Gastrointestinal Stromal Cell Tumors

Joshua D. I. Ellenhorn, M.D.Clinical Professor of Surgery

“GIST”

•46 year-old female presented with a 20 pound weight loss melena and dyspnea.

•Abdominal exam revealed an ill defined left upper quadrant mass.

•Hgb 4.9

Case Presentation

•The patient was transfused up to a Hgb of 11

•Abdominal CT scan was performed

mass 1

mass 3

mass 2

H&E c-Kit

CT guided core biopsy of the mid-abdominal mass revealed a spindle cell neoplasm which was positive for c-Kit by immunohistochemistry

How would you treat this patient?

How would you treat this patient?

How would you treat this patient?

GIST Near GEJ

How would you treat this patient?

How would you treat this patient?

GIST Is a Rare Gastrointestinal Sarcoma

• 4000 - 6000 new cases/year in US• 1500 - 2000 cases/year in Japan

• Most common GI mesenchymal neoplasm– 5%-6% of all sarcomas

• Wide age range– 75% of patients >50 years– Median age: ~58 years

• No gender predilection

GISTs Present With Variable Symptoms

• Often asymptomatic, especially when small

• Symptoms nonspecific– GI bleeding (53%)– Abdominal pain (32%)– Palpable mass (13%)

• Other symptoms may include– Early satiety– Fatigue from anemia– Rare obstruction

GISTs Occur Mainly in the Stomach

• Occur anywhere along the GI tract or elsewhere in the abdomen or retroperitoneum

Corless CL J Clin Oncol. 22:3813-3825 2004Miettinen M J Arch Pathol Lab Med. 130:1466-1478 2006

Arise From Interstitial Cells of Cajal

• Interstitial cells of Cajal (ICC)1

– “Pacemaker” cells associated with Auerbach’s plexus•GISTs share several characteristics with ICC1

– CD117 (c-KIT) expression, structural similarities• Other markers often positive in GIST2

– CD34 (60%-70%), muscle actin (SMA), S-100– ~4%-5% of GISTs are KIT-negative

1. Kindblom L-G et al. Am J Pathol. 1998;152:1259-12692. Fletcher CDM et al. Hum Pathol. 2002;33:459-65

c-KIT Staining

Cells of Cajal GIST

Structure of KIT Receptor

• Type III receptor tyrosine kinase• Extracellular domain binds ligand:

stem cell factor (SCF)• Downstream effects of SCF

binding to KIT are proliferative and antiapoptotic

• Intracellular domain has– 2 tyrosine kinase domains– Multiple autophosphorylation sites

− SCF binding site− 5 IgG domains

Cell membrane

Tyrosine kinasedomains

Taylor and Metcalfe. Hematol Oncol Clin North Am. 2000;14:517.

Normal KIT Signaling

PP PADP P

P

PP PATP

SIGNALING

Kinasedomains

Substrate

Effector

• The KIT kinase domain activates a substrate protein

• This activated substrate initiates a signaling cascade culminating in cell proliferation and survival

Savage and Antman. N Engl J Med. 2002;346:683.Scheijen and Griffin. Oncogene. 2002;21:3314.

Mutations in GIST

PDGFRA5%

Patient Workup Guides Surgical Procedure

• Initial patient workup should include– Complete lab studies– CT of abdomen and pelvis with oral IV contrast

• Selective use of tissue biopsy– EUS or CT-FNA– Cytology/pathology for spindle cell morphology, CD117(c-KIT)

• Comorbidity assessment

Surgical Treatment of GISTs

• Surgery optimal for resectable GIST

• Goals of surgery– Complete gross resection– Negative microscopic margins (R0 resection)

• If recurrence develops after surgery, disease is usually not curable

Important Surgical Considerations for theTreatment of GIST

• Metastasis commonly develop in liver and peritoneum1,2

– Liver (65%-72%)– Peritoneum (21%-64%)– Bone (4%-6%)– Lung (2%-4%)– Lymph node metastases are rare

• Tumors typically grow extraluminal3

• Careful tumor handling is critical– Soft fragile tumors that may rupture during surgery– Rupturing of pseudocapsule may cause tumor bleeding and/or dissemination

1. DeMatteo RP et al. Ann Surg. 2000;231:51-58.2. Burkill GJC et al. Radiology. 2003;226:527-532.3. Corless CL et al. J Clin Oncol. 2004;22(18):3813-3825.

Important to Differentiate BetweenAdenocarcinoma and GIST

Small Proximal Gastric GIST Infiltrating adenocarcinoma

GIST vs Adenocarcinoma Resections EntailDifferent Considerations

GIST AdenocarcinomaMargins • Wide margins not required • For clear margins, need a 4-cm

distance from tumor• Need 10-cm margins for

diffuse-type tumors

Gastrectomy •Wedge or segmentalresection often sufficient• Formal gastrectomy forlarge proximal gastricGISTs

•Total gastrectomy fortumors in proximal third ofstomach

Lymphadenectomy •Lymphadenectomyunnecessary

• Lymphadenectomy for staging and therapeutic purposes

•No difference in OR time

•No difference in margin clearance or recurrence

•Less blood loss (25 vs. 100 ml)

•Shorter hospital stay (4 vs. 7 days)

Laparoscopic Resection of Gastric GISTSize Matched comparison to Open (<8cm)

40 open patients40 laparoscopic patients

Karakoussis, Ann Surg 18:1599 2011

http://nomograms.mskcc.org/GastroIntestinal/GastroIntestinalStromalTumor.aspx

Imatinib Mesylate: Mechanism of Action

P

PP PATP

SIGNALING

Imatinib mesylate

Kinasedomains

• Imatinib mesylate occupies the ATP binding pocket of the KIT kinase domain

• This prevents substrate phosphorylation and signaling

• A lack of signaling inhibits proliferation and survival

Savage and Antman. N Engl J Med. 2002;346:683.Scheijen and Griffin. Oncogene. 2002;21:3314.

Imatinib Mesylate

• Metastatic or Unresectable• Adjuvant• Neoadjuvant

Advanced GIST(N = 147)

Imatinib, 400-600 mg once daily (QD)

Multicenter trial of Imatinib in Advanced GIST

Demetri GD, et al. N Eng J Med. 2002;347:472-480

54% response rate28% stable disease

Metastatic GIST Survival Before and After Imatinib

Sur

viva

l

Pre-Imatinib

Imatinib

Artinyan and Ellenhorn, Cancer Epidemiol Biomarkers Prev  17:2194

Artinyan and Ellenhorn, Cancer Epidemiol Biomarkers Prev  17:2194

Metastatic GIST Before and After Imatinib552 patients

Imatinib in Advanced GIST

• 5-yr OS differed according to c-KIT mutation status

Blanke CD, et al. Proc Am Soc Clin Oncol. 2007. Abstract 21.

0102030405060708090

100

Exon 11 Exon 9 No Mutation

87%

48%

0%

Surv

ival

at 5

yea

rs

Impact of Initial Dose of Imatinib on Time To Progression

Debiec-Rychter, et al. European Journal of Cancer. 2006;42:1093-1103. Am J Clin Pathol 2004;122:11-13

100

90

80

70

60

50

40

30

20

10

00 4 8 12 16 20 24 28 32 36

Progression free survivalPatients harboring KIT exon 9 mutations

(months)

O N Number of patients at risk:26 27 14 10 9 6 4 3 1 021 31 26 21 20 18 14 9 8 6

800 mg

P=0.0013

400 mg

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4

Progression free survivalPatients harboring KIT exon 11 mutations

(years)

O N Number of patients at risk:67 118 94 53 1168 130 113 67 22

Treatment800 mg400 mg

P = 0.25

800 mg

400 mg

Imatinib Duration in Advanced DiseaseNon-progression after 3 years of Imatinib

Le Cesne The Lancet Oncology 11:942 – 949 2010

Management of Imatinib-Resistant GIST: Sunitinib

• Approved for treatment of GIST resistant to or intolerant of imatinib

• Inhibits multiple receptor tyrosine kinases• Antitumor and anti-angiogenic activities in preclinical

studies

Phase III, Trial of SunitinibImatinib Failures

Demetri GD, et al. Lancet. 2006;368:1329-1338.

100

90

80

70

60

50

40

30

20

10

00 6 12 18 24 30 36 42 48 54

Time (weeks)

Tim

e-to

-tum

our-

prog

ress

ion

prob

abili

ty (%

)

P<0.0001

Sunitinib (n=207)

Placebo (n=105)

Rel

apse

free

sur

viva

l (%

)

Placebo

Regorafenib

Demetri, Lancet 381:295 2013

Regorafenib after Failure of Imatinib and Sunitinib

Imatinib Mesylate

• Metastatic or Unresectable

• Adjuvant• Neoadjuvant

ResectableGIST >3cm

RANDOMIZE

Palcebo

ACOSOG Z9001: Adjuvant Imatinib in Resected Localized Primary GISTACOSOG Z9001: Adjuvant Imatinib in Resected Localized Primary GIST

Imatinib 400mg/d

DeMatteo R, et al. DeMatteo R, et al. Lancet. 2009; 373:1097-1104.

Crossoverat

Recurrence

ACOSOG Z9001: Adjuvant Imatinib in Resected Localized ACOSOG Z9001: Adjuvant Imatinib in Resected Localized Primary GISTPrimary GIST

DeMatteo R, et al. DeMatteo R, et al. Lancet. 2009; 373:1097-1104.

ACOSOG Z9001: Adjuvant Imatinib in Resected Localized ACOSOG Z9001: Adjuvant Imatinib in Resected Localized Primary GISTPrimary GIST

DeMatteo R, et al. DeMatteo R, et al. Lancet. 2009; 373:1097-1104.

Adjuvant Imatinib 12 vs. 36 Months : Final Results of a Randomized Trial (SSGXVIII/AIO)

• 400 patients randomized 1-yr vs. 3-yr (400 mg/day)• 5-yr RFS: 65.6% v. 47.9% (HR 0.46; p<0.001)

Joensuu et al. JAMA 307:1265 2012 Joensuu et al. JAMA 307:1265 2012

Relapse

Adjuvant Imatinib 12 vs. 36 Months : Final Results of a Randomized Trial (SSGXVIII/AIO)

• 400 patients randomized 1-yr vs. 3-yr (400 mg/day)• 5-yr OS: 92.0% v. 81.7% (HR 0.45; p=0.19)

Joensuu et al. JAMA 307:1265 2012 Joensuu et al. JAMA 307:1265 2012

Survival

• Adjuvant therapy for >3 years should be considered in patients with intermediate to high risk GIST

• The optimal duration has not yet been determined

• Adjuvant Imatinib should be continued if any persistent gross disease is seen after resection

Adjuvant Imatinib

Imatinib Mesylate

• Metastatic or Unresectable• Adjuvant• Neoadjuvant

Neoadjuvant Imatinib for GIST(RTOG 0132/ACRIN 6665)

• Phase II trial of pre-operative imatinib for advanced GIST

– Primary Kit+ GIST > 5cm; median 9 cm.– Metastatic/recurrent Kit+ GIST > 2cm

• Treatment:– 600 mg imatinib/day for 8-12 weeks prior to surgery– Resume imatinib post-op for 2 years adjuvantly

Eisenberg BL et al. J Surg Oncol 2009; 99:42-47.Eisenberg BL et al. J Surg Oncol 2009; 99:42-47.

Neoadjuvant Imatinib for GIST(RTOG 0132/ACRIN 6665)

• Results: 63 patients enrolled; 52 analyzable– Locally advanced (PR 7%; SD 83%; unknown 10%)

• Surgery: R0 (77%); R1 (15%); R2 (8%)

– Recurrent/Metastatic (PR 4.5%; SD 91%; PD 4.5%)• Surgery: R0 (58%); R1 (5%); R2 (32%); unspecified (5%)

– 2 yr PFS: Loc Advanced (82.7%), Rec/Met (77.3%)– 2 yr OS: Loc Advanced (93.3%), Rec/Met (90.9%)

Eisenberg BL et al. J Surg Oncol 2009; 99:42-47.Eisenberg BL et al. J Surg Oncol 2009; 99:42-47.

•Unresectable or metastatic GIST

•Marginally resectable GIST

• Surgical morbidity could be improved by preoperative reduction of tumor size

• Recommended starting dose is 400 mg/day•dose of 800 mg/day for patients with KIT exon 9 mutations

• Dosing can be stopped right before surgery and restarted as soon as the patient is able to tolerate oral medications

Neoadjuvant Imatinib

• Anemia and Neutropenia

• Nausea and vomiting

• Edema (swelling of the face, feet, hands)

• Muscle cramps and bone pain

• Diarrhea

• Hemorrhage

• Skin rash

• Fever

Imatinib – Side Effects

•46 year-old female presented with a 20 pound weight loss melena and dyspnea.

•Abdominal exam revealed an ill defined left upper quadrant mass.

•Hgb 4.9

Case Presentation

•The patient was transfused up to a Hgb of 11

•Abdominal CT scan was performed

mass 1

mass 3

mass 2

H&E c-Kit

CT guided core biopsy of the mid-abdominal mass revealed a spindle cell neoplasm which was positive for c-Kit by immunohistochemistry

Day 0 Day 60Imatinib

Day 5Imatinib

10 weeks

•At the time of operation the patient was found to have a bilobed mass involving the third portion of the duodenum and an additional lesion involving segments 2/3 of the liver.

•She underwent resection of the third portion of the duodenum along with the proximal jejunum. A left lateral segmentectomy of the liver was performed.

Pathology revealed an 8 cm GIST in the liver and two separate GIST tumors adjacent to the duodenum 7.5 and 10 cm in size. All lesions were resected with negative margins

She is currently 4 years postop and has no evidence of disease. She remains on 400 mg of imatinib daily.

Day 1 Day 4 Day 45

Patient Case Example: How Would You TreatThis Patient?

GIST Near GEJ

GIST Near GEJ

Conclusions

• Surgery is first-line treatment for patients with resectable GISTs

– Up to 50% patients have recurrence after complete resection

• Tyrosine kinase inhibitor imatinib now standard treatment for unresectable or metastatic or advanced GIST

• Adjuvant Imatinib now standard treatment for high risk GIST

• Neoadjuvant Imatinib for locally advanced GIST