1. Adjuvant Therapy for Biliary Cancer
Abby Siegel MD, MS
Associate Professor of Medicine
Columbia University
Co-Chair, Hepatobiliary Committee, SWOG
NCI Task Force for Hepatobiliary Cancers

2. Adjuvant Therapy for Biliary Cancers
Models and Meta analyses
Trials
Which chemo (s) to use?
Potential targets to consider for the future
Treatment guidelines

3. Anatomic and Molecular Heterogeneity
Gallbladder
EHCC
IHC
KRAS
3-38
10-15
45-54
BRAF
0-33
0-22
EGFR
9-12
5-18
10-20
ERBB2/HER2 16 5
PI3K 4 9
Adapted from De Groen et al. NEJM; 341(18): , 1999
Hezel et al, JCO, :

4. Gallbladder Nomogram
1137 patients from SEER-Medicare between
ChemoRT performed better than chemo alone for almost all groups, particularly T2, node (+)
Caveats: margin status and performance status not reported in SEER, numbers too small to control for radical resection
Most got 5FU, and chemo likely underreported
Wang et al. JCO; 29: , 2011

5. Gallbladder cancer:
Online prediction calculator estimating benefit of adjuvant chemotherapy or chemoradiotherapy
Wang et al. JCO;29: ,2011

6. Review and Meta-analysis
Pooled analysis of 20 studies; 6712 pts
Overall survival improved with adjuvant therapy compared with surgery alone (p=0.06)
Node and margin-positive patients benefit most (OR, 0.49; P =0.004, and OR, 0.36; P= 0.002)
CT or CRT gave statistically greater benefits than RT alone (P = 0.02)
Suggestion of benefit for radiation only for margin positive disease
Horgan et al. JCO; 30: , 2012

7. Efficacy Outcomes for Overall Population
Horgan et al. JCO;30: , 2012

8. Efficacy Outcomes for Node-Positive Disease
Horgan et al. JCO;30: , 2012

9. Efficacy Outcomes for Margin-Positive Disease
Horgan et al. JCO;30: , 2012

10. Meta analysis and Model Summary
Depends whom you ask!
Chemo looked better in the Knox meta analysis
ChemoRT looked better in SEER-Medicare
Few received radical resection in SEER-Medicare (maybe radiation was more important there?)
Different types of chemo
More “modern” in meta analysis
Better recording of chemo in meta analysis
SEER-Medicare claims don’t include those in HMOs or who go to another setting, like VA

11. Clinical Trials Also limited so far
No large randomized controlled trials reported
Asian randomized trial
SWOG 0809: Intergroup Phase II

12. One Randomized Trial
From Japan, pts with pancreas, biliary, gallbladder, and ampullary cancers assessed
Chemo: 5FU, mitomycin “atypically given”
Only difference seen for GB cancer
No difference by ITT
Benefit only seen for GB cases who underwent noncurative resections (were they really “adjuvant?”)
Takada et al. Cancer, 95(8): , 2002

13. Phase III Adjuvant Chemotherapy: Gallbladder Cancer
Takada et al. Cancer, 95(8): , 2002

14. SWOG 0809 Eligibility T2-T4 N1 Positive margins
Gallbladder cancer or EHCC
At least one of the following:
T2-T4 N1
Positive margins
Gemcitabine 1000 mg/m2 IV over 30 min D1 and D8
+ Capecitabine 750 mg/m2 PO BID x 14 days X
4 cycles
Concurrent EBRT with
Capecitabine 665 mg/m2 BID x 7 days for 6 weeks
(45 Gy to regional lymphatics, Gy to the tumor bed)

15. SWOG 0809: Statistical plan
With 80 evaluable pts, results would be promising if the 2-year survival was >45%
R0/R1 estimates were ≥65%/45%, respectively

16. SWOG 0809: Patient CharacteristicsR0
(n=54) R1
(n=25)
Age (years)
Median
65.0
59.2
Sex
Males 24
44% 14
56%
Females 30 11
Hispanic
Yes 4 7% 1 4% No 49
91% 17
68%
Unknown 2% 7
28%
Race
White 45
83% 21
84%
Black 5 9% 2 8%
Asian 0%
Primary disease site
Bile Duct 35
65% 19
76%
Gallbladder
35% 6
24%
Performance status 32
59% 22
41% 18
72%
Baseline lab values
CA 19-9 (U/ml) N 53 23
15.0
24.0
SWOG 0809: Patient Characteristics
Ben-Josef et al, in press, JCO

17. SWOG 0809 Results 2 year OS=65%, median OS=35 months
79 eligible; 54 R0, 25 R1
68% EHBD, 32% GB
86% completed treatment
Grade 3-4 toxicities included neutropenia (44%), hand-foot (11%), diarrhea (8%)
One death due to duodenal bleed
Ben-Josef et al, in press, JCO

18. Overall Survival: SWOG 0809
2-year estimate of OS=65%
OS not significantly different by margin status:
2-year OS 67% vs 60%

19. Sites of Recurrence Recurrence EHCC Distal (n=38) EHCC Hilar (n=13)
Recurrence
EHCC Distal
(n=38)
EHCC Hilar
(n=13)
GBCA
(n=25)
Local only
3 (8)
1 (8)
Local plus distant
5 (13)
2 (15)
2 (8)
Distant only
11 (29)
11 (44)
Total
19 (50)
4 (31)
13 (52)

20. Notable Findings
Feasibility established for national intergroup trial with central reviews of surgery, pathology, and radiation oncology plan
High rates of R0 resection (68%)
OS and local control similar in R0 and R1 groups (perhaps due to XRT)?
Difficult to compare biliary to GB due to differences in the populations

21. Adjuvant Therapy in Biliary Cancers: Current Landscape
S0809: completed
Data important to guide future study
UK phase 3 study: capecitabine versus observation in GB, IHCC, EHCC (n=360)
Completed, awaiting results
French phase 3 study: gemcitabine and oxaliplatin versus observation in GB, IHCC, EHCC (n=190)
German phase III gem/cis vs observation underway

22. Gem/platinum x 4 months (6 cycles) followed by
Planned North American Trial: A randomized phase II/III of gemcitabine and cisplatin followed by capecitabine/radiation versus gemcitabine and cisplatin alone
Gem/platinum x 4 months (6 cycles) followed by
5-FU (or capecitabine)/RT
Patients with EHCC or GB CA
Gem/platinum

23. Which Chemotherapy? Gem vs gem/cis Combination: Gemcitabine:
“It’s not that much more toxic”
“Looks better in the advanced setting”
Gemcitabine:
More is not always better in adjuvant setting…
Remember the adjuvant story with irinotecan in CRC?
Possibility of toxicity with cis is real: neutropenia, thrombosis risk
Moore et al, JCO 29:25, , 2011

24. Potential Targets for the Future?
HER-2
IDH
FGFR2

25. HER-2 Neu Javle… Siegel et al, submitted
Overexpressed or amplified in 10-15% of gallbladder cancers
Series of 8 GB pts with overexpression or amplification
Used HER-2 directed therapy in advanced disease; 1CR, 4PR
Should we try in adjuvant setting, like in breast?
Would use with chemotherapy backbone
Javle… Siegel et al, submitted

26. IDH Pathway Yen et al, Oncologist 2012 17:5-8

27. IDH Mutations Seen in Cholangiocarcinomas Borger et al, Oncologist, 2010 17:72-79

28. FGFR2 Fusions Define a Unique Molecular Subtype of Cholangiocarcinoma
Seen in intrahepatic cholangiocarcinomas
Most common mutation—up to 45%
Targetable!
Studies ongoing with BGJ398 showing responses in cholangiocarcinoma
Sia et al. Nat Commun. 6:6087,2015, Wu Y et al. Cancer Discovery; 3: ,2013, Arai et al, Hepatology; 59:1427, 2014

29. Incidental Gallbladder Cancer
750,000 cholecystectomies annually in the U.S.
Annual incidence of cancer of 0.3 to 1%
Stage
Residual disease
Lymph nodes
Recurrence Rate
5 Year Survival
T1b
10%
10-20%
20%
40% T2
20-30%
30%
15 % T3
50%
>50%
5 %*
* Or Node Positive
Hueman et al. Annals Surg Onc; 16: , 2009 (Slide courtesy of Dr. Milind Javle)

30. NCCN Surgical Re-evaluation: Gallbladder Cancer
T1b and greater tumors should undergo radical resection
Underused; compliance increased from 12% to 16% from to
Mayo et al. J Gast Surg 14: , 2010

31. NCCN Guidelines
Gallbladder: consider 5FU-based chemoRT (except T1a or T1b, N0), 5FU or gemcitabine chemotherapy, or observe
Extrahepatic cholangiocarcinoma
R0, (-) nodes or CIS at margin: 5FU ChemoRT or 5FU or Gem,
observe, or trial
R1 or R2 or (+) nodes:
5FU chemoRT, then 5FU or gem-based chemo
5FU or gem-based chemo for node (+)
Intrahepatic cholangiocarcinoma
R0: observe, trial, or 5FU or gem-based chemo
R1 or (+) nodes: 5FU-based chemoRT or 5FU or gem-based chemo
R2: Gem/Cis (category 1)
Or: clinical trial, 5FU or gem-based chemo, locoregional therapy, or best supportive care
Consider re-resection for any margin (+) disease

32. Summary For gallbladders: For extrahepatics:
T1b or greater: radical resection
T2 or node (+): give 6 months gemcitabine
R1: try to re-resect, or else give chemoRT then gem
For extrahepatics:
Clean margins: give 6 months gemcitabine
R1: consider re-resection, or give chemoRT followed by chemo
For intrahepatics, very little data:
I usually give 6 months gem
For R1, try 2 months gem, then try to re-resect, otherwise chemoRT, then complete 6 months gem
For R2, give gem/cis

33. Thank you!