Radiotherapy and chemotherapy play important roles in the treatment of carcinoma of the gallbladder. Adjuvant chemoradiotherapy after surgery has shown improved survival outcomes over surgery alone in retrospective studies, with a 30% reduction in mortality seen with the addition of chemoradiotherapy. High-risk patients such as those with node-positive disease or margins positive for tumor have been shown to benefit most from adjuvant chemoradiotherapy. For advanced or unresectable gallbladder cancer, chemotherapy with gemcitabine-based regimens represents the standard of care.

1. ROLE OF
RADIOTHERAPY
AND CHEMOTHERAPY IN
CARCINOMA GALL BLADDER
Presented By- Dr. Rashmi
JR-II
Department Of Radiation Oncology

2. BURDEN OF DISEASE-
GLOBOCAN 2018 DATA
• New Cases: 25,999
• Deaths: 19,676
• No. of people living with the disease
(5 year prevalence for all ages): 31,357

3. EPIDEMIOLOGYAND RISK
FACTORS
• Age >45 years
• Gender women
• Ethnicity
– Globally: more in India, Pakistan, Eastern Europe, South American countries,
East Asia and the lowest in Africa .
– India : north and North-east
• Gallstones and Chronic Inflammation of Gall bladder-
– Only about 1% patients with gall stones develop GBC .
– ‘porcelain gall bladder’- 25% (range 12% to 61%) association.
– A study from North India revealed that the prevalence of gallstones was more in
females (5.59%) than males (1.99%)

4. • Genetic Factors
a. Pancreas and bile duct abnormalities
b. Choledochal cysts
• Gall bladder polyps
• Family History
– first degree relatives- five times increased risk.
– Mutations in BRCA2 ,APOB

5. • Lifestyle Factors
a. Obesity
b. Infection – Approximately 6% of carriers of Salmonella
typhi developed gall bladder cancer and the association
showed a 12-fold increase in risk for developing GBC
Helicobacter pylori bacteria may also increase the risk
c. Diet – increased quantities of proteins, fats and
cholesterol and low in fibre, vegetables and fruits
• Chemicals- nitrosoamines (found in some industrial
products) strong correlation with heavy metal pollutants
in drinking water.
Studies also show that people who smoke or work in the
metal or rubber industry more likely to develop GB Ca.
• Smoking

6. CLINICAL PRESENTATION
The presentation of GBC has three situations:
1. as a mass lesion in the gallbladder.
2. incidental, upon histopathological examination of
resected gallbladder
3. advanced, inoperable form (most common
presentation)

7. Anorexia
Cachexia
Icterus
a palpable hard lump in the
right hypochondrium,
Ascites and
left supraclavicular
lymphadenopathy
Poor performance status

8. WORKUP
• Hemogram
• Liver Function Tests: Elevated alkaline phosphatase and bilirubin levels
- more advanced disease.
• Imaging tests:
1. USG Whole abdomen
2. CECT Abdomen: shows tumour infiltration into adjacent viscera or
vessels,lymph node and distant metastase.
3. MRCP/ERCP: validity in detection of biliary invasion, vascular invasion, hepatic
invasion and lymph node involvement. Indicated in patients with jaundice
4. FNAC is not indicated in resectable GBC because the tumor has propensity for
seeding the biopsy tracts and resection should be performed even if FNAC is
negative.
A tissue diagnosis should be obtained (FNAC, fluid cytology) from the metastasis.

9. • In a Jaundiced patient
a. Coagulation profile (PT,APTT,INR)
b. MRCP
c. ERCP/Percutaneous Transhepatic Cholangiography
(PTC) if a therapeutic intervention (biliary stenting) is
planned
• Optional Investigations
a. Positron Emission Tomography (PET) scan
b. Tumor markers: Serum Ca 19-9, CEA : not
very specific

10. AJCC STAGING
TX- Primary tumor cannot be asseesed
T0- No evidence of primary tumor
Tis- Carcinoma in situ
T1- Tumor invades the lamina propria or muscular layer
T1a- tumor invades lamina propria
T1b- tumor invades muscular layer
T2 - Tumor invades the perimuscular connectivetissue on
the peritoneal side, without involvement of the serosa (visceral peritoneum)
Or tumor invades the perimuscular connective tissue on the hepatic side,
with no extensión into the liver
T2a- tumor invades peri muscular connective tissue on peritoneal side,
without serosa involvement (visceral peritoneum)
T2b- tumor invades peri muscular connective tissue on hepatic side, with no extension
into liver.
T3- Tumor proliferates serosa (visceral peritoneum) and/or directly invades liver
and/or one other adjacent organ or structure such as stomach, duodenum, colon,
pancreas, omentum or extrahepatic bile ducts
T4- Tumor invades main portal vein or hepatic artery or two or more
extrahepatic organs

11. NX- Regional nodes cannot be assesed
N0- No regional lymph node metastasis
N1- metastasis to 1-3 regional lymph nodes
N2- metastasis to 4 or more regional lymph
nodes
M0- No distant metastasis
M1- Distant metastasis

12. When Tis AndN is AndM is Then stage
group is
Tis N0 M0 0
T1 N0 M0 I
T2a N0 M0 IIA
T2b N0 M0 IIB
T3 N0 M0 IIIA
T1-3 N1 M0 IIIB
T4 N0-N1 M0 IVA
Any T N2 M0 IVB
Any T Any N M1 IVB

13. TREATMENT OPTIONS
 Surgery
•Simple cholecystectomy : T1a
•Radical cholecystectomy : T1b,T2,T3 & T4
 Radiotherapy
 Chemotherapy
 Combined modality treatment
 Palliative therapy
•Surgical Palliation
•Non-surgical palliation

15. RADIOTHERAPY INDICATIONS
1. Advance disease
2. High T stage
3. Lymph Node involvement
4. Margin positivity
5. Loco-regional recurrence
6. Palliation of jaundice

16. ADJUVANT CHEMORADIATION IN GBC
• Retrospective study : n = 21 (Mayo Clinic)
• Protocol : EBRT (45-54Gy) + concurrent 5 FU 500mg/m2
D1-D3 on week 1 & week 5
• Median Follow Up = 5yr (range - 2.6-11yr)
• Maintenance CT may be considered - as risk of distant
failure was high i.e 67%
• 5yr OS 65% (Stage I-III)-superior to historical control(Sx
alone- 33%)
• Retrospective study : n= 73, Adjuvant CTRT(n=24)-Mayo
Clinic
• By CTRT: Improvement in survival with 30% decrease in
death rate

17. ADJUVANT CHEMORADIATIONTHERAPY
23 years result
• Retrospective study from Dukes University 1980-2003,
n=22,
91 % incidental (Stage II-III,III/IV)
• RT : 45 + 5.4-10.8 Gy boost
• CT : 5FU 500mg/m2 day 1-3 & day 29-31 concurrently
• MS : 1.9yr
• 5yr OS : 37%

18. ADJUVANT
CHEMORADIOTHERAPY/RADIOTHERAPY
INDICATIONS
High risk patients
 Node positive
 T2 and above
 Margin positive
Adjuvant Chemoradiotherapy vs Radiotherapy
 Gall bladder cancer is not a very chemosensitive disease
 Chemoradiotherapy has shown benefit
concurrent regimen:5FU /oral capecitabine

20. • 20 studies between 1960 to 2010, n=6712, GBC & biliary
(Sx=4915, Sx+RT= 1797)
• GBC (Sx=3553; Sx+RT=897)
• Non-significant improvement in survival in GBC by adjuvant
therapy(odds ratio 0.81, i.e. 19% death reduction;p=0.06)
• Node +, margin + and R1 disease shown larger benefit with adjuvant
therapy
• 5yr OS 26% v 14% with adjuvant CT vs surgery alone in GBC

21. TREATMENT PROTOCOL
 Surgery (simple/extended cholecystectomy)
+
 External Beam Radiation Therapy (45-50.4 Gy / 25-
28 fractions / 5-5½ wks)
+
 Chemotherapy (5 Fluorouracil / Capecitabine) during
and after RT x 6 cycles

22. RADIATION THERAPY PLANNING
 Radiation portals
GB fossa + lymphatic drainage area
including cystic, portal, pericholedochal, hepatico- duodenal,
posterio-pancreaticoduodenal, celiac, sup. mesentric and para-aortic
LN
 Radiation portal after Lap. Cholecystectomy
should include the trocar site/ tract & port of GB delivery otherwise
incidence of trocar site recurrence

23. PRE-OPERATIVE CT SCAN
 

24. RADIATION THERAPY PLANNING

25. RADIATION THERAPY PLANNING

26. Conformal Radiation Therapy : 3 D-CRT

27. Dose colour wash showing Gallbladder fossa and lymph node
drainage area covered in 95% Isodose

28. CHEMOTHERAPY IN UNRESECTABLE GBC
 GEMOX: Inj Oxaliplatin 80 mg/m2, 2 hours infusion in Dextrose 5%
Day 1 and 8,
Inj Gemcitabine 900 mg/m2 IV 30 minutes infusion day1 and 8
Cycles to be repeated every 3 weeks for maximum of 6 cycles
 GEMCIS: Inj Cisplatin 25 mg/m2 PO Days 1 and 8;
Inj Gemcitabine 1000 mg/m2 IV 30 minutes infusion day1 and 8
Cycles to be repeated every 3 weeks for maximum of 8 cycles
 GemCap: Inj Gemcitabine 1000 mg/m2 IV 30 minutes infusion
day1 and 8;
Capecitabine 650mg/m2 twice a day PO Days 1-14
Cycles to be repeated every 3 weeks.
Treatment should be continued until progression, unacceptable
toxicity, or withdrawal of patient

29. Primary Treatment of Unresectable Disease
All recommendations are Category 2A unless otherwise indicated.
REGIMEN DOSING
Gemcitabine +
cisplatin
(Category 1)
Days 1 and 8: Cisplatin 25mg/m2 IV (1-hour infusion)
followed by gemcitabine 1,000mg/m2 IV (0.5-hour
infusion).
Repeat every 21 days initially for 4 cycles then re-evaluate
and continue for an additional 4 cycles if warranted.
Fluoropyrimidine-
based or other
gemcitabine-based
chemotherapy
regimen
The collected clinical experience and a comprehensive
meta-analysis imply that gemcitabine and gemcitabine-
based platinum regimens are slightly advantageous
compared with fluoropyrimidine regimens.
Fluoropyrimidine
chemoradiation
There are limited clinical trial data to define a standard
regimen or definitive
benefit.

30. PALLIATIVE SETTINGS
• Relief of jaundice and pruritis – ERCP and
stenting (metallic/plastic stent)
• For pain relief – Medicines as per the WHO
step-ladder or celiac plexus block in refractory cases
• For relief of gastric outlet obstruction –
Gastrojejunostomy in patients with good
performance status

31. FOLLOW UP
• Every6 months for 2 yearsbyimaging.
• Re-stagingaccordingto initial work-upshould be
considered in the event of diseaserelapse or
progression

32. Overall survival as per AJCC-TNM stage
1201089636 48 60 72 84
Overall survival (months)
24120
1.2
1.0
.8
.6
.4
.2
0.0
5 yr OS stage I, II, III = 50, 26.7, 18.7%

33. CONCLUSION
• Primary modality - Surgery
• Radical/curative surgical procedure limited due to advance nature of
disease at presentation
• Surgery alone : High loco-regional recurrence
• Adjuvant chemoradiation therapy improves local control as well as
survival in retrospective series, randomized evidence needed
• High dose precise RT (IORT / Conformal RT/ IMRT with image
guidance) may further improve loco-regional control
• Role of CT – adjuvant to RT & metastatic GBC (level I)
• Adjuvant approach is favoured and used in upto 70% of centers
worldwide
• Benefit of radiotherapy indicated in node positive, positive margins and
>T2 tumors

34. THANK
YOU