interaction between lymph node status and the type of surgery ( p = 0. 1). Therefore, a subgroup analysis was performed for T3 disease, stratified by nodal status.
There was a trend toward improved survival among patients in that group who underwent extended surgery and had negative lymph node status (OR 0.20; 95% CI: 0.03-1.06); No survival benefit was observed in patients undergoing extended resection who had positive or unknown lymph node status.
No other pathological variable showed an association with survival for positive or negative lymph node status. Female sex had a suggestive protective effect in node-positive disease (RR 0.47; 95% CI: 0.21-1.04).
| Discussion |
Several important findings emerge from this study regarding surgical practice patterns and outcomes in stage T2 and T3 gallbladder cancer in Ontario. The use of extended resection was modest: only 24% of patients with T2 disease, and 37% of those with T3 disease, underwent extended resection.
In the T2 group, overall survival among patients who underwent extended resection was significantly better than those who had a simple cholecystectomy, with an ORR of 0.51. In the T3 group, a trend toward improved survival was noted only among lymph node-negative patients who underwent extended resection.
Although the proportion of patients who had an extended resection in this study was modest, it was higher than that reported in a 2009 US study using population-level data, 5.2% for T2 cancer and 13.3% for T3 [6]. However, the small proportion of patients who underwent extended resection is concerning, in view of the results.
The current National Comprehensive Cancer Network guideline recommends extended cholecystectomy for all stage T2 gallbladder cancers [4]. Support for extended resection is based on several older observational studies [6-9].
A population-based study by Coburn et al. [10], using data from the Surveillance, Epidemiology, and End Results (SEER) Program registry , showed a significant improvement in survival for extended versus simple cholecystectomy in the Kaplan-Meier analysis, but that effect was attenuated in the multivariable model.
However, the benefit of extended resection has recently been questioned [11-14]. Based on a series of 21 patients, Watson et al. [13], argued that extended resection for T2 gallbladder cancers simply eclipses the disease, with no change in overall survival.
Cho et al. [14] also reported that liver resection does not have a significant effect on survival in patients with T2 gallbladder cancer, with only lymph node metastases being a predictor of overall survival.
In contrast, the present study clearly shows that, in addition to the absence of nodal metastasis, the lack of lymphovascular invasion, a low degree of cellular differentiation, and extended resection, are all independent predictors of better overall survival.
In relation to T3 gallbladder cancer, an unadjusted Kaplan-Meier analysis found an improvement in overall survival with extended resection compared with simple cholecystectomy. However, the benefit of extended resection was attenuated in adjusted multivariable analysis.
Two large population-based studies in the US using the same SEER data also showed no improvement in overall survival between simple cholecystectomy and extended resection for T3 cancers [6,10].
A subgroup analysis for T3 disease stratified by lymph node status showed a trend toward improvement in overall survival with extended resection in patients with node-negative, compared with node-positive disease, or lymph node status. unknown lymph node, although the sample was small: among the 27 patients with T3 disease with negative lymph nodes, there were fewer than 6 in the simple cholecystectomy group and 23 in the extended resection group.
This result agrees with previous studies of isolated institutions. Benoist et al. [15] reported that there were no long-term survivors with node-positive disease among 21 patients who underwent radical resection with portal lymph node dissection. They concluded that radical resection should only be considered in the absence of regional lymph node metastases [15].
Dixon et al. [16], reported improved survival among 99 patients with gallbladder cancer who underwent curative extended resection. However, there were no 5-year survivors with node-positive disease in their series, suggesting that aggressive surgery rarely achieves long-term survival in patients who have positive lymph nodes.
In the present cohort of 46 patients with node-positive T3 disease, there appeared to be no improvement in survival among those who underwent extended resection compared with those who underwent simple cholecystectomy. However, the point estimate of the RT (0.63) still favored extended resection.
Therefore, these results should be interpreted with caution, and should not automatically dissuade surgeons from performing extended resection in node-positive patients.
In their cohort of 116 patients with gallbladder cancer, Sakata et al. [17], observed worse outcomes in patients with positive nodes than in those without regional lymph node disease; However, radical resection was found to be effective against 3 positive lymph nodes, a result replicated in the study by Shirai et al. [18].
Likewise, although the present study did not show an effect of adjuvant treatment for gallbladder cancer, Tran Cao et al. [19], reported that the best outcome for node-positive patients was an R0 resection followed by adjuvant chemotherapy and radiation, while adjuvant chemotherapy alone did not prove beneficial.
In agreement with previous studies [6,20], younger age and female sex showed a protective effect on T3 disease in the present study. However, sex-specific factors that influence the prognosis of patients with gallbladder cancer remain unknown.
> Limitations
The strength of this study, compared to previous population-based studies [6,10], lies in the availability of key oncological variables, such as adjuvant treatment data, and pathological variables, which allowed a more comprehensive evaluation of the role of aggressive surgery for gallbladder cancer.
Limitations include that a retrospective database was used, and that there was a modest sample size, in both cases, both a result of and a reflection of the rarity of gallbladder cancer. Furthermore, as in population-based studies using the SEER [6,10], the database does not contain variables related to patient comorbidities. However, in an aggressive disease such as gallbladder cancer, the effect of other comorbidities may be marginal.
On the other hand, to mitigate the effects of comorbidity, results for cancer-specific survival were calculated in the population subgroup in which these data were available (2002-2010). More than 90% of that cohort had cancer as the cause of death, and the median and 5-year survival data were consistent with overall survival results from other reports [6,7,10].
| Conclusion |
Extended resection, well-differentiated tumors, absence of positive lymph node disease, and absence of lymphovascular invasion were all independently associated with improved survival of patients with stage T2 gallbladder cancer. These results add to the existing literature on the benefits of extended resection for T2 disease.
For stage T3 disease, extended resection appears to be most beneficial in node-negative disease. The finding that extended resection was offered to only a small proportion of eligible patients with gallbladder cancer in Ontario highlights the need to improve knowledge translation at national surgical meetings.
