Download GIST

Surgical Management of Advanced
GIST Following KIT-Directed
Therapy
Chandrajit P. Raut, Jayesh Desai, Jeffrey A. Morgan, Suzanne George,
Matthew Posner, David Zahrieh, Christopher D. M. Fletcher,
George D. Demetri, and Monica M. Bertagnolli
Brigham and Women’s Hospital
Dana-Farber Cancer Institute
Harvard Medical School
November 20, 2005
Gastrointestinal Stromal Tumor
(GIST): Therapy in Advanced Disease
• Imatinib therapy results in disease regression
or stabilization in approximately 80% of
patients with advanced GIST
• Sunitinib may achieve significant anti-tumor
responses in imatinib-resistant tumors
• However, response to KIT-directed therapy is
not maintained indefinitely, resulting in
disease progression
GIST: Therapy in Advanced Disease
•
Once drug resistance occurs, disease
progression may be:
1. Limited
•
•
Drug responsiveness or growth stability in most
metastatic tumor deposits
Progressive growth in isolated lesions
2. Generalized
•
•
Progressive growth in most tumor deposits
Traditional role of surgery in advanced
disease: palliation
Survival in Advanced GIST
Verweij et al. (2004), Lancet 364:1127
• 964 pts with advanced GIST
• Randomized to imatinib 400 qd vs. bid
• Median f/u 760 days
Progression-Free Survival
25-mo PFS: 50-56%
Overall Survival
12-mo OS: 85-86%
24-mo OS: 69-74%
Should Advanced GIST Be
Managed More Aggressively?
• Treatment with imatinib has altered the
natural course of the disease
• However, drug resistance may limit long-term
efficacy
• Re-evaluation of the role of surgery in
advanced GIST
Study Objective
• Determine if resection or debulking of stable
or progressive advanced GIST after treatment
with KIT-directed therapy impacted survival?
Patient Cohort
• March, 2002 – November, 2004
• 69 consecutive patients with advanced,
biopsy-proven GIST
• Diagnosis confirmed by review of tumor
pathology
• Multidisciplinary team approach:
• Treatment with KIT-directed therapy
• Surgery
Patient Characteristics
No. Patients (%)
N=69
Age
Median
57.1 yrs
Range
21.3-76.5 yrs
Gender
Male
46 (67)
Female
23 (33)
Extent of disease at presentation
Unresectable primary without metastases
9 (13)
Metastatic disease
60 (87)
Tumor KIT immunoreactivity
Positive
68 (99)
Negative
1 (1)
Preoperative Therapy
Treatment Regimen
Imatinib only
Imatinib, then sunitinib
Imatinib, then doxorubicin
Observation
No. Patients (%)
N=69
45 (65)
21 (30.5)
1 (1.5)
2 (3)
Patient Cohort: Extent of Disease
• Stable disease
• Initially unresectable primary or metastatic disease who
demonstrated maximal response to drug
• No tumor progression prior to surgery for a median of 211
days (range 62-1196 days)
• All sites were resectable
• Limited disease progression
• Metastatic disease with limited progression on drug
• All progressing sites were resectable
• Generalized disease progression
•
•
•
•
Metastatic disease with generalized progression on drug
All progressing sites were not resectable
43% were emergent procedures
Remaining patients had excellent performance status
Indications for Surgery
No. Patients (%)
N=69
Indications for surgery
Stable disease
23 (33)
Limited progression
32 (47)
Generalized progression
14 (20)
Emergency Surgery Indications
10 (14)
Intestinal perforation
4
Gastrointestinal bleeding
4
Intratumoral abscess
1
Intratumoral abscess with fistula
1
Extent of Surgical Resection
Surgical Procedure
No. Patients
Gastrectomy  splenectomy
6
Gastrectomy + other bowel resection
4
Hepatic resection
7
Hepatic resection + other bowel resection
10
LAR / APR / transanal resection rectal tumor
7
Resection of single bowel segment
7
Resection of multiple bowel segments
14
Pancreatic and/or duodenal resection
5
Partial cystectomy + other bowel resection
2
Resection pelvic tumor
1
Resection retroperitoneal tumor
1
Hysterectomy and bilateral salpingo-oophorectomy
1
Resection abdominal wall tumor
4
Additional localized peritoneal stripping / omentectomy – 43/69 (62%)
Postoperative Therapy
Treatment Regimen
No. Patients
N=69
Imatinib alone
33
Sunitinib alone
19
Imatinib, then sunitinib
10
Imatinib, then phase I agent
3
Imatinib, then sunitinib, then phase I agent
2
Sunitinib, then imatinib plus rapamycin
1
No additional therapy
1
Surgical Outcome
• Results of operation were recorded as:
• No evidence of disease (NED)
No grossly visible residual disease
• Minimal residual disease
Visible tumor nodule(s) < 1 cm
• Bulky residual disease
Visible tumor nodule(s) ≥ 1 cm
Surgical Outcome According to
Disease Presentation
• Disease presentation prior to surgery strongly
correlated with surgical result (p<0.0001)
NED
Minimal
Residual
Disease
Bulky
Residual
Disease
TOTAL
Stable disease (%)
18 (78)
4 (17)
1 (4)
23
Limited progression (%)
8 (25)
19 (59)
5 (16)
32
Generalized progression (%)
1 (7)
7 (50)
6 (43)
14
27
30
12
69
TOTAL
Progression-Free Survival
12-mo PFS
± SE (%)
Median
TTP (mo)
Stable
disease
80% ± 9%
NR
Limited
progression
33% ± 9%
7.7
Generalized
progression
0%
2.9
Median follow-up 14.6 mo
Overall Survival
12-mo OS
± SE (%)
Median
Survival
(mo)
Stable
disease
95% ± 5%
NR
Limited
progression
86% ± 6%
29.8
Generalized
progression
0%
5.6
Median follow-up 14.6 mo
Stable Disease
• 21/23 (91%) pts with stable disease
prior to surgery were treated with
imatinib preoperatively
• Outcomes:
• 5/21 (24%) recurred
PFS recalculated from the time imatinib
commenced (median follow-up 25 mo)
12-mo PFS
24-mo PFS
36-mo PFS
• 2/21 (9.5%) died
100%
88% ± 8%
59% ± 15%
Conclusions
• Patients with stable disease on KITdirected therapy have prolonged
PFS/OS after resection
• Patients with limited disease
progression may benefit from debulking
procedures
• Benefits of surgery in patients with
generalized disease progression are
limited
Future Directions
• Prospective clinical trial in patients with stable
advanced GIST randomized to KIT-directed
therapy alone vs. surgery plus KIT-directed
therapy
Arm 1: KITdirected therapy
plus surgery
Patients with stable
metastatic
gastrointestinal
stromal tumor
C
o
n
s
e
n
t
Registration and
randomization
Follow
Arm 2: KITdirected therapy
Dana-Farber / Brigham and Women’s Cancer Center:
Sarcoma Center
• Medical Oncology
Karen Albritton, MD
George Demetri, MD
Suzanne George, MD
Jeffrey Morgan, MD
Rhaea Photopoulos, NP
Kathleen Polson, NP
• Surgical Oncology
Monica Bertagnolli, MD
Chandrajit Raut, MD
• Radiation Oncology
Elizabeth Baldini, MD
Philip Devlin, MD
Karen Marcus, MD
• Orthopedic Oncology
John Ready, MD
• Pathology
Christopher Fletcher, MD
Jonathan Fletcher, MD
Surgical Complications
No. Patients
Post-operative bleeding requiring re-operation
2
Anastomotic leak
3
Enterocutaneous fistula
2
Abscess requiring drainage
4
Ureteral leak
1
Wound infection requiring readmission
1
Urinary tract infection
2
Prolonged ileus
2
Urinary retention
1
Delayed gastric emptying
2
Postoperative myocardial infarction
1
Postoperative atrial fibrillation
1
Pulmonary embolus
1
Transfusion reaction
1
Surgical Complications
• Overall complication rate
33%
• Complication rate, generalized progression pts
50%
• Complication rate, emergency surgery
40%
Postoperative Therapy
Treatment Regimen
No. Patients (%)
N=69
Imatinib alone
33 (48)
Sunitinib alone
19 (28)
Imatinib, then sunitinib
10 (14)
Imatinib, then phase I agent
3 (4)
Imatinib, then sunitinib, then phase I agent
2 (3)
Sunitinib, then imatinib plus rapamycin
1 (1.5)
No additional therapy
1 (1.5)