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)