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					Gastrointestinal Stromal Tumors
  Twelfth GRW Symposium


      Surgical Grand Rounds
             1-15-04
Gastrointestinal Stromal Tumors
            Case Presentation
HPI: 31yo male with a recent history of UGI
  bleed. EUS c/w duodenal mass. EUS bx –
  GIST tumor. Admitted OUMC 12/122/03
PMHX: Local excision of duodenal GIST in
  Oct 01
PE: Unremarkable except for well healed
  abdominal scar
Gastrointestinal Stromal Tumors
Hosp course: Underwent pylorus preserving
   Whipple on 12/12/03 with findings: Mass in
   second portion of duodenum, no gross tumor
   elsewhere. Post-op developed RUQ fluid
   collection, amylase poor, resolved. Patient did
   well and discharged on 12/23/03
Pathology: 3.0 cm malignant GIST, c-Kit positive, 1
   of 7 nodes positive
Gastrointestinal Stromal Tumors
Postoperative plans: Referred for
  consideration of adjuvant Imatinib
  Mesylate (Gleevec)
Gastrointestinal Stromal Tumors
             Case Presentation 2
HPI: 39 YO F transferred from outlying
  hospital 5 days S/P lap for UGI bleed with
  finding of duodenal mass. Bx c/w GIST
  tumor. Mass not resected.
PMHx: Hepatitis C
PE: Neg except for healing midline wound
Gastrointestinal Stromal Tumors
Hospital course: Patient had no further UGI
  bleeding. Was seen in consultation by
  Med/Onc who recommended D/C until role
  of neoadjuvant therapy could be defined.
  Ultimately recommended against
  neoadjuvant therapy.
Gastrointestinal Stromal Tumors
Hospital course: Underwent re-exploration
  and pylorus preserving Whipple on
  10/27/03. Findings – mass in 2nd portion of
  duodenum without evidence of metastases.
  Pathology – 4.5 cm, hypercellular GIST
  tumor, c-Kit positive, no evidence of nodal
  metastases, uncertain malignant potential.
  Patient did well and discharged for follow-
  up by surgery and med/onc.
Gastrointestinal Stromal Tumors
What are they?
1. Soft tissue sarcomas
2. Arise from interstitial cells of Cajal
3. Represent 0.1% - 3% of GI cancers
4. Represent 5% of all soft tissue sarcomas
5. 10% - 30% are highly malignant
6. c-kit or PDGFRA positive tumors
                   Int J Cancer 107:2003
Gastrointestinal Stromal Tumors
            Tyrosine Kinase Receptors
   1 of 4 classes of cell-surface receptors
   1 of 2 types of protein kinases
   Lack catalytic activity
   Ligand binding forms dimeric receptor
   Activates a cytosolic protein-tyrosine
    kinase
Gastrointestinal Stromal Tumors
   All are potentially malignant
   1st tumor to benefit from “targeted” therapy
   Criteria to predict behavior tumor behavior
       Size
       Necrosis
       Mitotic rate
Gastrointestinal Stromal Tumors
               Risk of Metastases
Risk group       Size        Mitotic count
Very low         <2 cm       <5 per 50 HPFs
Low              2-5 cm      <5 per 50 HPFs
Intermediate     <5 cm       6-10 per 50 HPFs
                 5-10 cm     <5 per 50 HPFs
High             >5 cm       >5 per 50 HPFs
                 >10 cm      any mitotic rate
                 any size    >10 per HPFs
Gastrointestinal Stromal Tumors
   Incidence appears to be increasing
   Mayo clinic study indicates incidence
    stable but diagnostic criteria changed
   Median age at diagnosis 58 years (range
    40-80 years ?)
   5 year survival variable (28 –60%)
                 Ann Surg 231:2000
Gastrointestinal Stromal Tumors
                  Location
   Stomach 54%
   Small bowel 47%
   Rectum 6%
   Retroperitoneum 7%

                Clin Cancer Res 9(9):2003
Gastrointestinal Stromal Tumors
                  Presentation
   Generally nonspecific
   GI bleeding 50%
   Abdominal pain pain 20-50%
   Obstruction 10-30%
   Asymptomatic 20%
    Int J Cancer 107:2003, Ann Surg 231:2000,Ann Chir Gynaecol 87:1998
Gastrointestinal Stromal Tumors
                    Genetics
c-kit, a 145 kD transmembrane glycoprotein
      Activating mutation usually at codon 11
      Constitutive ligand-independent activation of
       kinase
Gastrointestinal Stromal Tumors
                    Genetics
Platelet derived growth receptor alpha
   (PDGFRA)
 Tyrosine kinase activator
 Similar to c-kit
 Helps define GIST
Gastrointestinal Stromal Tumors
                    Treatment
   Surgical excision is primary treatment
    option but recurrence rates are high
   Resistant to standard chemotherapy
    regimens due to over-expression of efflux
    pumps (p-glycoprotein & MDR-1)
   Radiation therapy limited by large tumor
    sizes and sensitivity of adjacent bowel
Gastrointestinal Stromal Tumors
                Imatinib Mesylate
   Orally bioactive tyrosine kinase inhibitor
   Shown to be effective against GIST tumors
    in two trials in the US and Europe reported
    in 2001 & 2002
                 N Engl J Med 347:2002
                 Lancet 358:2001
Gastrointestinal Stromal Tumors
                    Studies
   University of Chicago
   Oregon University and Health Sciences
   Washington Hospital Center
   Johns Hopkins Hospitals
Gastrointestinal Stromal Tumors
             University of Chicago
   Retrospective study 1995-2002
   57 patients
   96% c-kit positive
   Curative resection in 50%
   Treatment of metastatic disease 50%
            Wu, et al. Surgery. 2003;134(4): 656.
Gastrointestinal Stromal Tumors
           University of Chicago
Imatinib mesylate treatment
 29 patients treated for metastatic disease
 3 received adjuvant therapy after resection
 Median follow-up 18 months
Gastrointestinal Stromal Tumors
           University of Chicago
Results
 23 (40%) patients alive and NED
 22 (39%) patients alive with disease
 7 (13%) patients died
 5 (10%) lost to follow-up
 Overall survival 87% at 18 months
Gastrointestinal Stromal Tumors
            University of Chicago
Results in 26 patients with metastatic disease
 All treated with Imatinib mesylate
 5 (2%) died
 22 (84%) stable disease or regression
Gastrointestinal Stromal Tumors
            University of Chicago
Imatinib mesylate adjuvant therapy results
 Only 3 patients in adjuvant group
 All considered “high risk” due to tumor
  characteristics
 All NED with mean follow-up of 7 months
 1 “high risk” patient who refused adjuvant
  therapy developed liver mets at 9 months
Gastrointestinal Stromal Tumors
               University of Chicago
Toxicity of Imatinib mesylate
 Generally well tolerated
 Mild fatigue
 Periorbital edema
 Mild diarrhia
 2 deaths not due to disease not relate to therapy
Gastrointestinal Stromal Tumors
             University of Chicago
Study summary
 No neoadjuvant data
 Patients in “low risk”group with R0
   resections did well
 Patients treated with metastatic disease did
   well in short term
 Adjuvant data group too small for analysis
Gastrointestinal Stromal Tumors
               Oregon University Study
   Prospective study of 127 patients in phase II
    multi-center trial of Imatinib mesylate
   Evaluated relationship between mutation type (c-
    kit & PDGFR) and clinical outcome
   Further evaluated codon mutation site and
    outcome
   Evaluated in-vitro response to Imatinib
   Evaluated clinical response to Imatinib
       Heinrich, et al. J Clin Onc, 1(23), 2003:4342.
Gastrointestinal Stromal Tumors
         University of Oregon Study
Results
 Invitro responses differ with mutation and
  codon site
 Clinical responses differ with mutation and
  codon site
 May eventually allow even more directed
  therapy as newer drugs are developed
Gastrointestinal Stromal Tumors
       Washington Hospital Center Study
   Retrospective
   69 patients with compatible histology and
    c-kit positivity
   Study purposes
       Develop prognostic indicators
       Establish the natural history of the tumor
Gastrointestinal Stromal Tumors
          Washington Hospital Center Study
Results
 Tumor site
       Even distribution between stomach and small bowel
   Prognostic factors
       Tumor size
       Peritoneal cancer index
       Completeness of cytoreduction
Gastrointestinal Stromal Tumors
                   Johns Hopkins
   38 tumors studied
   Evaluated tumor suppressor genes
   Assessed degree of hypermethylation
            House, et al. J Gastroint Surg, 7(8);2003:1004.
Gastrointestinal Stromal Tumors
                 Johns Hopkins
   Hypermethylation of CpG-rich islands is
    common in human malignancies
   Occurs in promotor area of gene
   Can it be used to predict tumor behavior?
   Does it explain resistance to Imatinib?
Gastrointestinal Stromal Tumors
                  Johns Hopkins
   38 tumors resected from 1989 to 2001
   All c-kit positive
   11 candidate tumor suppressor genes
    studied
Gastrointestinal Stromal Tumors
                 Johns Hopkins
   84% of tumors had hypermethylation of at
    least 1 gene
   Multigene methylation seen in 42% of
    tumors
   E-cadherin hypermethylation and absence
    of methylation of hMLH1 predicted early
    recurrence
Gastrointestinal Stromal Tumors
                    Summary
   GIST tumors now well characterized
   All have malignant potential
   Complete surgical resection important
   Metastatic disease responds to Imatinib
   Role of neoadjuvant therapy unclear
   Role adjuvant therapy unclear
Gastrointestinal Stromal Tumors
        Currently Available Trials
Neoadjuvant study
      RTOG S-0132/ACRIN 6665
      Patients with recurrent or measurable
       peritoneal disease
      8 wks Imatinib followed by resection
 Gastrointestinal Stromal Tumors
              Currently Available Trials

Adjuvant study EORTC 64024
 Patients with R0 resections eligible
 Patients stratified according to risk factors
 Patients randomized to either
       Imatinib 400 mg/day X 2 years
       Observation
Gastrointestinal Stromal Tumors
             Currently Available Trials
Adjuvant study ACOSOG Z9001
 Eligible patients
       Complete gross resections
       R0 or R1 (microscopic + margins)
   Randomization arms
       Imatinib 400 mg/day X 1 year
       Placebo
       Placebo patients with recurrence receive Imatinib for
        2 years
Gastrointestinal Stromal Tumors

          Thank-you