Approach to Gastrointestinal Stromal Tumors (GIST) David A. Kooby, M.D. Associate Professor of...

Approach to Gastrointestinal Stromal Tumors (GIST)

David A. Kooby, M.D.Associate Professor of Surgery

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.

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

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

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.

GIST

c-kit Gene Mutations

TK1

TK2

Extracellular

Intracellular

EXON 9 (~5%–10% of mutations)

EXON 11 (~70% 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

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.

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.

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.

GIST

Ulcerated Gastric GIST

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

GIST

Left Upper Quadrant Mass

Liver

Spleen

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.

GIST

CT Imaging of Primary Disease

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.

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

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

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.

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

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?

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

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

GIST

Years, post-resection

Per

cent

al

ive

Z9001, Overall survival


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.


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.

GIST

Pushing tumors

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

GIST

Novitsy YW, et al. Ann Surg. 2006 June; 243(6): 738–747.

Suggested port placement

GIST

Laparoscopic resection of gastric GIST

Novitsy YW, et al. Ann Surg. 2006 June; 243(6): 738–747.

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

GIST

Case 1: Laparoscopic wedge resection

VIDEOClear margin2.4 cm tumor12 mitoses / 50 HPF

Adjuvant gleevecLife long surveillance

GIST

Case 2: Distal duodenal lesion

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

GIST


LIVER

SPLEENSTO

MACH

GIST


GIST


• 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

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

GIST


• Surgical evaluation

• Deemed unresectable

LIVERSPLEEN

STOMACH

PANCREAS

COLON

GIST


• Medical therapy

• PET scan

• 6 months STI571

• Repeat scans

GIST


GIST


• 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

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

GIST


GIST


• 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

GIST


Front view Side view (looking left)

GIST


HEAD

LIVER

GIST


GIST


• 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

GIST

December 2005

GIST


GIST

December 2005

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

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

GIST

Thank you

?

GIST

DeMatteo RP, et al. ASCO 2008

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

GIST

DeMatteo RP, et al. ASCO 2008

GIST

DeMatteo et al., ASCO 2007

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


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


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

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

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.

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.

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.

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)


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.

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.


• Surgical evaluation

• Contemplated resection for recurrent leiomyosarcoma

• Referred to surgical oncologist

• Repeat biopsy CD117 postive

• Referred for gleevec therapy

GIST

Approach to Gastrointestinal Stromal Tumors (GIST) David A. Kooby, M.D. Associate Professor of...

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