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81]

Original Article

Influence of adjuvant therapy on pattern of

failure and survival in curatively resected
gallbladder carcinoma Sunil Choudhary,
Neha Gupta1,
Chandra Prakash
ABSTRACT
Verma1,
Purpose: The study was done to evaluate the role of adjuvant therapy in curatively resected Stage II and III gallbladder carcinoma (GBC). Avipsa Das2,
Materials and Methods: This was a retrospective analysis of patients of GBC registered between 2008 and 2017 in Lalit Mohan
outpatient department of a tertiary cancer hospital in India. Patients who had any of the following adjuvant treatment after Aggarwal,
radical surgery: (a) external beam radiotherapy (RT) alone, (b) chemotherapy (CT) alone, and (c) RT with CT (CRT) were Mallika Tewari3,
considered for the study. Abhijit Mandal,
Anupam Kumar
Results: A total of fifty patients could meet the selection criteria. It was seen that seven patients were treated with RT, 20 with CT,
Asthana
and 23 with CRT. Median follow‑up for patients who were alive was 26.7 months. Nineteen patients had locoregional failure while
eight had distant failure. Patients treated with CRT had a significantly better mean overall survival compared to those treated with RT Departments of
or CT (44.0 months, 12.5 months, and 15.1 months, respectively; P = 0.003). Similarly, mean disease‑free survival was superior Radiotherapy
in CRT arm compared to RT and CT arms (43.6 months, 9.6 months, and 12.4 months, respectively; P = 0.002). and Radiation
Medicine and
Conclusions: Adjuvant CRT had better survival outcome compared to patients treated with either RT or CT with Stage II and III 3
Surgical Oncology,
disease after curative cholecystectomy. Institute of Medical
Sciences, Banaras
Hindu University,
KEY WORDS: Adjuvant chemotherapy, adjuvant radiotherapy, cholecystectomy, combined modality therapy, gallbladder cancer
1
Department of
Radiotherapy, Apex
Cancer Institute, Apex
Hospital, Varanasi,
INTRODUCTION where only Stage II and III GBC patients were Uttar Pradesh,
included so as to evaluate the effect of adjuvant 2
Department of
Gallbladder cancer is a disease with dismal Radiation Oncology,
treatment.
Tata Memorial Centre,
prognosis that affects thousands of people annually. Kolkata, West Bengal,
The 2004 National Comprehensive Cancer Network MATERIALS AND METHODS India
does not recommend adjuvant treatment for Stage
I disease. Patients who present with metastatic For correspondence:
Patients of GBC registered in our radiotherapy (RT)
Dr. Neha Gupta,
disease are usually offered best supportive care outpatient department between 2008 and 2017 Apex Cancer
or palliative chemotherapy (CT). Most of the were considered for this study. The record files of Institute, Apex
retrospective series addressing adjuvant therapy these patients were thoroughly studied for patient, Hospital, Varanasi,
have small sample size and are heterogenous due to disease, and treatment characteristics. Patients Uttar Pradesh, India.
E‑mail: drneha_500@
the inclusion of the following: (a) patients with both who fulfilled the selection criteria as mentioned yahoo.com
complete and incomplete surgery with residual below were included in the study.
disease, (b) Stage II and III are mixed with Stage • Histopathologically proven gallbladder cancer Submitted: 02-Aug-2019
I/IV diseases, and (c) gallbladder carcinoma (GBC) • Curative cholecystectomy Revised: 20-Aug-2019
included with other intrahepatic and extrahepatic • Stage II and III GBC Accepted: 23-Aug-2019
cholangiocarcinoma. Therefore, it is very difficult to • Completed any of the below adjuvant treatment: Published: 28-Oct-2020
draw any meaningful conclusion from these trials. Access this article online
This is an open access journal, and articles are distributed under the terms of the Website: www.cancerjournal.net
It is very difficult to have prospective studies for Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which DOI: 10.4103/jcrt.JCRT_550_19
allows others to remix, tweak, and build upon the work non‑commercially, as
Stage II and III GBC for two reasons: (1) GBC is long as appropriate credit is given and the new creations are licensed under the
Quick Response Code:

very rare and (2) GBC usually presents in advanced identical terms.

stage. Therefore, we could do a retrospective study For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com

Cite this article as: Choudhary S, Gupta N, Verma CP, Das A, Aggarwal LM, Tewari M, et al. Influence of adjuvant therapy
on pattern of failure and survival in curatively resected gallbladder carcinoma. J Can Res Ther 2021;17:1064-8.

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Choudhary, et al.: Adjuvant therapy in gallbladder carcinoma

1. External beam RT (EBRT) alone to a dose of 40–54 Overall FU duration for entire population was 14.4 months.
Gy/4–6 weeks Median FU for patients who were alive was 26.7 months. The
2. CT alone: 5–6 cycles status of the patients at the time of analysis is mentioned
3. EBRT and CT combined. in Table 1. The pattern of disease failure and survival
outcome based on the treatment group is mentioned in
Patients were treated with telecobalt or linear accelerator Table 2. There was no difference in OS and DFS between RT
with conventional/three‑dimensional conformal RT and CT arms (P = 0.561 and 0.942) [Figure 1]. However, the
technique (3DCRT) or intensity‑modulated RT (IMRT). Patients difference in OS and DFS between CRT and RT or CT was
were treated with conventional fractionation schedule. significant (P = 0.003 and 0.002) [Figure 2]. We compared the
Tumor bed with draining regional lymph nodes were demographic profile of the patients in these three treatment
included in the treatment voulme. Radical dose of 40 Gy–54 arms and found that they were comparable in all the aspects
Gy in 20–30 fractions were prescribed. Two anterolateral except the grade of the tumor [Table 3].
wedge pair fields were used when the patients were treated
on telecobalt unit. Multiple fields were used with 3DCRT Univariate analysis was done to find the factors which could
and IMRT techniques. have affected the survival. It was tested for age, stage of
the disease, LVI, PNI, and resection margin. None of these
CT was given 3 weeks after completion of adjuvant RT. factors were found to have significant impact on survival
Gemcitabine and cisplatin were used in combination as outcome [Table 4].
3 weekly regimes. The patients were planned for six cycles
of CT. Most of the patients had completed RT in the intended duration
of treatment. CT toxicities were usually confined to nausea
Statistical analysis was done using SPSS Inc, (Chicago, and vomiting. CT dose modification was deemed necessary
USA). The primary endpoints were overall survival (OS) and in few patients because of hematological toxicities. No major
disease‑free survival (DFS). DFS and OS were estimated by complication was recorded in any of these patients. There was no
the Kaplan–Meier method and differences between curves difference in late toxicities among the three treatment groups.
tested by the Log‑rank test. All endpoints were measured
from the date of registration, and patients dying of any DISCUSSION
cause (or lost to follow‑up (FU) were considered as events
for both the end points of DFS and OS. Gallbladder cancer is known to fail both at locoregional sites as
well as distant regions. Therefore, it is reasonable to combine
Since this was a retrospective study, permission of the ethical treatment modalities so as to reduce both locoregional and
committee and consent of the patients were not deemed distant failure. Both locoregional and distant failure were less
necessary. in patients who were treated with CRT than those compared
to patients treated with only one modality. The results of
RESULTS
Table 1: Status of patients on last follow‑up
A total of 50 patients were found who could fulfill all the Status of patient on last follow‑up RT alone CT alone CRT
selection criteria. Majority of the population cohort was Alive without disease 0 3 11
female (84%). The median age was 55 years (range 24–73 years). Alive with disease 0 0 3
LFU without disease 0 4 0
All except two patients had adenocarcinoma. Stage II and III
LFU with disease 3 8 4
had almost equal distribution. Dead due to other cause 0 0 1
Dead due to disease 4 5 4
All the patients had cholecystectomy with no gross residual RT=Radiotherapy, CT=Chemotherapy, CRT=Chemoradiation, LFU=Lost to
follow up
disease at the primary site. Lymph node dissection was not
done in thirty patients. Lymphovascular invasion (LVI) was
Table 2: Pattern of failure and disease outcome
not reported in half of the patients. Perineural invasion (PNI)
was unknown in 58% of population. Resection margin was RT alone CT alone CRT
negative in about two‑third of cohort. (n=7) (n=20) (n=23)
Failure
Locoregional 4 9 8
Seven patients had received RT alone, twenty patients were Distant 2 0 2
treated with CT alone while remaining 23 patients were Locoregional + distant 1 3 0
treated with CRT. Median dose of RT was 45 Gy and median RT Survival (months)
OS (mean) 12.5 15.2 44.0
duration was 34.5 days. Gemcitabine with cisplatin regimen
DFS (mean) 9.6 12.4 43.6
was given to 43 patients, and they had received 5–6 cycles at RT=Radiotherapy, CT=Chemotherapy, CRT=Chemoradiation, OS=Overall
3 weeks’ interval. survival, DFS=Disease‑free survival

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Choudhary, et al.: Adjuvant therapy in gallbladder carcinoma

Figure 1: Overall survival based on treatment arm Figure 2: Disease‑free survival based on treatment arm

Table 3: Demographic profile of patients 28 patients (40%). Twelve patients had isolated distant failure.
Variables RT alone CT alone CRT P Based on the initial pattern of failure, the author suggested
Age (years) adjuvant RT after curative cholecystectomy for GBC with pT2
≤54 2 10 12 0.535 or beyond.
>54 5 10 11
Sex
Male 2 3 3 0.610 Meta‑analysis of ten retrospective observational studies
Female 5 17 20 was done by Ma et al. to determine the impact of adjuvant
Stage treatment on OS in GBC patients.[2] They observed that there
II 1 9 13 0.145
III 6 11 10 was a no significant survival benefit with adjuvant treatment
Grade compared with surgery alone. However, sensitive analysis
I 6 0 10 0.001 showed that adjuvant CT improved OS significantly (hazard
II 1 12 5
III 0 6 4
ratio [HR], 0.42; 95% confidence interval [CI], 0.22–0.80). HR
Unknown 0 2 4 for RT and chemo‑RT was 0.64 and 0.65, respectively. Patients
LVI with either R1 resection or lymph node‑positive disease or
Positive 0 5 7 0.324 Stage II and beyond benefitted the most.
Negative 1 6 6
Unknown 6 9 10
PNI Takada et al. in a Phase III multicentric prospective randomized
Positive 1 2 6 0.605 controlled trial in patients with resected pancreaticobiliary
Negative 1 5 6
Unknown 5 13 11
carcinoma had compared surgery alone with surgery
Margin followed by adjuvant CT (5FU and Mitomycin C). They had
Positive 1 2 2 0.790 reported that the 5‑year survival rate in GBC patients was
Negative 4 16 17
significantly better in the adjuvant CT group. The authors
Unknown 2 2 4
R T = R a d i o t h e r a p y, C T = C h e m o t h e r a p y, C R T = C h e m o r a d i a t i o n ,
had noted that adjuvant treatment was not effective for
LVI=Lymphovascular invasion, PNI=Perineural invsion Stage I GBC.[3]

our study have shown that combination of RT and CT gave
us better survival outcome compared to single modality
treatment with comparable toxicity.
Kim had studied the pattern of failure in 70 patients of
GBC who had undergone curative‑intent cholecystectomy.[1]
About 80% of these patients had pathological T2 and beyond
disease. None of these patients had adjuvant RT while
about a quarter of patients were treated with adjuvant CT.
Median FU period was 29 months. A total of 41 patients had
disease failure. Locoregional recurrence as any component
of first failure was seen in 29 patients (41.4%), with isolated
locoregional recurrence in 13 (18.6%). Distant metastasis with
or without concomitant locoregional recurrence was found in
Wang et al. had developed a prediction model for estimating
the survival benefit of adjuvant RT for GBC. [4] They
did a multivariate regression analysis using data from
4,180 patients with resected GBC diagnosed between 1988
and 2003 from the surveillance, epidemiology, and end
results (SEER) database. The authors reported that adjuvant
RT produced a survival benefit in node‑positive or >T2
disease. Based on the above evidences, we had excluded
Stage I disease from our study.
Kim et  al. had done a systematic review and meta‑analysis
of 14 retrospective studies which had compared adjuvant
chemo‑RT with surgery alone in GBC patients.[5] Despite more
patients with unfavorable characteristics in the adjuvant

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Choudhary, et al.: Adjuvant therapy in gallbladder carcinoma

Table 4: Univariate analysis (95% CI = 23.3–34.1), and 36.5% (95% CI = 27.2–45.8) among

Factors Mean OS P Mean DFS P patients who had surgery alone, adjuvant chemo‑RT, adjuvant
(months) (months) CT, and adjuvant RT, respectively. The 3‑year OS in our study
Age group (years) (n) was 38% and 17% for chemo‑RT and CT groups, respectively.
≤54 (24) 21.6 0.616 21.9 0.441 It is important to note that about 20% patient populations in
>54 (26) 21.9 20.9
Sex the study by Mitin et al. had Stage I disease which resulted in
Male 29.7 0.915 28.9 0.984 superior survival outcome compared to that of ours.
Female 21.1 19.2
Stage Tran Cao et al. had done a retrospective analysis to evaluate the
II (23) 21.9 0.092 20.0 0.785
III (27) 27.2 26.1 role of surgery and adjuvant therapy in lymph node‑positive
Grade cancers of the gallbladder (n = 1335) and intrahepatic
I 34.6 0.238 35.1 0.208 bile ducts (n = 1009). The median OS of patients in the
II 17.3 15.3
III 16.7 14.4
nonoperative, surgery, and surgery plus adjuvant treatment
Unknown 21.1 20.2 group was 11.6, 13.3, and 19.6 months, respectively, for those
LVI with GBC (P < 0.001). On subset analysis, it was noted that
Positive (12) 22.5 0.738 21.5 0.647 adjuvant therapy that included RT was associated with a lower
Negative (13) 18.8 17.3
Unknown (25) 25.1 23.2
risk of death relative to surgery alone for patients with GBC,
PNI but adjuvant CT alone was not.[9]
Positive (9) 14.9 0.073 10.8 0.061
Negative (12) 32.4 31.6 A retrospective was study done by Kresl et  al. where 21
Unknown (29) 23.5 21.8
Margin consecutive patients of GBC Stage I‑IV were treated with
Positive (5) 20.1 0.696 15.3 0.963 adjuvant RT and concurrent 5‑FU. Patients with complete
Negative (37) 26.0 25.9 resection had a favorable survival outcome compared those
Unknown (8) 20.5 16.2 to those with microscopic and residual disease after surgery.[10]
OS=Overall survival, DFS=Disease‑free survival, LVI=Lymphovascular
invasion, PNI=Perineural invasion Unlike our study, this trial had included GBC with all stages
that had complete resection as well as gross residual disease.
arm, OS and DFS of these patients were significantly better
compared to patients in the other group. Exploratory analyses Gold et  al. had evaluated the role of EBRT with concurrent
clearly demonstrated a survival advantage for patients with 5‑FU for gallbladder cancer after complete resection in 73
R1 resection and lymph node‑positive disease. patients of Stage I and II. Only 25 patients had received
adjuvant therapy.[11] The median OS for patients who had
Wang et  al. had developed a nomogram for predicting the received adjuvant chemo‑RT and surgery alone was 4.8 years
benefit of adjuvant chemo‑RT for resected GBC.[6] The authors and 4.2 years, respectively (P = 0.56).
had worked on the SEER database between 1995 and 2005.
A total of 1137 GBC patients could fit into their selection Czito et  al. had shared a 23‑year experience of treating
criteria. The model they developed predicts that certain subsets Stage III and IV patients of gallbladder with adjuvant EBRT
of patients with at least T2 or N1 disease have a survival with concurrent 5‑FU. Of these 22 patients, 20 had undergone
advantage when treated with adjuvant chemo‑RT compared simple cholecystectomy while the remaining two had
to CT alone. radical surgery. The authors suggested the use of adjuvant
RT with radiosensitizing agent to improve the survival
Kasumova et  al. had analyzed the data National Cancer outcome in GBC.[12]
Database 2004–2014. [7] GBC patients who had surgical
resection and were pT2/T3 were selected. A total of Mantripragada et al. had analyzed patients with T2–3 or node
6825 patients were selected for analysis, of which positive, nonmetastatic GBC using National Cancer Data base
2168 patients had received adjuvant CT or CRT. Patients who between 2004 and 2011. Adjuvant CT was administered to
were treated with both RT and CT had survival advantage 28.8% of 4775 patients and upfront concurrent chemo‑RT to
over those who had received CT alone, irrespective of extent 13.5%. Patients with T3 or node‑positive tumors who were
of cholecystectomy (P = 0.0001). treated with upfront adjuvant chemo‑RT had a modest early
survival advantage.[13]
Mitin et  al. had retrospectively evaluated the survival
outcome of adjuvant treatment in 5029 patients of GBC taken Our study has several limitations. The most important caveat
from National Cancer Data Base 2005–2013.[8] The authors of this study is its retrospective nature resulting in selection
reported that adjuvant chemo‑RT improved survival in all bias. Extended cholecystectomy was done in limited number
categories except T1No and in patients with negative margin. of patients. Many of the histopathology findings were missing
The 3‑year unadjusted all‑cause survival rates were 38.7% in several patients. Toxicities of treatment modalities were not
(95% CI = 36.5–40.8), 43.0% (95% CI = 38.4–47.5), 28.6% documented meticulously.

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Choudhary, et al.: Adjuvant therapy in gallbladder carcinoma
CONCLUSIONS
Our study supports the use of adjuvant RT combined with CT
instead of CT alone or RT alone for patients of GBC of Stage II
and III after curative surgery.
Randomized controlled trial may be conducted prospectively
to compare single modality treatment (RT or CT alone) with
combined treatment (RT with CT) after curative surgery for
GBC so as to strengthen the results of this study.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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