Treatment of biliary cancers
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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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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

Biliary Anatomy

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


Treatment of biliary cancers

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


Gemcitabine c isplatin in perspective

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?


  • Single agent t argeted therapy

    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


    Combination targeted agents

    Combination Targeted Agents


    Cytotoxic chemotherapy with targeted a gents

    Cytotoxic Chemotherapy with Targeted Agents


    Adjuvant therapy for biliary cancers

    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)


    Treatment of biliary cancers

    Adjuvant Therapy for Biliary Cancer:

    Horgan A M et al. JCO 2012;30:1934-1940


    Adjuvant therapy for biliary c ancers

    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


    Adjuvant therapy swog 0809

    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


    Adjuvant therapy in biliary c ancers current l andscape

    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)


    Potential n ew t argets in c holangiocarcinoma

    Potential New Targets in Cholangiocarcinoma

    • MEK

    • IDH1/2

    • FGFR


    Mek inhibition in cancer therapy

    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


    Mek inhibitors in biliary cancer

    MEK Inhibitors in Biliary Cancer

    Bekaii-Saab et al. JCO 2011 29:2357-63, Finn et al, GI ASCO 2012


    Mek i nhibition second line trametinib swog 1310

    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)


    Idh pathway yen et al oncologist 2012 17 5 8

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

    Yen et al, Oncologist 2012 17:5-8


    Idh mutations s een in c holangiocarcinomas borger et al oncologist 2010 17 72 79

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

    Borger et al, Oncologist, 2010 17:72-79


    Idh inhibitors

    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


    Fgfr2 fusions d efine a unique m olecular s ubtype of c holangiocarcinoma

    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


    Optimizing the evaluation of targeted a gents in c holangiocarcinoma

    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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