gastrointestinal stromal tumors twelfth grw symposium

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.


Imatinib mesylate treatment 29 patients treated for metastatic disease 3 received adjuvant therapy after resection Median follow-up 18 months


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


Results in 26 patients with metastatic disease All treated with Imatinib mesylate 5 (2%) died 22 (84%) stable disease or regression


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


Toxicity of Imatinib mesylate Generally well tolerated Mild fatigue Periorbital edema Mild diarrhia 2 deaths not due to disease not relate to therapy


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.


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?


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

studied


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


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


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

gastrointestinal stromal tumors twelfth grw symposium

Documents

hypercellular gist tumor

malignant gist

eus bx gist tumor

bx cw gist tumor

gross tumor

findings mass

ckit positive

malignant ckit