The document discusses adjuvant radiation therapy for gallbladder carcinoma based on available literature. It summarizes several retrospective studies that found improved survival outcomes with adjuvant radiation or chemoradiation after surgical resection compared to surgery alone, especially for node-positive or advanced-stage disease. However, it notes the evidence is limited due to the rarity of the disease and lack of large randomized controlled trials. While adjuvant therapy appears logical, more research is still needed to better define its role and optimal use.

1. ADJUVANT RADIATION
IN CA GALLBLADDER

2. Gallbladder Carcinoma
 Gallbladder cancer is the most common of all the biliary tract
cancers
 5th most common and one of the most aggressive gastro intestinal
tract malignancies.
 In the Indian Cancer Registry, it ranks 5th in all G.I Cancers
 Owing to the incidence ,randomised controlled trials
have hardly been conducted to look into the optimum
treatment.
 Therefore, the treatment decisions are derived from
retrospective studies and small prospective cohort studies

3.  Although, surgery in the form of complete resection
remains the mainstay of treatment
 It is possible only in 10-30% patients.
 About 10% of cases have the disease confined to the
gallbladder
Another 10 to 20% involve associated local spread.
. Even after curative surgery the median survival
reported is 14-15 months and 5-year survival rates
and outcome still remains guarded
 Stage 0-I, 33-100%;
 Stage II, 9-33%;
 Stage III, 0-25%
Stage IV, 0 5%

4.  The high rates of loco regional failures in addition to
systemic metastasis despite an R0 resection have
been attributed to the dismal prognosis in GBC.
 Therefore, adjuvant radiation or chemo-radiation
appears very much logical and has been adopted in
many centers to optimize tumor control and thereby
improve survival.

5. Boset et al- 1989
 was one of the first to report the benefit of adjuvant
radiotherapy in GBC
 They reported the outcome of 7 patients who received
adjuvant radiotherapy after complete surgery for gall
bladder cancer.
 When they initially published their data in 1989 after a
minimum follow up of 5 months
 5 out of the 7 patients were alive with no evidence of
disease.
Thus they advocated the use of post-operative adjuvant
radiotherapy after complete surgery for GBC

6.  Yang et al.
 reported a retrospective single institute experience of treating 127 gall
bladder patients
 84 patients in this series underwent radical resection alone, while 43
patients underwent radical resection with adjuvant radiotherapy.
 The median survival time of patients who underwent surgery and
postoperative radiotherapy was 16.9 months,
 Among Stage III & IV patients all the - 1 year, 3 year, and 5 year
survival rates were significantly higher in PORT group than that of the
simple R0, R1 resection group ( all p <0.05). But with a non-
significant difference between the stage I and II patients
 They concluded that survival rates of the postoperative radiotherapy
group were higher than the surgical resection alone group

7. Zhonghua zhong liu za zhi [Chinese journal of oncology] 2013; 35: 534-539

8.  Kresl et al.
 a retrospective review of 21 GBC patients who underwent adjuvant
chemoradiotherapy at the Mayo Clinic .
 The study included 1 patient of Stage I and 20 patients of Stage
III/IV.
 The median radiation dose was 54 Gy (range 50.4–60.8 Gy) and
concurrent 5-fluorouracil was used with radiotherapy.
 They had found that a 5-year survival rate of 64% for the
patients treated with this approach and the results were superior to
historical surgical controls from the Mayo Clinic.
 Tumor stage and extent of resection was shown to be important
factors that influence survival and local control in these patients.
 Thus their data showed a probable benefit of adding
adjuvant chemoradiotherapy in GBC after surgical
resection

9.  Aim ( data from 4459 patients with resected gall bladder
from the SEER database who were diagnosed between
1995-2005)
 Multivariate regression analysis using this model showed
age, sex,papillary histology, stage and adjuvant
radiation are significant predictors of OS
 The analysis predicted that certain subsets of patients
with at least T2 or N1 disease gain a survival benefit
from adjuvant RT, and the magnitude of benefit for an
individual patient can vary.
Wang et al

10. SWOG S0809- Ben josef et al

11. Patients and methods :
 S0809 was designed to estimate 2-year survival (overall and after R0 or
R1 resection), pattern of relapse, and toxicity in patients treated with
this adjuvant regimen.
 Stage pT2-4 or N+ or positive resection margins, M0, and performance
status 0 to 1.
 Patients received four cycles of gemcitabine (1,000 mg/m2
intravenously on days 1 and 8) and capecitabine (1,500 mg/m2 per day
on days 1 to 14) every 21 days followed by concurrent capecitabine
(1,330 mg/m2 per day) and radiotherapy (45 Gy to regional lymphatics;
54 to 59.4 Gy to tumor bed).
 With 80 evaluable patients, results would be promising if 2-year
survival 95% CI were 45% and R0 and R1 survival estimates were 65%
and 45%, respectively

12.  Results
 A total of 79 eligible patients (R0, n 54; R1, n 25; EHCC,
68%; GBCA, 32%) were treated (86% completed).
 For all patients, 2-year survival was 65% (95% CI, 53% to
74%); it was 67% and 60% in R0 and R1 patients,
respectively and median survival was 35 months.
 86%completed therapy and was well tolerated
 The most common grade 3to grade 4 adverse effects were
neutropenia followed by hand foot syndrome and
diarrhea

13. conducted a systematic review and meta-analysis of published
institutional and registry data to evaluate the benefit of adjuvant
therapy for biliary tract cancer .
 The meta-analysis included twenty studies involving 6712
patients(1960-2010).
 The authors reported a non-significant benefit with adjuvant
therapy vs. surgery alone( OR 0.74; P= 0.06).
 The survival was found better in patients treated with CT or CRT
compared with radiotherapy alone ( OR, 0.39,0.61 & .98 ; P=
.02).
 The greatest benefit for AT was in those with LN positive disease
(OR 0.49 ; P=0.04) and R1 disease(OR,0.36; P= 0.02)
Horgan et al

14.  analyzed the SEER data base to define the role of adjuvant radiotherapy
for GBC .
 The authors identified 5011 patients with GBC who underwent surgical
resection from 1998 to 2009.
 75% had a localized disease and only 17.9% patients received adjuvant
radiation.
 Adjuvant radiation was used mostly for younger age, tumor extension
beyond the serosa, intermediate to poorly differentiated tumors and
patients with lymph node metastasis.
 In a propensity matched multivariate analysis the authors reported
significantly improved 1 year survival with the use of adjuvant
radiotherapy and the survival benefit was more pronounced for N1
disease and moderately -poorly differentiated tumors.
 However, the benefit was not significant at 5 years.
Hyder et al

15. Conclusion: Gall bladder cancers are aggressive and lethal. Early diagnosis
and curative surgery, followed by appropriate adjuvant radiation
therapy, may improve survivals, with no established consensus till
date. Following curative surgery, pathological T stage and stage grouping, are
the significant prognostic factors for outcome .

16. Is the evidence given sufficient enough to support the
claim?

17. difficult to define the exact role of adjuvant
therapy in gall bladder cancers
 Mostly retrospective, small numbers of series
reported in literature, addressing the issue of
adjuvant radiation therapy owing to low incidence
 In these small series, differences in patient
selection criteria, staging systems, extent of
resections, radiation therapy techniques and doses
and chemotherapy schedules
 In the absence of phase III data , it is difficult to
get level-I evidence for adjuvant radiotherapy

18. NCCN guidelines ?

19. NEWER RADIOTHERAPY TECHNIQUES
 Over the last decade the radiotherapy technique
has witnessed a paradigm shift from 2D
planning to conformal radiation with an
aim to optimize tumor control and minimize
both acute and chronic radiation morbidity
 The improvement in radiation delivery
with intensity modulated radiotherapy (IMRT),
image guided radiotherapy (IGRT),SBRT has
further paved the way for exploration of
adjuvant radiation for GBC.

20. Target volume
TUMOR BED AND THE REGIONAL LYMPH NODES.
The regional lymph nodes must include the porta hepatis, celiac, para-aortic, and
pancreaticoduodenal nodes.
The CTV PRIMARY includes the GB fossa as evident in the pre-operative
CECT image and the surgical clips with 1 cm isotropic expansion

21. Planning
A dose of 45 Gy in 25 fractions over 5 weeks may be acceptable and has
been shown to improve outcome in patients with GBC.
A boost of 5.4 Gy may be considered in an R1 resection.
A boost of 15 Gy may be given in cases of gross residual lesion

22. Treatment

23. o Fluorouracil is the most commonly used drug in the concurrent
setting in GBC.
o Capecitabine an oral analog of fluorouracil may be a logical
substitution and has been proven to be equally effective as
fluorouracil in various gastro intestinal malignancies.
o Gemcitabine is another agent that has proven its efficacy in
metastatic GBC and has possible radio sensitizing effect and may be
considered in concurrent setting .
o But the high toxicity associated with gemcitabine when
given concurrently with radiotherapy as shown in
pancreatic cancers must be kept in mind when advising
gemcitabine concurrent with radiotherapy
Most of the studies which have shown the benefit of adjuvant
radiotherapy include concurrent chemotherapy also. Hence
chemotherapy must be added to the adjuvant radiotherapy
protocols whenever possible

24. UNRESECTABLE- Cases
 There are very few data on the outcome of
primary RT for unresectable GBC.
 Most patients with locally advanced unresectable
disease receive a combination of chemotherapy and
RT to take advantage of the radiation-sensitizing
properties of certain chemotherapeutic agents,
Despite uncertainty as to benefit, chemoradiotherapy
is an acceptable choice for locoregional therapy of a
locally advanced unresectable GBC

25. CONCLUSION
 In the absence of phase III data , it is difficult to
get level-I evidence for adjuvant radiotherapy.
 Radiotherapy must be used as an adjuvant
therapy in resected cases of GBC when the disease
is T2 or node positive to reduce local recurrence
and to improve survival with the current available
best evidence.
 It must be combined with chemotherapy in all
feasible patients to improve local control and to
reduce distant recurrences.
.

26.  With the availability of newer sophisticated
radiation techniques it may be feasible to deliver
adequate dose to the target while keeping the
organs at risk within tolerable limits.
 There is also a feasibility of increasing the dose to
by using image guidance and better radiation
delivery techniques
 A multicenter phase III trial may help us in giving a
definite answer regarding the role of radiotherapy
in adjuvant treatment of GBC