1. Metastatic gallbladder cancer can be detected through staging laparoscopy in approximately 23% of patients undergoing diagnostic imaging. 2. First line treatment options for fit patients include gemcitabine plus cisplatin or gemcitabine plus oxaliplatin chemotherapy, while gemcitabine monotherapy is preferred for frail patients. 3. Second line options are limited, though some studies showed benefit from capecitabine or 5-FU regimens for patients who have progressed on gemcitabine. Supportive care focuses on relieving biliary obstruction.

1. MANAGEMENT OF METASTATIC GALL
BLADDER CANCER
Dr Deepak kumar
Senior resident; SGPGIMS, Lucknow
Moderator: Dr Neeraj rastogi

2. WHAT ARE METASTATIC DISEASE?

3. HOW IT IS MADE?
 Routine CT/ MRI for diagnostic purpose.
 Staging Laproscopy
 23% undergoing staging laproscopy are detected to
be metastatic disease. Agarwal et al. Ann Surg. 2013 Aug;258(2):318-
23. doi: 10.1097/SLA.0b013e318271497e

4.  Clinical examination / Performance status
 Lab investigation: CBC/LFT/KFT/ CA-19-9
 CA 19-9 level > 20units/ml could be suggestive of
gall bladder cancer. (Storm BL et al 1990)
 Higher specificity 92.7%, but lower Sensitivity 50%.
 Elevated in jaundice.
 Baseline assessment only and not diagnostic
 Biopsy- distant metastasis site (if possible)
WORK UP

5. Metastatic Ca
Gall bladder
Clinical trial
systemic
chemotherapy Best supportive
care
Fluropyramidine OR
Gemcitabine based

6. PRE TREATMENT MANAGEMENT
Jaundice
Stenting or
decompression
Systemic
chemotherapy
Base line CA
19-9

7. Fluro-Pyrimidine based regimen

8. TREATMENT OF ADVANCED ADENOCARCINOMAS OF THE EXOCRINE PANCREAS
AND THE GALLBLADDER WITH 5-FLUOROURACIL, HIGH DOSE
LEVOFOLINIC ACID AND ORAL HYDROXYUREA ON A WEEKLY
SCHEDULE RESULTS OF A MULTICENTER STUDY OF THE SOUTHERN ITALY
ONCOLOGY GROUP ; VITTORIO GEBBIA, ET AL. 1998
 Aim: A multicenter Phase II trial, to evaluate the clinical
effectiveness and tolerability of weekly 5-fluorouracil (5-FU) in
modulation with high dose levofolinic acid and oral
hydroxyurea.
70 pts
30 GBC
Stage IV-27
Stage III-340 Ca
Pancreas
Levofolinic acid
100mg/m2
5FU
600mg/m2
Hydroxyurea
1000mg/m2
Weekly X
6weeks

9. Response rate
Partial response 30%
Stable disease 27%
Progressive
disease
43%
Median survival 8 mos (1-11 mos)
Conclusion: 5-Fluorouracil, High Dose Levofolinic Acid and
Oral Hydroxyurea on a Weekly Schedule is well tolerated and
active agent in pancreatic and gall bladder cancer.

10. GEMCITABINE, 5-FLUOROURACIL, AND LEUCOVORIN IN
ADVANCED BILIARY TRACT AND GALLBLADDER CARCINOMA: A NORTH
CENTRAL CANCER TREATMENT GROUP PHASE II TRIAL
ALBERTS, S.R ET AL 2005
42 pts
35-IVB
14 - GB
4 cycles
1000 mg/m2 gemcitabine D1,8,15
25 mg/m2 LV
600 mg/m2 5-FU
Partial response 9.5%
Median time to disease
progression
4.6mos
Median survival 7.2 mos
> 6mos surviving patients 57%

11. EFFECTIVE TREATMENT OF ADVANCED BILIARY TRACT CARCINOMA USING
5- FLUOROURACIL CONTINUOUS INFUSION WITH CISPLATIN
DUCREUX, M ET AL. 1998
25 pts
10- male
15 female
5-FU: 1g/m2/day
D1-5 + cisplatin
100 mg/m2/day
D2
Phase II trial
Response rate
CR+PR
24% (7%-41%)
CR 12%
Median survival 11.5 mos

12. PHASE II STUDY OF CAPECITABINE PLUS CISPLATIN AS FIRST-
LINE CHEMOTHERAPY IN ADVANCED BILIARY CANCER
T. W. KIM ET AL. 2003
 Total pts: 42 (19/45 (45%) –Ca GB)
 Chemotherapy: Oral capecitabine 1250 mg/m2 BD
D1–14 + cisplatin 60 mg/ m2 D1 Q3wkly.
Response rate
(CR+PR)
21.4%
Median PFS 3.7mos
Median OS 9.1 mos
Grade 3-4 neutropenia 20%;
vom(12%)
Conclusions: Capecitabine and cisplatin has promising antitumor
activity and is well tolerated in patients with advanced biliary cancer

13. COMBINING GEMCITABINE AND CAPECITABINE IN
PATIENTS WITH ADVANCED BILIARY CANCER: A PHASE II
TRIAL JENNIFER J. KNOX, J CLIN ONCOL 23:2332-2338. 2005
Ca Gall bladder
Median FU 11 mos
Response rate
CR+PR+SD
59%
Median PFS 4.4mos
Median OS 6.6 mos
Capecitabine 650 mg/m2 BD D1-14
+ Gemcitabine 1,000 mg/m2 Days 1,
8

14. CAPECITABINE PLUS OXALIPLATIN AS FIRST-LINE TREATMENT IN
PATIENTS WITH ADVANCED BILIARY SYSTEM ADENOCARCINOMA: A
PROSPECTIVE MULTICENTRE PHASE II TRIAL O NEHLS ET AL. BRITISH JOURNAL OF
CANCER (2008) 98, 309 – 315
65 pts
Group A (47)
GB=27
EHB=20
Group B (18)
IHB=18
Oxaliplatin (130 mg m2 , D 1 +
Capecitabine 1000 mg m2 BD, D1–
14) every 3 weeks
Response rate
CR+PR+SD
63%; SD (33%)
Time to Tumor
progression
(TTP)
4.7 mos
Median Overall
Survival
8.0 mos

15. GEMCITABINE BASED REGIMEN

16. Gemcitabine
1000mg/m2 q3wkly
Response rate:
PR
Stable
Progression
36%
25%
40%
Median cycle 4.2 (1-10)
Median survival 30 weeks
Grade 3-4
neutropenia
Grade 1-2
nausea/vomiting
1 pts
9 pts

17. A PHASE II STUDY OF GEMCITABINE AND CISPLATIN IN
CHEMOTHERAPY NAIVE, UNRESECTABLE GALL BLADDER
CANCER
DC DOVAL, JS SEKHON ET AL. BRITISH JOURNAL OF CANCER (2004) 90, 1516–1520.

19. Gemcitabine +
Cisplatin
Response rate
CR 13.3%
PR 23.3%
SD 23.3%
Progression 13.2%
Median time to
progression
18 weeks
Median Overall
survival
20 weeks
Gemcitabine 1000mg/m2 + Cisplatin 70mg/m2 Q3wkly

20. GEMCITABINE ALONE OR IN COMBINATION WITH CISPLATIN IN PATIENTS WITH
ADVANCED OR METASTATIC CHOLANGIOCARCINOMAS OR OTHER BILIARY TRACT
TUMOURS: A MULTICENTRE RANDOMISED PHASE II STUDY – THE UK ABC-01
STUDY JW VALLE, BRITISH JOURNAL OF CANCER (2009) 101, 621 – 627

22. GEMCITABINE ALONE OR IN COMBINATION WITH CISPLATIN IN PATIENTS WITH
BILIARY TRACT CANCER: A COMPARATIVE MULTICENTRE STUDY IN JAPAN
OKUSAKA T ET AL. (2010). BR J CANCER 103: 469–474

24. CISPLATIN PLUS GEMCITABINE VERSUS GEMCITABINE
FOR BILIARY TRACT CANCER
VALLE J, WASAN H, PALMER DH, CUNNINGHAM D, ANTHONEY A, MARAVEYAS A, MADHUSUDAN S, IVESON T, HUGHES S, PEREIRA SP,
ROUGHTON M, BRIDGEWATER J; ABC-02 TRIAL INVESTIGATORS. N ENGL J MED. 2010;362:1273–1281.
 Aim: Improvement in PFS in ABC-01 trial, trail
extended to ABC-02 to see OS and PFS benefits.
Total 410 pts
N=206
Gemcitabine
N= 204
Gemcitabine
+ cisplatin
Gem:
1000mg/m2
D1,D8,D15
q4wkly
Gem: 1000mg/m2
D1,D8+ Cis
25mg/m2 D1,D8
q3wkly
12 weeks
Continue
for 12
more
weeks
Assessment

26. Compliance to
treatment
Gemcitabine +
Cisplatin
Gemcitabine
First 12 weeks 73.5% 66.5%
Second 12
week treatment
63% 52% P=0.02
Treatment
response
Gemcitabine +
Cisplatin
Gemcitabine
CR+PR+SD 81.4% 71.8% P=0.049

27. Gemcitabine +
Cisplatin
Gemcitabine
Median OS 11.7 mos 8.1mos P<0.001
Median PFS 8 mos 5 mos P<0.001
6-month PFS 59.3% 42.5%

28. Conclusions:
1. Biliary tract cancer are sensitive to chemotherapy
2. Gemcitabine + Cisplatin prove to be better than Gemcitabine
alone.

29. GEMCITABINE COMBINED WITH OXALIPLATIN (GEMOX)
IN ADVANCED BILIARY TRACT ADENOCARCINOMA: A
GERCOR STUDY T. ANDRE´ ET AL. ANNALS OF ONCOLOGY 15: 1339–1343, 2004
56 pts
Group A (33)
GB=11
PS<2; Bil<2.5x
Group B (23)
GB=8
PS>2; Bil>2.5x
Group A
N=33
Group B
N=23
Response
rate
(CR+PR)
35% 22.5%
Median PFS 5.7 mos 3.9 mos
Median OS 15.4mos 7.6 mos
GB N=11 N=8
RR 54.4% NR
Median PFS 6 mos NR
Median OS 16 mos NR
Gemcitabine 1000 mg/m2
as a 10 mg/m2 /min D1, +
Oxaliplatin 100 mg/m2 D2,
Q2wkly.

30. BEST SUPPORTIVE CARE COMPARED WITH CHEMOTHERAPY FOR
UNRESECTABLE GALL BLADDER CANCER: A RANDOMIZED CONTROLLED
STUDY. SHARMA A ET AL. 2011
AIM: Efficacy of modified
gemcitabine and oxaliplatin
(mGEMOX) over best supportive
care (BSC) or fluorouracil (FU) and
folinic acid (FA) in unresectable
gall bladder cancer (GBC)
Methods:
Total : 81 pts
Arm A, BSC
Arm B, FU 425 mg/m2 + FA 20
mg/m2 weekly for 30 weeks
(FUFA);
Arm C: Gemcitabine 900 mg/m2
and oxaliplatin 80 mg/m2 D1,8;
Q3wkly, 6 Cycles.

32. CONCLUSIONS: CONFIRMED THE EFFICACY OF
CHEMOTHERAPY (GEMOX) COMPARED WITH BSC AND
FUFA IN IMPROVING OS AND PFS IN UNRESECTABLE
GBC.

34. OXALIPLATIN AND CAPECITABINE AFTER GEMCITABINE FAILURE IN
PATIENTS WITH ADVANCED PANCREATIC, BILIARY, AND GALLBLADDER
ADENOCARCINOMA (APBC) A. SANCHO ET AL.
 Aim: Pts with advance pancreatic, biliary, and GB
adenoca, have poor prognosis. No consensus about
second line after disease progression.
 Total : 18 pts (GB=4 pts)
 2005-2007
 CAPOX (O 130 mg/m2 D1 and Cap 1000 mg/m2 D2–
14)
Response rate
PR
Stable/ progression
5.6%
44%/27%
Decrease in Ca19-9 27%
Median PFS 16wks
Median OS 24 weeks
PS0>PS1 p=0.001

35. BACKGROUND: NO STRONG EVIDENCE FOR SECOND LINE CHEMOTHERAPY AFTER GEMCITABINE
AND CISPLATIN. FLUROPYRAMIDINE BASED REGIMEN ARE SAFE AND HAS SHOWN EFFICACY IN GI
CANCERS.
Angela Lamarca et al.

36. PALLIATIVE TREATMENT
 Symptomatically Advanced disease
jaundice, pruritus, cholangitis, pain, and biliary
tract/gastrointestinal obstruction.
 Roux-en-Y or jejunal loop anastomosis with common
hepatic duct or left duct.
 endoscopic stenting
 No distinct advantage has been shown for one approach
versus the other.
 Obstruction
 30% of patients with advanced gallbladder cancer .
 Palliative gastrojejunostomy
mortality and morbidity rates are high at 7.2% and 42%,
respectively
 Bowel obstruction/ perforation
 intestinal bypass procedures

37. BEST SUPPORTIVE CARE (ESMO 2016)
 Biliary obstruction is common occurrence in BTC
 endoscopic stenting; if is not possible, Percutaneous
transhepatic drainage is recommended.
 Life expectancy of >3 months, metal prosthesis is
preferred; some patients require re-stenting.
 Sepsis secondary to biliary obstruction is common and
needs to be treated.

38. FOLLOW UP
 No standard schedule
 Clinical examination at every clinic
 Blood test
8-12 weeks interval
 Tumor marker
 CT/ MRI abdomen/ thorax

39. CONCLUSION
 Systemic chemotherapy is the treatment of choice for patients
with metastatic at presentation.
 Combination chemotherapy for PS 0-1 patients and monotherapy
for PS 2 patients •
 Cisplatin/gemcitabine- Good PS (0-1);
 Oxaliplatin may be substituted for cisplatin where there is a
concern about renal function.
 Gemcitabine monotherapy may be considered for PS 2 patients.
 There is no established second-line chemotherapy regimen.
 Patients should be encouraged to participate in clinical trials

40. Thank you