Gastrointestinal Stromal Tumors Twelfth GRW Symposium

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Gastrointestinal Stromal TumorsTwelfth GRW
Symposium

• Surgical Grand Rounds
• 1-15-04

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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

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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

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Gastrointestinal Stromal Tumors

• Postoperative plans Referred for consideration
  of adjuvant Imatinib Mesylate (Gleevec)

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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

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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.

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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.

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Gastrointestinal Stromal Tumors

• What are they?
• Soft tissue sarcomas
• Arise from interstitial cells of Cajal
• Represent 0.1 - 3 of GI cancers
• Represent 5 of all soft tissue sarcomas
• 10 - 30 are highly malignant
• c-kit or PDGFRA positive tumors
• Int J Cancer 1072003

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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

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Gastrointestinal Stromal Tumors

• All are potentially malignant
• 1st tumor to benefit from targeted therapy
• Criteria to predict behavior tumor behavior
• Size
• Necrosis
• Mitotic rate

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Gastrointestinal Stromal Tumors

• Risk of Metastases
• Risk group Size Mitotic count
• Very low lt2 cm lt5 per 50 HPFs
• Low 2-5 cm lt5 per 50 HPFs
• Intermediate lt5 cm 6-10 per 50 HPFs
• 5-10 cm lt5 per 50 HPFs
• High gt5 cm gt5 per 50 HPFs
• gt10 cm any mitotic rate
• any size gt10 per HPFs

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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 2312000

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Gastrointestinal Stromal Tumors

• Location
• Stomach 54
• Small bowel 47
• Rectum 6
• Retroperitoneum 7
• Clin Cancer Res 9(9)2003

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Gastrointestinal Stromal Tumors

• Presentation
• Generally nonspecific
• GI bleeding 50
• Abdominal pain pain 20-50
• Obstruction 10-30
• Asymptomatic 20
• Int J Cancer 1072003, Ann Surg 2312000,Ann
  Chir Gynaecol 871998

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Gastrointestinal Stromal Tumors

• Genetics
• c-kit, a 145 kD transmembrane glycoprotein
• Activating mutation usually at codon 11
• Constitutive ligand-independent activation of
  kinase

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Gastrointestinal Stromal Tumors

• Genetics
• Platelet derived growth receptor alpha (PDGFRA)
• Tyrosine kinase activator
• Similar to c-kit
• Helps define GIST

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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

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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 3472002
• Lancet 3582001

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Gastrointestinal Stromal Tumors

• Studies
• University of Chicago
• Oregon University and Health Sciences
• Washington Hospital Center
• Johns Hopkins Hospitals

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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. 2003134(4) 656.

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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

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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

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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

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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

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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

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Gastrointestinal Stromal Tumors

• University of Chicago
• Study summary
• No neoadjuvant data
• Patients in low riskgroup with R0 resections
  did well
• Patients treated with metastatic disease did well
  in short term
• Adjuvant data group too small for analysis

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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), 20034342.

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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

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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

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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

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Gastrointestinal Stromal Tumors

• Johns Hopkins
• 38 tumors studied
• Evaluated tumor suppressor genes
• Assessed degree of hypermethylation
• House, et al. J Gastroint Surg,
  7(8)20031004.

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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?

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Gastrointestinal Stromal Tumors

• Johns Hopkins
• 38 tumors resected from 1989 to 2001
• All c-kit positive
• 11 candidate tumor suppressor genes studied

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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

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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

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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

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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

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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

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Gastrointestinal Stromal Tumors

• Thank-you