Management of GISTManagement of GIST

Dr Kwan Ming WaDr Kwan Ming Wa

Tuen Mun HospitalTuen Mun Hospital

ContentsContents

Mainly concern aboutMainly concern about OncogensisOncogensis Surgical treatmentSurgical treatment Targeted therapyTargeted therapy

IntroductionIntroduction

GIST GIST the most common Sarcoma of the GI tractthe most common Sarcoma of the GI tract derived from the Interstitial cells of Cajalderived from the Interstitial cells of Cajal

Oncogenesis of GISTOncogenesis of GIST

Gene expression

Gene expression

Signal-Transduction ATP ADP

Signal-Transduction ATP ADP

Plasma MembranePlasma MembraneSignal

MoleculeSignal

Molecule

KIT Receptor

KIT Receptor

Earl W. Sutherland (Nobel Prize – 1971)

Mutated KIT receptor become autonomous Mutated KIT receptor become autonomous and cell proliferation become uncontrolledand cell proliferation become uncontrolledMutated KIT receptor become autonomous Mutated KIT receptor become autonomous and cell proliferation become uncontrolledand cell proliferation become uncontrolled

Understanding of the oncogenesis Understanding of the oncogenesis is the key to is the key to

the advances of diagnosis and the advances of diagnosis and targeted therapytargeted therapy

Differentiation of GIST from Differentiation of GIST from smooth muscle tumoursmooth muscle tumour

KITKIT CD34CD34 DesminDesmin

GISTGIST ++ 60-70%60-70% rarerare

Smooth muscle Smooth muscle tumourtumour

__ 10-15%10-15% ++

Targeted therapy (Glivec)Targeted therapy (Glivec)

Gene expression

Gene expression

ATP ADPATP ADP

Plasma MembranePlasma Membrane

Autonomous

KIT Receptor

Autonomous

KIT Receptor

Competitive inhibition of Tyrosine KinaseCompetitive inhibition of Tyrosine KinaseCompetitive inhibition of Tyrosine KinaseCompetitive inhibition of Tyrosine Kinase

Clinical features of GISTClinical features of GIST

Incidence Incidence Worldwide 10-20/ millionWorldwide 10-20/ million Tuen Mun ~13 cases/ year Tuen Mun ~13 cases/ year

Median age at 60Median age at 60

Sex ratio 1:1Sex ratio 1:1

Location of GISTLocation of GIST

SiteSite worldwideworldwide Tuen MunTuen Mun

stomachstomach 40-60 %40-60 % 55%55%

Small intestineSmall intestine 20-40%20-40% 29%29%

Colon and Colon and rectumrectum 5-15%5-15% 8%8%

esophagusesophagus <5%<5% 2%2%

othersothers 5-7%5-7% 7%7%

PresentationPresentation

GI Bleeding GI Bleeding the most common presenting symptomthe most common presenting symptom

Mass effect Mass effect when tumour is large enoughwhen tumour is large enough

Small GIST Small GIST Usually found incidentallyUsually found incidentally

Symptoms related to gastric GIST Symptoms related to gastric GIST in TuenMunin TuenMun

Others11.1%

Asymptomatic3.7%

Abdominal Mass3.7%

Abdominal Pain

18.5%Anaemia

7.4%Haematemesis

11.1%

Malaena44.4%

Preoperative biopsyPreoperative biopsyNot advocatedNot advocated

GIST is highly vascular and friableGIST is highly vascular and friable Risk of bleedingRisk of bleeding Risk tumour ruptureRisk tumour rupture Risk tumour dissemination and early recurrenceRisk tumour dissemination and early recurrence

Imaging for diagnosis and stagingImaging for diagnosis and staging

CT scan, endoscopy and EUS are commonly CT scan, endoscopy and EUS are commonly used to diagnose GISTused to diagnose GIST A well circumscribed, vascular mass associated with A well circumscribed, vascular mass associated with

stomach/ intestinestomach/ intestine

Staging primary GIST Staging primary GIST CT scan and CXR is sufficientCT scan and CXR is sufficient metastasis is usually confined to peritoneum and the metastasis is usually confined to peritoneum and the

liverliver

For complicated disease, PET-CTFor complicated disease, PET-CT Recurrent disease/ extraperitoneal metastasisRecurrent disease/ extraperitoneal metastasis

SurgerySurgery

The primary treatment for resectable GISTThe primary treatment for resectable GIST

The goal is complete resection of the The goal is complete resection of the mass without disruption of the mass without disruption of the pseudocapsulepseudocapsule

GIST generally displace rather than GIST generally displace rather than infiltrating the surrounding structureinfiltrating the surrounding structure

Achieving negative margin is usually Achieving negative margin is usually possiblepossible

Dissection of lymph node Dissection of lymph node does notdoes not

prolong survival or delay recurrenceprolong survival or delay recurrence

Connolly EM, Br J Surg 2003Connolly EM, Br J Surg 2003Sammiian L, Am Surg 2004Sammiian L, Am Surg 2004

Type of operation for gastric GIST Type of operation for gastric GIST in Tuen Munin Tuen Mun

19

3 32

0

2

4

6

8

10

12

14

16

18

20

No. of Patients

Laparotomy+wedgeexcision

Laparoscopicwedge excision

Partial gastrectomy Total gastrectomy

Types of Operation

Outcome of gastric GIST resection Outcome of gastric GIST resection in TMHin TMH

Outcome after complete resectionOutcome after complete resection

5yr survival (overall) : 48-65%5yr survival (overall) : 48-65%

Poor outcome is associated with Poor outcome is associated with Big tumour size (>5cm)Big tumour size (>5cm) High mitotic figure (>5/50HPF)High mitotic figure (>5/50HPF)

Example of excising a big GISTExample of excising a big GIST

1 year later..1 year later..

Conventional adjuvant therapyConventional adjuvant therapy

Chemotherapy: refractoryChemotherapy: refractory

Radiotherapy: limited useRadiotherapy: limited use

Targeted therapyTargeted therapy

Evidence of benefit inEvidence of benefit in Treatment of advanced GISTTreatment of advanced GIST As adjuvant to primary tumour resectionAs adjuvant to primary tumour resection

Advanced GIST treated with GlivecAdvanced GIST treated with Glivec

U.S./ U.S./ Finland Finland study study (n=147)(n=147)

EORTC EORTC study (n=36)study (n=36)

Partial Partial responseresponse

54%54% 69%69%

Stable Stable diseasedisease

28%28% 19%19%

progressionprogression 14%14% 11%11%

ACOSOG Z9001:ACOSOG Z9001: A randomized, double blind A randomized, double blind study of adjuvant Glivec versus placebo following study of adjuvant Glivec versus placebo following resection of primary GISTresection of primary GIST

10 years or until death

Design:

Primary GIST

(≥ 3 cm)

Placebo x 1 year

Glivec 400mg x 1 year

RecurrenceGlivec 400mg

(or 800mg) x 2 years

FOLLOW

Complete Gross Resection

Data monitoring committee evaluated data on >600 pts with Data monitoring committee evaluated data on >600 pts with complete resection of primary GISTcomplete resection of primary GIST

At 1 year follow-up, 97% of patients on Glivec arm were free of At 1 year follow-up, 97% of patients on Glivec arm were free of recurrence compared with 83% of patients on placebo arm recurrence compared with 83% of patients on placebo arm

Approximately 65% less likely to experience recurrence within two Approximately 65% less likely to experience recurrence within two yearsyears

All patients will be unblinded, and patients in the placebo arm will be All patients will be unblinded, and patients in the placebo arm will be offered 1 year of Glivecoffered 1 year of Glivec

ACOSOG Trial Prematurely Stopped ACOSOG Trial Prematurely Stopped Due to Superior Rates of Due to Superior Rates of RRecurrence Free Survival (RFS) ecurrence Free Survival (RFS)

with Glivecwith Glivec

Available at: http://www.cancer.gov/newscenter/pressreleases/GISTtrial

Treatment modelTreatment model

Normal Normal Normal Normal Pre-CancerPre-CancerPre-CancerPre-Cancer Metastatic Cancer Metastatic Cancer Metastatic Cancer Metastatic Cancer Cancer Cancer Cancer Cancer

preventionpreventionPrimary +/-Adjuvant

Primary +/-Adjuvant systemic

therapysystemic therapy 1st Line1st Line 2rd Line2rd Line

TreatmentStageTreatmentStage

ThankyouThankyou