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![Page 1: Approach to Gastrointestinal Stromal Tumors (GIST) David A. Kooby, M.D. Associate Professor of Surgery.](https://reader036.fdocuments.us/reader036/viewer/2022062407/56649e2a5503460f94b1892f/html5/thumbnails/1.jpg)
Approach to Gastrointestinal Stromal Tumors (GIST)
David A. Kooby, M.D.Associate Professor of Surgery
![Page 2: Approach to Gastrointestinal Stromal Tumors (GIST) David A. Kooby, M.D. Associate Professor of Surgery.](https://reader036.fdocuments.us/reader036/viewer/2022062407/56649e2a5503460f94b1892f/html5/thumbnails/2.jpg)
GIST
Gastrointestinal Stromal Tumors (GISTs)
• Described in 1983
• Type of sarcoma• Cancer of mesenchymal origin• Smooth muscle and neural elements• Intestinal pacemaker cells (interstitial cells of Cajal)
• Epidemiology• ~1000-1500 cases annually in the United States• 6% of sarcomas• 80% of GI sarcomas
• Median age at presentation is 60Miettinen M et al. Hum Pathol. 1999;30:1213-1220.Joensuu H et al. Lancet Oncol J. 2002;3:655-664. Kindblom LG. Ann Oncol. 2002;13:157. Abstract 5770.Sircar K et al. Am J Surg Pathol. 1999;23:377-389.Wang L et al. Arch Pathol Lab Med. 2000;124:1471-1475.
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GIST
Historical Misclassification
7%
13%
18%
34%
28%
GIST (~40% high risk)
Leiomyoma (benign)
Leiomyosarcoma (malignant)
Leiomyoblastoma (malignant)
Other
Variable criteria / confusing nomenclature
Higher incidence than thought
80% of GI soft tissue tumors now identified
Kindblom LG et al. Ann Oncol. 2002;13:157. Abstract 5770. Kindblom LG. www.peerviewpress.com/asco2003c.
Smooth muscle tumors all sites
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Genetic Basis for GIST
• Genetic mutation
• c-kit proto-oncogene
• Exon 11: Gain of function mutation
• KIT protein over-expressed
• Kit protein function
• Transmembrane receptor
• Activated by stem cell factor ligand
• Increases tyrosine kinase activity
• Cascade of intracellular signals
Hirota S, et. al. Science. 1998;279:577-580.
SCF
TK
TKA
EXON 11
Extracellular
Intracellular
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GIST
Normal KIT Function
Normal function of KIT protein:
– Hematopoiesis
– Melanogenesis
– Fertility and gametogenesis
Kit activation effects:
– Proliferation
– Differentiation
– Apoptosis / survival
– Adhesion / chemotaxis
– Angiogenesis
Taylor ML, Metcalfe DD. Hematol Oncol Clin North Am. 2000;14:517-535.
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GIST
c-kit Gene Mutations
TK1
TK2
Extracellular
Intracellular
EXON 9 (~5%–10% of mutations)
EXON 11 (~70% of mutations)
EXON 13 (~5% of mutations)
EXON 17 (~5% of mutations)
Kinase insert
Ligand (SCF)-binding
.Heinrich MC et al. Hum Pathol. 2002;33:484-495.Corless CL et al. Proc Am Assoc Can Res. 2003;44. Abstract R4447.
7% of GISTs have a PDGFR mutation
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GIST
KIT Mutations Predict Overall Survival
0 100 200 300 400 500 600 700 8000
10
20
30
40
50
60
70
80
90
100
Days
Ov
era
ll s
urv
ival
(%
)
KIT exon 11 (n=85)
KIT exon 9 (n=23)
No kinase mutation (n=9)
Heinrich et al. J Clin Oncol. 2003;21:4342.
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GIST
Classification
• Immunohistochemistry
• CD117 (c-kit) positive (95%)
• CD34 positive (70%)
• Smooth muscle actin positive (40%)
• PS100 positive (5%)
• Desmin positive (2%)
• Molecular analysis
• CD117 negative cases (5%)
• KIT mutation
• PDGFR mutationCD117 (c-kit) positive
Miettinen M, Lasota J. Virchows Arch. 2001;438:1-12.
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GIST Clinical Presentation
• Asymptomatic
• Incidental finding (11%)
• Symptomatic
• Vague GI pain or discomfort (38%)
• Abdominal mass (20%)
• GI hemorrhage
• Anorexia, weight loss, nausea, anemia, shortness of breath
Miettinen M et al. Hum Pathol. 1999;30:1213-1220.
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GIST
Ulcerated Gastric GIST
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GIST
Anatomic Location
GISTs may occur anywhere in the GI tract/abdomen
Miettinen M et al. Hum Pathol. 1999;30:1213-1220.
Site Incidence
Gastric 50%–70%
Small Intestine 20%–30%
Colon <5%
Other <5%
Other- omentum, mesentery, retroperitoneum, esophagus
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GIST
Left Upper Quadrant Mass
Liver
Spleen
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GIST
Initial workup
• Diagnosis• EGD
• Characterize a mass• Histology is can be difficult to obtain
• Staging (CT or MRI)• Evaluate the extent of the mass
• Detect metastases
• Assess tumor resectability
• 18FDG-PET
• Endoscopic ultrasound
Demetri et al. JNCCN. 2007;5(suppl 2):S1-S29.
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GIST
CT Imaging of Primary Disease
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GIST
Staging
High Risk (~40%)
• Primary with unfavorable features
• Metastasis
• Invasion of adjacent organs, structures
• Recurrence
Low Risk (~60%)
• Primary with favorable features
• Can still spread
Miettinen M et al. Hum Pathol. 1999;30:1213-1220.DeMatteo RP et al. Hum Pathol. 2002;33:466-477.
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GIST
Staging
• Tumors classified as low risk can metastasize
Fletcher CD et al. Hum Pathol. 2002;33:459-465.Tornoczky T et al. J Clin Pathol. 2003;56:363-367.
Prevalence Risk Size Mitotic Rate
Very Low
Low
Intermediate
High
Overtly Malignant
<2 cm
2–5 cm
<5 cm
5–10 cm
>5 cm
>10 cm
Any size
<5/50 hpf
<5/50 hpf
6–10/50 hpf
<5/50 hpf
>5/50 hpf
Any mitotic rate
>10/50 hpf
98/106
31/106
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GIST
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
Es
tim
ate
d p
rop
ort
ion
of
su
rviv
ors
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Time since diagnosis (years)
Very low 12
Low 33 65
Intermediate 20
Normal population
High 23
Overtly 12 35 malignant
Overall Survival by Risk Group
Risk groups % of Patients
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GIST
Proposed Mechanism of gleevec
TK
TKA
EXON 11
Extracellular
Intracellular
STI571• A selective tyrosine kinase inhibitor of:
– Bcr-Abl
– PDGF-R
– Kit
• First used in Philadelphia chromosome–positive (Ph+) CML
– Target Bcr-Abl
Druker BJ et al. Nat Med. 1996;2:561-566.
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GIST
Joensuu H et al. N Engl J Med. 2001;344:1052-1056.
Marked Biologic Response Revealedby PET Scan
Multiple liver and upper abdominal 18FDG-accumulating metastases
A marked decrease in 18FDG uptake4 weeks after starting imatinib mesylate
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GIST
Ramifications of gleevec
• Treatment of metastatic and unresectable disease
• Adjuvant therapy?• Which patients?
• How long?
• Does it reduce recurrence?
• Does it improve survival?
• Are bridges burned?
• Neoadjuvant therapy?• Which patients?
• How long?
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GIST ACOSOG Trial Z9001:phase III randomized, multicenter trial
adjuvant gleevec vs. placebo
Resected GIST 3 cm
Confirm Kit+GIST
400mg/day
Placebo
Recurrence800 mg/day
No recurrence,continue 1 year
Recurrence, switch to gleevec
No recurrence,continue 1 year
RecurrenceRestart gleevec
1 year Follow-up>5 yearsObjectives:
1) Overall survival2) Recurrence-free survival3) Safety of gleevec in the adjuvant setting
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GIST
Z9001, Recurrence-free survival
DeMatteo R, et al. The Lancet. 2009;373: 1097-1104
Years, post-resectionPer
cent
al
ive
with
out
recu
rren
ce
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GIST
Years, post-resection
Per
cent
al
ive
Z9001, Overall survival
DeMatteo R, et al. The Lancet. 2009;373: 1097-1104
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GIST
Z9001, Conclusions
•Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with palcebo after the resection of primary gastroinstestinal stromal tumour.
DeMatteo R, et al. The Lancet. 2009;373: 1097-1104
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GIST
Surgery for Primary GIST
• Fragility of tumor risks rupture
• Bleeding (tumor vessels)
• Dissemination
• Abdomen should be examined for metastases
• Peritoneal surfaces
• Liver
• Lymph node dissection unnecessary
• <5% incidence of nodal involvement
• GIST can often be lifted off surrounding organs
• “Pushers not Invaders”Demetri et al. JNCCN. 2004;21(suppl 1):S1.
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GIST
Pushing tumors
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GIST Laparoscopic resection of gastric GISTLong-term outcomes
• 50 patients in 8 year interval
• Tumor characteristics
• Mean tumor size 4.4 cm
• 9 (18%) had >10 mitotic figures/50 HPF
• Majority in proximal stomach
• Operative characteristics
• Mean operative time 135 min
• Mean blood loss 85 cc
• Follow up (mean 36 months)
• No port site recurrences
• 46 (92%) disease free
Novitsy YW, et al. Ann Surg. 2006 June; 243: 738–747.
Conclusion:Laparoscopic approach to small – medium sized gastricGISTs may be preferred over the open approach
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GIST
Novitsy YW, et al. Ann Surg. 2006 June; 243(6): 738–747.
Suggested port placement
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GIST
Laparoscopic resection of gastric GIST
Novitsy YW, et al. Ann Surg. 2006 June; 243(6): 738–747.
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GIST Laparoscopic Versus Open Gastric Resections for GIST: A Size-Matched Comparison.
Lap (N=40) Open (N=40) P value
OR time (min) 96 (48-200) 89 (30-249) 0.32
Blood loss (ml) 25 (5-200) 100 (5-400) 0.006
Length of stay (days)
4 (2-7) 7 (4-25) 0.002
Complications n(%)
6 (15%) 10 (25%) NS
Karakousis G, et al. Ann Surg Oncol. 2011 Jan 5. [Epub ahead of print]
Median follow up of 34 months, 1 recurrence in each group
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Cases
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GIST
Case 1: Laparoscopic wedge resection
VIDEOClear margin2.4 cm tumor12 mitoses / 50 HPF
Adjuvant gleevecLife long surveillance
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GIST
Case 2: Distal duodenal lesion
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GIST
Case 3: Primary - untreated
• 45 yo healthy man
• Symptoms• Vague abdominal pain x 6 months
• Weight loss, 20 lbs
• Exam• Left upper quadrant mass
• Evaluation• EGC
• CT (20 cm mass) and biopsy-proven GIST
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GIST
Case 3: Primary - untreated
LIVER
SPLEENSTO
MACH
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GIST
Case 3: Primary - untreated
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GIST
Case 3: Primary - untreated
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GIST
Case 3: Primary - untreated
• Organs resected• Total gastrectomy• Partial hepatectomy
• Pathology• 15 cm• High grade• Negative margins
• Additional treatment• 6 months gleevec• Noncompliant due to nausea
• Follow up• Dead of disease at 2 years
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GIST
Case 4: Primary - pretreated
• 60 yo healthy man
• Symptoms• Vague abdominal pain x 6 months
• Weight loss, 25 lbs
• Exam• Left upper quadrant mass
• Evaluation• EGC
• CT (20 cm mass) and biopsy-proven GIST
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GIST
Case 4: Primary - pretreated
• Surgical evaluation
• Deemed unresectable
LIVERSPLEEN
STOMACH
PANCREAS
COLON
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GIST
Case 4: Primary - pretreated
• Medical therapy
• PET scan
• 6 months STI571
• Repeat scans
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GIST
Case 4: Primary - pretreated
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GIST
Case 4: Primary - pretreated
• Organs resected
• Partial gastrectomy
• Partial colectomy
• Pathology
• 21 cm
• High grade with significant necrosis
• 20% viable tumor remaining
• Negative margins
• Additional treatment
• Gleevec for 2 years
• Follow up:• Currently NED at 5 years
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GIST
Case 5: Recurrent - symptomatic
• 63 yo woman
• 1998, explored for presumed leiomyosarcoma of uterus
• At operation, found to arise from stomach
• Final diagnosis, leiomyosarcoma
• Next presentation
• 2003, developed abdominal bloating and malaise
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GIST
Case 5: Recurrent - symptomatic
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GIST
Case 5: Recurrent - symptomatic
• Treatment course
• Received 4 months of gleevec
• Poor response on PET and no clinical improvement
• Admitted with malnutrition, shortness of breath and hypoglycemia
• Surgical consultation
• Palliative resection offered
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GIST
Case 5: Recurrent - symptomatic
Front view Side view (looking left)
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GIST
Case 5: Recurrent - symptomatic
HEAD
LIVER
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GIST
Case 5: Recurrent - symptomatic
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GIST
Case 5: Recurrent - symptomatic
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GIST
Case 5: Recurrent - symptomatic
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GIST
Case 5: Recurrent - symptomatic
• Organs resected• Partial colectomy
• Pathology• 44 cm mass• Additional foci• High grade
• Additional treatment• 8 months of adjuvant gleevec• 8 months of second-line therapy
• Follow up• Progression of disease
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GIST
December 2005
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GIST
December 2005
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GIST
December 2005
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GIST
Case 5: Recurrent - symptomatic
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GIST
December 2005
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GIST Summary
• CD117 positive mesenchymal tumors of the GI tract
• Low (60%) vs. high (40%) risk for metastasis and recurrence
• Optimal therapy is complete resection, possible in 50% at dx
• Standard chemotherapy and radiotherapy are ineffective
• Imatinib mesylate is effective and safe for adjuvant therapy of Kit–positive GIST and can be used preoperatively as well
• Laparoscopic resection may be preferred for small to medium primary gastric GIST over the open approach
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GIST GISTResectable Unresectable
Complete Resection Gross Residual DiseaseGleevec
Tumor Progression
Gleevec dose escalationOr consider 2nd line Tx
Clinical Response
Re-evaluate Resectability
Resectable
Resection +/-Adjuvant Gleevec
Unresectable
MaintenanceGleevec
High RiskLow Risk
Observation Gleevec, at least 1 year
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GIST
Thank you
?
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GIST
DeMatteo RP, et al. ASCO 2008
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GIST
At: http://www.acosog.org/studies/synopses/Z9000_Synopsis.pdf.
Phase II Trial (ACOSOG Z9000): Study Design (cont’d)
Complete resection of high-risk primary GIST
Imatinib mesylate(400 mg/dfor 1 year)
FollowforOS
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GIST
DeMatteo RP, et al. ASCO 2008
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GIST
DeMatteo RP, et al. ASCO 2008
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GIST
DeMatteo RP, et al. ASCO 2008
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GIST
DeMatteo et al., ASCO 2007
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GIST
First GIST Case Study: Proof-of-Concept
• 50-year-old woman with a large abdominal mass
• Resection of primary tumor and omental metastases
• Multiple subsequent resections
• Postsurgical treatment:
• 4-agent chemotherapy (MAID)
• IFN- and thalidomide
• No clinical response
Joensuu H et al. N Engl J Med. 2001;344:1052-1056.
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GIST
First GIST Case Study: Proof-of-Concept
Purpose/Dosage – Exploratory study in GIST
– 400mg/day orally
Clinical response – Total tumor size decreased by>75% at 8-month follow-up
– Excess metabolic activitydisappeared (PET scan)
– Tumor biopsies showedhistologic evidence of myxoiddegeneration and lack of mitoticactivity
Adverse effects – Mild nausea and increasedfrequency of bowel movements
Joensuu H et al. N Engl J Med. 2001;344:1052-1056.
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GISTGIST: Recurrence-Free Survival Following Surgical
Treatment of Primary GIST
• Recurrence-free survival is predicted by tumor size and mitotic index
Singer et al. J Clin Oncol. 2002;20:3898.
0
0.25
0.50
0.75
1.0
0 20 40 60 80
<5 cm
5-10 cm
>10 cm
P=0.03
Months
Rec
urr
ence
-fre
e su
rviv
al
0
0.25
0.50
0.75
1.0
20 40 60 80Months
3 mitoses/30 HPF
>3 to 15 mitoses/30 HPF
>15 mitoses/30 HPFP=0.0001
0 R
ecu
rren
ce-f
ree
surv
ival
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GIST
Classification
• Variants
• Spindle cell (70%)
• Epithelioid cell (20%)
• Mixed (10%)
• Light microscopy
• Eosinophilic spindle or round cells
• Short fascicles or storiform growth pattern
• Indistinct cell borders
• Cystic stromal degeneration
• Stromal hemorrhage
• Skenoid fibers
Spindle
Mixed
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GIST
Risk for recurrence
Mitotic index
Tumor size (cm)
Stomach Duodenum Jejunum Rectum
<5/50 HPF
2 0 0 0 0
>2 - <5 2 8 4 9
>5 - <10 4 NA 24 NA
>10 12 34 52 57
>5/50 HPF
2 0 NA 50 54
>2 - <5 16 50 73 52
>5 - <10 55 NA 85 NA
>10 86 86 90 71
Miettinen L, Lasota J. Semin Diagn Pathol. 2006;23:70-83.
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GIST
Kit Mutation Status and Prognosis
• KIT mutations are the best predictors of clinical response to imatinib mesylate
• 3 prognostic groups can be defined
• KIT Exon 11—favorable response (PR 83.5%, n=85)
• KIT Exon 9—intermediate response (PR 47.8%, n=23)
• No kinase mutation or PDGFRA D842V—worst response (no PR, n=12)
Heinrich et al. J Clin Oncol. 2003;21:4342.
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GIST Phase III Trial (ACOSOG Z9001): Study Design
Objectives: Primary: OS with imatinib mesylate in adjuvant setting relative to placebo
Secondary: Recurrence-free survivalSafety/efficacy in adjuvant setting
Treatment: Imatinib mesylate administered at 400 mg/d
Inclusion: 3 cm GIST Surgery within 70 days prior to registrationKIT-positive GISTImatinib mesylate–naive No prior adjuvant therapy
At: http://www.acosog.org/studies/synopses/Z9001_Synopsis.pdf.
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GIST
Results Z9001
• Completed accrual in 2007
• Gleevec arm, N=359
• Placebo arm, N=354
• Median follow up of ~20 months
• Improved recurrence-free survival from 83% to 98% (HR 0.35% 95% CI 0.22-0.53)
DeMatteo R, et al. The Lancet. 2000;373: 1097-1104
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GIST
Surgical Margins for Primary GIST
• R0 resection of disease is the goal
• Management of positive margins unclear
• Repeated resection of unclear value
• Role for adjuvant imatinib mesylate therapy being evaluated
• Lymphadenectomy is generally unnecessary
Demetri et al. JNCCN. 2004;21(suppl 1):S1.
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GIST
High risk GIST
• Median time to recurrence is 7 months to 2 years
• Only 10% of patients remain disease-free after extended follow-up
• Investigational protocols are indicated to reduce the rate of recurrence following resection
• Recurrent disease should be treated as metastatic disease
DeMatteo et al. Hum Pathol. 2002;33:466.Buemming et al. Proc Am Soc Clin Oncol. 2003;22:818. Abstract 3289.Ng et al. Cancer. 1992;69:1334.
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Case 5: Recurrent - symptomatic
• Surgical evaluation
• Contemplated resection for recurrent leiomyosarcoma
• Referred to surgical oncologist
• Repeat biopsy CD117 postive
• Referred for gleevec therapy
GIST