Gastrointestinal Stromal TumorsTwelfth GRW Symposium
Surgical Grand Rounds
1-15-04
Gastrointestinal Stromal TumorsCase 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 TumorsHosp 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 TumorsPostoperative plans: Referred for
consideration of adjuvant Imatinib Mesylate (Gleevec)
Gastrointestinal Stromal TumorsCase 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 TumorsHospital 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 TumorsHospital 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 TumorsWhat 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 TumorsTyrosine 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 TumorsRisk of Metastases
Risk group Size Mitotic countVery low <2 cm <5 per 50 HPFsLow 2-5 cm <5 per 50 HPFsIntermediate <5 cm 6-10 per 50 HPFs
5-10 cm <5 per 50 HPFsHigh >5 cm >5 per 50 HPFs
>10 cm any mitotic rateany 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 TumorsLocation
Stomach 54% Small bowel 47% Rectum 6% Retroperitoneum 7%
Clin Cancer Res 9(9):2003
Gastrointestinal Stromal TumorsPresentation
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 TumorsGenetics
c-kit, a 145 kD transmembrane glycoprotein Activating mutation usually at codon 11 Constitutive ligand-independent activation of
kinase
Gastrointestinal Stromal TumorsGenetics
Platelet derived growth receptor alpha (PDGFRA)
Tyrosine kinase activator Similar to c-kit Helps define GIST
Gastrointestinal Stromal TumorsTreatment
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 TumorsImatinib 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 TumorsStudies
University of Chicago Oregon University and Health Sciences Washington Hospital Center Johns Hopkins Hospitals
Gastrointestinal Stromal TumorsUniversity 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 TumorsUniversity of Chicago
Imatinib mesylate treatment 29 patients treated for metastatic disease 3 received adjuvant therapy after resection Median follow-up 18 months
Gastrointestinal Stromal TumorsUniversity 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 TumorsUniversity 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 TumorsUniversity 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 TumorsUniversity 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 TumorsUniversity 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 TumorsOregon 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 TumorsUniversity 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 TumorsWashington 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 TumorsWashington 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 TumorsJohns Hopkins
38 tumors studied Evaluated tumor suppressor genes Assessed degree of hypermethylation
House, et al. J Gastroint Surg, 7(8);2003:1004.
Gastrointestinal Stromal TumorsJohns 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 TumorsJohns Hopkins
38 tumors resected from 1989 to 2001 All c-kit positive 11 candidate tumor suppressor genes
studied
Gastrointestinal Stromal TumorsJohns 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 TumorsSummary
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 TumorsCurrently Available Trials
Neoadjuvant study RTOG S-0132/ACRIN 6665 Patients with recurrent or measurable
peritoneal disease 8 wks Imatinib followed by resection
Gastrointestinal Stromal TumorsCurrently 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 TumorsCurrently 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