Does Timing of Completion Radical Cholecystectomy Determine the Survival Outcome in Incidental Carcinoma Gallbladder - a Single Center Retrospective Analysis
Conditions: Gall Bladder Carcinoma, Survival
Sponsor: Sanjay Gandhi Postgraduate Institute of Medical Sciences

COVER PAGE: 
I am submitting a manuscript for consideration of registration in Clinical Trials. The manuscript 
is entitled “Does timing of completion radical cholecystectomy determine the survival 
outcome in incidental carcinoma gallbladder – a single center retrospective analysis”. 
NCT number – not available 
Date – 05.11.2021  (Results were last updated on 01.01.2019) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

STUDY PLAN: 
Surgical Gastroenterology department at our institute is a tertiary referral center for hepatobiliary 
malignancies; covers a large part of North and North-east India. The details and progress report 
of patients of Gallbladder Cancer (GBC) being referred to and treated at the institute is 
maintained in a prospective manner on hospital data base. This included demographic data, 
presenting complains, details of relevant investigations done outside and in the hospital, previous 
surgery, pre-hospital course, operative findings, post operative course and final histopathology. 
During the study period (Jan 2009 to Dec 2018), 1049 participants with the diagnosis of GBC 
(including 91 IGBC patients) were admitted; 239/958 participants with the diagnosis of GBC and 
48/91 participants with the diagnosis of IGBC could undergo resection with curative intent. 
Information regarding adjuvant therapy, recurrence, and survival were retrieved through data 
maintained on follow up out-patient cards till December 2019. Few participants who stopped 
visiting the hospital were contacted telephonically or through letters.  
 
Tumors were staged as per 8th edition of AJCC-TNM staging. Preoperative workup included 
contrast enhanced axial imaging (CECT – contrast enhanced computed tomography). In few 
cases with high risk features (residual disease on CT scan or late presentation), Positron 
Emission Tomography (PET) scan was added. Participants found fit for surgery and those with 
resectable disease on imaging were considered for the definite procedure. Laparoscopy was done 
preferably in those presenting beyond 4 weeks of index surgery or residual disease (local or 
nodal) on imaging to rule out metastasis. In absence of obvious distant metastasis (ascites, 
peritoneal nodules, mesenteric nodules, serosal nodules), inter-aortocaval (IAC) tissue was sent 
for evaluation of nodal metastasis. Once IAC node was found negative for deposits on frozen-
section examination, radical re-resection was attempted. It included wedge resection of liver or 
Segment 4b/5 excision with regional lymphadenectomy. Extrahepatic bile duct excision was 
added in presence of positive cystic duct margin or direct invasion into the duct. 
All available histopathology blocks and slides following the index cholecystectomy were re-
reviewed by the pathologists at our institute. Tumor type, differentiation and primary T stage 
were documented for majority of cases. Interval between index cholecystectomy and date of re-
operation was calculated for all the participants and divided into 3 groups: Early (<4weeks), 

Intermediate (4-12 weeks) and Late (>12 weeks). Primary objective was to assess the effect of 
tumor characteristics and the time gap (between index surgery and re-resection) on overall 
survival following curative (R0/R1) resection.  
 
Statistical Analysis: 
Continuous variables were presented in median (range) while categorical data was expressed in 
frequency (%). A variable was considered as normally distributed when the Z-score was within 
±3.29 (n≥50). To compare the means/medians between two groups, independent samples t-
test/Mann Whitney U test was used. To test the association between categorical variables, Chi 
square tests or Fisher exact test was used. Event free survival was calculated for the patients 
using the Kaplan-Meier survival plots using Log rank test and Breslow test. Univariate and 
multivariate Cox regression analysis were used to identify the predictors of survival. Variables 
found significant in Univariate analysis were included for multivariate analysis. A two tailed p-
value of <0.05 was considered statistically significant. Statistical package for social sciences 
version-23 (SPSS-23, IBM, Chicago, USA) and MedCals software was used for data analysis. 
 
RESULTS: 
During the study period, 48 participants {11 (22.9%) in Group ‘E’, 31 (64.5%) in Group ‘I’ and 
6 (12.5%) in Group ‘L’} underwent re-resection with curative intent. The demographic profile 
(age and gender), co-morbidities, tumor characteristics, extent of resection, resection margin and 
nodal clearance were similar in the three groups (each p>0.05). Median age of participants with 
IGBC was 55 years and 2.7 times more common among females.  
Similarly, presence of residual disease, grades of the tumor, primary stage of the tumor following 
index cholecystectomy, final stage after curative resection, adjuvant therapy and associated 
morbidity were statistically equal among the groups (each p>0.05). No post operative mortality 
was recorded. The most common complication in the postoperative period was surgical site 
infection (SSI), recorded in 8 patients. Three patients required postoperative percutaneous 
drainage for intra-abdominal collection. No patient required prolonged hospital stay or 
reoperation. 
Overall Survival (OS) and Disease-free survival (DFS): 

Mean and median follow-up was 51.6 and 40.6 months, respectively (range: 1.2-130.6). Total 
9(18.7%) patients were reported lost to follow up during the study period. Mean overall survival 
(OS) in study patients was 91.75(95% CI: 8.32-75.44) months. As OS percentage did not reach 
<50%, resultant median survival could not be computed.  Similarly the mean DFS following 
curative resection was 85.63 (95% CI: 69.48-101.79) months (As the patient recurrence free 
survival percentage did not reach below 50%, resultant median recurrence free survival time 
could not be computed).  
In present study, 29(60.4%) of those undergoing definitive surgery received chemotherapy. 
Around 58% received >1 cycle and 44% could complete their therapy. Radiotherapy was given 
to 42% participants. The most important indications for adjuvant therapy included good 
performance status with advanced stage and margin positive and/or node positive disease. OS 
among participants who received adjuvant therapy was similar to those who were not offered 
chemotherapy [88.10 (95% CI: 67.18-109.03) Vs 87.56 (95% CI: 61.66-113.45) months 
(p=0.916) (Fig 1). Similarly DFS among participants who received adjuvant therapy was similar 
to those who did not receive any post operative treatment. [86.18 (95% CI: 65.73-106.64) Vs 
85.37 (95% CI: 59.82-110.91) months (p=0.915). 
 
 

 
Figure 1: Overall impact of adjuvant therapy on event free survival. 
 
 
 
Figure 2 : Overall event free survival in study patients as per timing of treatment.  
 
 
Kaplan Meier method (log rank test) was used to compare the event free and disease-free 
survival time of the patients among the three groups. Though the participants operated within 4 
weeks and between 4-12 weeks fared a better OS and DFS than those operated beyond 12 weeks, 
the difference could not achieve statistical significance. (Event free survival time (p=0.575) and 

disease-free survival time (p=0.581))(Figures 2&3)
 
Figure 3: Overall disease free survival in study patients as per timing of treatment.  
 
Survival Analysis: 
On Univariate analysis of factors associated with significantly poor survival following curative 
resection were: presence of nodal metastasis, poor differentiation and lesions necessitating CBD 
excision. Other factors portending an unfavorable outcome included presence of residual disease, 
lympho-vascular invasion and delay in re-resection beyond 12 weeks, though the difference was 
not statistically significant. Primary tumor stage, resection margin and use of adjuvant therapy 
did not affect the overall survival (each p>0.05). Residual disease was present in 20 out of 48 
(41.6%) participants. The distribution of residual disease following re-resection, according to the 
index T-stage was (16% in T1, 29% in T2 and 72% in T3 tumors). 
To further assess the predictors of survival among the participants, multivariate Cox regression 
analysis was used. Three variables (Node status, Grades and Extent of resection) which were 
significant on Univariate analysis were included in multivariate analysis. Results showed that 
disease grade was the only significant independent predictor of survival. Presence of positive 

nodes (p=0.052) and the need for CBD excision (0.133) was associated with increased relative 
risk of disease related mortality, although the difference was not statistically significant.