MANAGEMENT OF GASTROINTESTINAL

STROMAL TUMOR
Dr. M. Hafidh Komar, Sp.B-KBD
EPIDEMIOLOGY
• GISTs Account for 0.1 – 3 % of all GI cancers
• Annual Incidence : 10 - 15 cases per million
• 5000 – 6000 New cases per yerars in the US
• Median age at diagnosis : 60-65 years
• Men and women affected equally
• Occult at any age including children (0.4% < 20 years)
• Total GIST Patients operated between November 2017 to
August 2018 at RSMH Palembang were 66 patients.

Keung EZ, Raut CP. Sung Clin N Am 2017;97:437-452.

Tryggvason G et al. Int J Cancer 2005;117:289-293
PATHOLOGY
• Concept of GISTs introduced in 1980s, but wide variation in
categorisatision (GIST, GANT, leiomyoma,
leiomyosarcoma.........)
• 1998 – mutations in the KIT oncogene noted
• Arise from the interested cells of cajal (Pacemaker cells of
the Gut, controling peristalsis) in the myenteric plexus
• Three morphology patterns :
Spindle cell, epitheloid, mixed
PATHOLOGY
• Diagnosis is by morphology and immunohistochemistry :
• KIT receptor (CD117)
• DOG – 1 (Highly specific, positive in 95%)
• 5% KIT Negative, but most of these express DOG-1
PATHOLOGY
MOLECULAR PATHOLOGY
• Caused by activating mutations of two specific genes which
code for trans-membrane cell surface reseptors :
• 75 – 80 % of GISTs have KIT mutations
• 7-8 of GISTs have PDGFRA mutations (wild-type)
• Gene mutations can also predict response to therapy
DIAGNOSTICS
SYMPTOMS
• Gi Bleed, anemia
• Abdominal pain and Distension
• Systemic symtomps (poor appetite,
weight loss, malaise) if
advanced/metastatic disease
• Incidental finding on endoscopy or
CT/MRI done for other reason (25%)

Adelbaker I, Hammam W, Elsherbini. Gastrointestinal

stromal tumor : diagnostic and challenges. J Surgery.
September 20, 2014
DIAGNOSTICS
Endoscopic
Akahoshi K et al. Current management of GIST
DIAGNOSTICS

Akahoshi K et al. Current management of GIST

DIAGNOSTICS

Akahoshi K et al. Current management of GIST

DIAGNOSTICS
CT scan
• Delineates the large exophytic
masses and local and distant
metastases
• Guides tissue biopsy

Large heterogeneous duodenal GIST

(D)
with multifocal hepatic metastases
(M).
The biliary tree and pancreatic duct
are not dilated.

Image reprinted from Lau et al. Clin Radiol 2004;59:487-98.

 DIAGNOSTICS
FDG-PET (Fluorodeoxyglucose-positron emission tomography)
 MANAGEMENT
MANAGEMENT OF EARLY STAGE
LOCALISED GIST
• Tumors < 2 cm – monitoring with endoscopy
• Tumors > 2 cm – R0 surgical excision
• Endoscopic resection not recomended
• Laparascopic resection – R0 excision may not be
achieved for larger tumors
• Lymph node dissection not required
OUTCOMES FOLLOWING SURGERY

15 YEAR RECURRENCE –
FREE SURVIVAL RATE 59.9 %

Joesuu et all Lancet Oncology 2012, 13-256-74

Prognostic factors predicting outcome following surgery
Tumor Size Mitotic Rate

Tumor Site Tumor Rupture

Joensuu et all Lancet Oncology 2012, 13-256-74

PREDICTION OF RISK OF RECURRENCE AFTER SURGERY

Mattinem M & Lasota J, Seminars in Diagnostic Pathology 2006 23 70-83

PREDICTION OF RISK OF RECURRENCE AFTER SURGERY

Akahoshi K et al. Current management of GIST

Approach for defining Risk of Aggressive
Behavior in Gastrointestinal Stromal Tumors
• 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
 ADJUVANT IMATINIB

• Phase III randomised blinded placebo controlled study

• 713 patients : Imatinib 400mg vs placebo for 1 year
• Localised GIST > 3 cm KIT Positive tumors
• Primary end point – Recurrence free survival

De Matteo R et al, Lancet Oncology 2009 373:1097-1104

 RESULT
• Median follow up of 19.7 month
• 8 % patients in imatinib group and 20 % in placebo group had
tumor recurrence or had died
• Imatinib significantly improved recurrence free survival
compared with placebo : 98% vs 83 % at 1 year (p<0.0001)
• No Difference in overall survival
 RESULT
Reccurence Free Survival Recurrence Free Survival

>3 – 8cm

Overall Survival Recurrence Free Survival

>10cm

Dematteo R et al, Lancet Oncology 2009, 373,

1097-1104
Recurrence Free Survival Overall Survival
5 years RFS 65% vs 49.7% 5 years OS 92% vs 81.7%

Juensuu H et al, Jama 2012-307 1265-1272

 Adjuvant imatinib
Imatinib now aproved by FDA and EMA for adjuvant use
• 2008: for patient with resected c-kit positive GIST at
significant risk of recurrence
• Patient at low or very low should not be treated
• 2012: approved by FDA and EMA for 3 years duration for
high risk patient
N Engl J Med 347:2002
Lancet 358:2001
 Management of metastatic GIST

• Imatinib is used as first line treatment for locally advanced

and metastatic GIST
• Introduced in 2001, prior to this no active drug therapy
• Oral therapy given once daily
• Generally wel tolerated but 5% of patient get significant
toxicity
 Management of metastatic GIST

• Side effect : fatigue, nausea, vomiting, diarrhoea, skin rash,

periorbital oedema, generalised oedema, anemia
• Approximately 85% of patients respond to Imatinib
• Average benefit 2-2.5 years
• Initial phase I and II studies showed very high activity. Phase
III studies were not placebo controlled, but compared closed
 Phase III : Studies of Imatinib in metastatic GIST

Study Dosing n RR Median Survival

follow up

EORTC 400mg 946 CR -5% 25 months 2 years OS

62005 vs PR – 47% 69-74%
800mg SD -32%

Intergroup 400mg 746 CR – 3% 29 months 2 year OS

S0033 Vs PR – 45% 76%
800mg SD – 26% 2 years PFS
47%

Blanke C D et al, J Cin oncol 26 626-832 2008

 MetaGIST meta-analysis
• Meta-analysis of the EORTC 62005
and US intergroup S0033 studies
1,640 patients
• Small PFS advantages for 800mg arm,
HR 0,89
P=0,04
• No difference in overall survival for
800mg
• Optimal dose 400mg

MetaGIST gastrointestinal stromal tumor, Meta-analysis group J Cin Oncol-2010 1247-1253 2010
 How long does Imatinib works for
• B2222 study: phase II study of 147 patients
• Compared 400mg vs 600mg (no difference)
• Conducted 2001; long term follow up result in 2008
• Median duration of response 29 months
• 34% responders still had not progressed at 60 months

Blanke C et al, JCO 2008, 26 620-25

B2222 study: 5 years overall survival 55%
 Can we predict who will respond to treatment?

• B2222 phase II study of imatinib for enhanced or metastatic

GIST
• n-=127 patients
• Tumor examined for mutations in KIT ad PDGFRA
• Activating mutations of KIT in 88.2% and PDGFRA in 4.7%
• KIT – most common mutations in exon 11 (67%) and exon 9
(18%)

Heinrich M et al, JCO 2008 26 5380-5387

 Gene mutation predicts response to Imatinib
Genotype N PR (%) SD (%)
Exon 11 71 83,5% 8,2%
Exon 9 23 47,8% 26,1%
No KIT/PDGFRA 9 0% 33,3%
mutation

Heinrich M et al, JCO 2008 26 5360-5367

Gene mutation predicts response to Imatinib
Gene mutation and Imatinib dose response

• KIT exon 11 mutations – no influence of imatinib

dose
• Wild type – no infuence of imatinib dose
• Exon 9 mutations – significant improvement in PFS
with imatinib 800mg with 400mg
 What to do when imatinib stops working?
• 10-15% of patients will display primary imatinib resistance
wihin 3 months of starting treatment
• By 2 years >50% of patients will have progressed (secondary
imatinib resistance) – ussualy due to development of
secondary KIT/PDGFRA mutations
• Options
- Dose escalation of imatinib dose to 800mg
- 2nd line treatment (sunitinib)
- 3rd line treatment (regofenib)
- Non medical treatment – surgery? RFA?
 2nd line treatment : sunitinib (sutent)

• Phase III randomized

prospective placebo controlled
study of sunitinib in GIST after
relapse on Imatinib
• 312 patients
• Median TTP 27,3 weeks
sunitinib vs 6.4 weeks on
placebo (HR 0,33 p<0,0001)
• Overall surival superior on
sunitinib vs placebo (median
not reached) HR 0,49 p=0,007

Demetri G et al, lancet 2006, 14, 368 1329-38

 3rd line treatment : regorafenib (stivarga)

• Efficacy and safety of regorafenib

for advanced gastrointestinal
stromal tumors after failure of
imatinib and sunitinib (GRID). An
international, muticenter,
randomised, placebo-controlled,
phase 3 trial
• 240 patient
• Median progression-free survival
4,8 vs 0,9 months (HR 0,27
p<0,0001)

Demetri G et al, lancet 2006, 14, 368 1329-38

 Summary
• Early stage disease:
- Complete R0 surgical resection
- Risk stratification to guide follow up
- Adjuvant therapy – 3 years imatinib for high risk disease
• Gene mutation analysis – increasingly important to tailor
treatment for individual patient
• Advance disease
- 1st line: imatinib
- 2nd line: sunitinib
- 3rd line regorafenib
- Surgery/RFA
Thank You