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Treatment of Biliary Cancers

Treatment of Biliary Cancers. Abby B. Siegel, MD, MS Columbia University Co-Chair, SWOG Hepatobiliary Committee NCI Task Force, Hepatobiliary Cancers. Biliary Anatomy. Adapted from De Groen et al, NEJM 1999 Oct 28;341(18):1368-78 .

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Treatment of Biliary Cancers

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  1. Treatment of Biliary Cancers Abby B. Siegel, MD, MS Columbia University Co-Chair, SWOG Hepatobiliary Committee NCI Task Force, Hepatobiliary Cancers

  2. Biliary Anatomy Adapted from De Groen et al, NEJM 1999 Oct 28;341(18):1368-78

  3. Gemcitabine With or Without Cisplatin in Advanced or Metastatic Biliary Cancer(UK ABC-02 trial)

  4. Gemcitabine/Cisplatin in Perspective • A standard for advanced disease • Study results influenced by: • GB vs IHCC vs EHCC • Included ampullary cancers • Patient selection: • AST/ALT/Alkphos<3XULN • T Bili < 1.5 ULN • Accrual in select centers with experience • 27% locally advanced disease • Caution about using Gem/cis as the only backbone in first line therapy • What about other effective therapies: Gem/cape?

  5. Single Agent Targeted Therapy Bengala C et al, British Journal of Cancer 2010,102: 68 – 72; Rizell et al, Int J ClinOncol 2007 13:66-70 Philip, P. A. et al. J ClinOncol2006, 24:3069-3074, Ramantaan et al, Cancer ChemotherPharmacol 2009 64:777–783

  6. Combination Targeted Agents

  7. Cytotoxic Chemotherapy with Targeted Agents

  8. Adjuvant Therapy for Biliary Cancers • No clear prospective randomized data • Best evidence so far is a meta-analysis • 6712 patients, non significant improvement in OS for any adjuvant therapy (HR 0.74, p=0.06)

  9. Adjuvant Therapy for Biliary Cancer: Horgan A M et al. JCO 2012;30:1934-1940

  10. Adjuvant Therapy for Biliary Cancers • No large randomized trials yet, and no clear guidelines • Metaanalysis suggests possible benefit of chemotherapy for all, particularly for node (+) and margin positive disease • Radiation is often added in margin (+) disease I usually give 6 months gem or gem/cis for margin (-), consider XRT + chemo for margin (+) disease; consider re-resection also Horganet al. JCO 2012;30:1934-1940

  11. Adjuvant Therapy: SWOG 0809 • Eligibility • 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 + Capecitabine750 mg/m2 PO BID x 14 days X 4 cycles Concurrent EBRT with Capecitabine 665 mg/m2 BID x 7 days For 6 weeks 4500 cGy (5 days a week, 180 cGy daily) with 900 cGy boost

  12. Adjuvant Therapy in Biliary Cancers: Current Landscape • BILCAP (UK): Phase 3: capecitabine versus observation in GB, IHCC, EHCC (n=360) • French phase 3 study: gemcitabine and oxaliplatin versus observation in GB, IHCC, EHCC (n=190) • ACTICCA-01: Phase 3: adjuvant gemcitabine and cisplatin versus BSC or capecitabine (depends on BILCAP)

  13. Potential New Targets in Cholangiocarcinoma • MEK • IDH1/2 • FGFR

  14. Mutated and activated in multiple cancers MEK1&2 ERK1&2 MEK Inhibition in Cancer Therapy Receptor Tyrosine Kinase RAS-RAF-MEK pathway implicated in many tumors • B-Raf mutations: 0-22% Bile duct tumors • K-Ras mutations 3-54% Bile duct tumors N-Ras H-Ras K-Ras A-Raf B-Raf C-Raf Activation of Transcription/Proliferation

  15. MEK Inhibitors in Biliary Cancer Bekaii-Saab et al. JCO 2011 29:2357-63, Finn et al, GI ASCO 2012

  16. MekInhibition Second Line: Trametinib(SWOG 1310) 5-FU or capecitabinea(N = 40) Patients with refractory advanced biliary cancer who have failed one prior line of treatment Randomize Single Agent Trametinib (2mg QD) (N=40)

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

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

  19. IDH Inhibitors • Isocitrate dehydrogenase mutations lead to production of 2-hydroxyglutamate • 2HG as potential non-invasive biomarker of response • Plasma • MRS • Inhibitors being actively developed

  20. FGFR2 Fusions Define a Unique Molecular Subtype of Cholangiocarcinoma Wu Y et al. Cancer Discovery 2013;3:636-647, Arai et al, Hepatology 2013, EPUB ahead of print

  21. Optimizing the Evaluation of Targeted Agents in Cholangiocarcinoma • Choosing the “relevant” target(s) or combination of targets • Having appropriate preclinical models • Stratifying by site if target differs based on location • Enriching clinical trial population for target

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