The Gist of GIST
-
Upload
joshua-ellenhorn -
Category
Healthcare
-
view
3.794 -
download
2
Transcript of The Gist of GIST
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