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 HospitalDana-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 GISTVerweij 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 CharacteristicsNo. 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 RegimenNo. Patients (%)
N=69
Imatinib only 45 (65)
Imatinib, then sunitinib 21 (30.5)
Imatinib, then doxorubicin 1 (1.5)
Observation 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 ResectionSurgical 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 RegimenNo. 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 diseaseVisible tumor nodule(s) < 1 cm
• Bulky residual diseaseVisible tumor nodule(s) ≥ 1 cm
Surgical Outcome According to Disease Presentation
NEDMinimal 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
TOTAL 27 30 12 69
• Disease presentation prior to surgery strongly correlated with surgical result (p<0.0001)
Progression-Free Survival
12-mo PFS ± SE (%)
Median TTP (mo)
Stable disease80% ± 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 disease95% ± 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 100%
24-mo PFS 88% ± 8%
36-mo PFS 59% ± 15%
• 2/21 (9.5%) died
Conclusions
• Patients with stable disease on KIT-directed 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
Patients with stable metastatic
gastrointestinal stromal tumor
Consent
Registration and randomization
Arm 1: KIT-directed therapy
plus surgery
Arm 2: KIT-directed therapy
Follow
Dana-Farber / Brigham and Women’s Cancer Center:Sarcoma Center
• Medical OncologyKaren Albritton, MDGeorge Demetri, MDSuzanne George, MDJeffrey Morgan, MDRhaea Photopoulos, NPKathleen Polson, NP
• Surgical Oncology Monica Bertagnolli, MDChandrajit Raut, MD
• Radiation OncologyElizabeth Baldini, MDPhilip Devlin, MDKaren Marcus, MD
• Orthopedic OncologyJohn Ready, MD
• PathologyChristopher Fletcher, MDJonathan Fletcher, MD
Surgical ComplicationsNo. 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 RegimenNo. 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)