Adjuvant therapy Carcinoma Gall Bladder: evidence and controversies

1. ADJUVANT CHEMOTHERAPY IN
CARCINOMA GALL BLADDER:
CURRENT TRENDS
DR. AMIT SEHRAWAT
ASSISTANT PROFESSOR
DEPARTMENT OF MEDICAL ONCOLOGY

2. OVERVIEW
Disease Burden
Rationale of Adjuvant therapy in GBC
Adjuvant Modalities
Evidence
Guidelines
May 11, 2019 Dr. Amit Sehrawat 2

3. OVERVIEW
Disease Burden
Rationale of Adjuvant therapy in GBC
Adjuvant Modalities
Evidence
Guidelines
May 11, 2019 Dr. Amit Sehrawat 3

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United States
(1.5/100,000)
Japan(7/100,000)Israel
(5/100,000)
India, Central Europe – Poland
(14/100,000),
Pakistan (11/100,000);
Chile (16-27/100,000)
DISEASE BURDEN
ICMR-2014

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ICMR,PBCR-2014

8. OVERVIEW
Disease Burden
Rationale of Adjuvant therapy in GBC
Adjuvant Modalities
Evidence
Guidelines
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9. Stagewise distribution of GBC patients: India
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Singh et al. J Gastrointest Cancer. 2018
MORE PATIENTS REQUIRE PALLIATIVE TREATMENTS THAN
CURATIVE

10. THE STAGE DISTRIBUTION: INTERNATIONAL
• T1 – 11 percent
• T2 – 58 percent
(61 percent peritoneal [T2a] and 39 percent
hepatic [T2b])
• T3 – 30 percent
• T4 – 2 percent
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Shindoh J et al. Ann Surg. 2015
(Japan, US, Europe)
QUITE CONTRAST TO THAT OF THE INDIAN SENARIO

11. T STAGE HAS A MAJOR IMPACT ON PROGNOSIS
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T-STAGE LYMPH NODE METASTASES Peritoneal/Liver METASTASES
T2 33% 16%
T3 58% 42%
T4 69% 79%
Fonn et al. Ann Surg. 2000

12. Patterns of disease recurrence:
Post surgical resection with curative intent
Retroperitoneal lymph nodes (28 percent)
Intrahepatic (22 percent)
Locoregional recurrence (hilum, bilioenteric anastomosis, hepatic resection margin; 20.9
percent)
Peritoneum, lung, bone, and abdominal wall (totaling 15 percent)
Other distant lymph nodes (14 percent)
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Kim et al. J Gastrointest Surg. 2010

13. ADJUVANT THERAPY
Paucity of high-quality evidence to support adjuvant treatment
No consensus as to the optimal adjuvant approach
Maximum Benefit in
Completely resected ≥T2
Node-positive
Margin-positive GBC
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14. OVERVIEW
Disease Burden
Rationale of Adjuvant therapy in GBC
Adjuvant Modalities
Evidence
Guidelines
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15. ISSUES
• Whether to give or not
• CT Alone
• RT Alone
• CTRT Combined
• Which drug (s)
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16. Why paucity of Evidence?
• Indian Subcontinent / Latin American Disease
• Western trials: of Hepatobiliary Cancers, GBC just a subset
• Different disease than west?
• Advanced presentation in majority
• Most data retrospective , fewer RCTs
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17. OVERVIEW
Disease Burden
Rationale of Adjuvant therapy in GBC
Adjuvant Modalities
Evidence
Guidelines
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18. Adjuvant RT
• Lone Modality role not established
• Can diminish local recurrence rates, but the lack of RCTs
• Retrospective reports of RT alone - Prolonged survival
• 5-year OS up to 73% in R0, 40% in R1 and 0% for R2 resection
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Itoh et al. Dig Dis Sci. 2005

19. Adjuvant Chemoradiotherapy
• Mostly retrospective
• Single center experiences
• Probably most benefit on node/margin positive
• apparent survival prolongation due to fitter and younger
patients ?
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21. CTRT- evidence..
• A retrospective analysis of a multi-institutional database of 291
patients
• curative-intent resection between 2000 and 2015
• 186 who underwent surgery alone
• 61 who received adjuvant chemotherapy
• 44 who received adjuvant chemoradiotherapy
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Kim Y et al. Ann Surg Oncol. 2016

22. • Only high-risk + benefitted
• T3/T4 stage (HR 0.41)
• LN metastasis (HR0.45)
• R1 disease (HR 0.21) (all
P0.05)

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24. Retrospective study :Mayo Clinic
• 73 patients
• 25 received adjuvant chemoradiotherapy
• no OS difference b/w Surgery +FU and RT Vs Surgery Alone
• But those higher stage and involved lymph nodes were
significantly benefited
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Gold DG et al. Int J Radiat Oncol Biol Phys. 2009
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26. NCDB…
• 5029 patients diagnosed with T1-3N0-1 GBC
• Treated with surgical resection from 2005 to 2013
• Adjuvant RT use decreased from 4.2% to 1.7% (P < .001)
• Adjuvant chemotherapy increased from 8.3% to 13.8% (P < .001)
• Adjuvant CRT remained stable at 15.9% (P= .98).
• Conclusion: Adjuvant CRT was associated with improved survival in
all categories, except T1N0, and in patients with negative margins
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29. SWOG…
• T2-4 or N1 or positive resection margins
• 79 eligible patients
• R0 = 54; R1= 25; EHCC, 68%; GBCA, 32%
• 86% completed treatment
• Treatment: 4 cycles of gemcitabine (1,000mg/m2 intravenously on days 1
and 8) and capecitabine (1,500 mg/m2 per day on days 1 to 14) every
21days
• f/b concurrent capecitabine (1,330 mg/m2 per day) and radiotherapy (45
Gy to regional lymphatics; 54 to 59.4 Gy to tumor bed)
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30. SWOG: Results
• 2-year survival was 65% (95% CI, 53% to 74%);
• 67% and 60% in R0 and R1 patients, respectively
• Median overall survival was 35 months
• R0, 34 months; R1, 35months
• Conclusion: Regimen is well tolerated, has promising
efficacy
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31. Adjuvant Chemotherapy Alone
• PROSPECTIVE TRIALS
BILCAP Trial
PRODIGE 12-ACCORD 18-UNICANCER GI
Takada et al. Japanese Study
• RETROSPECTIVE DATA
German Registry
NCDB
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Takada et al. Cancer, 2002
• April 1986 and June 1992, a total of 508 patients post surgery
• 140 GBC
• MF (Trial Group) received –MMC+FU
• Control group- Observation
• Conclusion: The 5-year OS gallbladder carcinoma patients was significantly better
in the MF group (26.0%) compared with the control group (14.4%)

33. Phase III BILCAP trial
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34. BILCAP: Ph-III RCT
• Total 447 patients with completely resected cholangiocarcinoma or GBC (n
= 79, 18 percent)
• Eight Cycles of Single agent Capecitabine vs Observation
• Provisional Report: ASCO 2017- Trend towards benefit
• Intent to treat analysis: mOS 51 versus 36 months, HR 0.81, 95% CI 0.63-
1.06
• Pitfalls:
oAnalysis was not stratified according to primary tumor site
oOnly a small minority of patients were GBC
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36. PRODIGE12:RCT Ph-III
• 196 patients with resected biliary tract cancer (19 percent GBC)
• Six months of GEMOX vs Observation
• 86 percent) had complete (R0) resections
• Approximately 50 percent had node-positive disease.
• At a median follow-up of 47 months
• Conclusion: Preplanned subgroup analysis failed to demonstrate
any subgroup with a benefit from adjuvant chemotherapy,
including those with GBC
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37. Retrospective Analyses: Conflicting Results
1. Mitin T et al. J Natl Cancer Inst. 2017:
• 5029 patients diagnosed with T1-3 N0-1 GBC
• Treated with surgical resection, b/w 2005 and 2013
Results:
• significant improvement in three-year survival
• Chemoradiotherapy adjusted HR 0.47 [95% CI 0.39-0.58],
Chemotherapy alone adjusted HR 0.77 [95% CI 0.61-0.97]
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38. 2. Mantripragada KC et al. J Natl Cancer Inst. 2017:
• T2-3 or node-positive, nonmetastatic gallbladder cancer, resected with
grossly negative margins
• 2004 and 2011, 4775 patients
• Adjuvant chemotherapy was administered to 28.8%
• Chemoradiation to 13.5%
• Overall survival at three years was 40 percent
• Unaffected by adjuvant therapy HR 1.01, 95% CI 0.92-1.10)
• Surgical techniques and adjuvant therapy strategies were not optimized
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39. Indian Experience: Recent Evidence
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41. Ostwal V et al. TMH, Mumbai-2018
• Retrospectively upfront curative resection for GBC from 2010 to 2016 were
analyzed
• 242 stage II–III GBC
• 125 patients received Gem+Cis regimen as adjuvant chemotherapy
• 113 (90.4%) underwent R0 resection
• median follow-up of 36.88 months
• 3-year RFS was 60.3%
• Stage II, IIIA and IIIB,3 Years OS was 91.9, 67 and 58.1% (p=0.001) respectively
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42. OVERVIEW
Disease Burden
Rationale of Adjuvant therapy in GBC
Adjuvant Modalities
Evidence
Guidelines
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43. GUIDELINES
• ICMR-2014
• ESMO-2016
• ASCO-2019
• NCCn-2019
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• Adjuvant therapy (radiotherapy, chemoradiotherapy or chemotherapy
alone) may be offered
• The evidence base is weak and only after risk–benefit assessment
• Participation in clinical trials should be encouraged
CONCLUSION:

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55. Future
• Precision medicine
• Targeted therapy in GBC
• Immunotherapy in GBC
• Chemoimmunotherapy in GBC
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56. Conclusion
• Majority of GBC advanced/metastatic
• Paucity of high-quality evidence to support adjuvant treatment
• Surgery alone is curative only for early GBC (Stage I)
• Combination of surgery and peri-operative systemic therapy results in
favorable outcomes even in stage II/III disease
• Optimum strategy still needs to be defined
• No consensus as to the optimal adjuvant approach
• Adjuvant CTRT best choice?
• RCTs from India ?
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57. THANK YOU
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