1. Metastatic/Recurrent Gastrointestinal Stromal Tumors (M/R-GIST): Does surgical resection improve survival?

2. Rahul Gadde MD1, Fady Elabbasy MD1, Mena Hanna MD1, Johnathan Trent MD PhD2,3, Nipun Merchant MD FACS1,3, Alan Livingstone MD FACS1,3, Danny Yakoub MD PhD1,3 1Division of Surgical Oncology at Department of Surgery 2Division of Hematology/Oncology at Department of Medicine 3Sylvester Comprehensive Cancer Center University of Miami – Miller School of Medicine Miami, Florida, USA

3. Historical Perspective
1983 – Description of GIST as a separate entity. (Mazur MT, Am J Surg Pathol 1983)
1998 – Accurate molecular identification by discovering that 80% of GISTs contain a gain-of- function mutation in the proto-oncogene c-kit (CD 117). (Hirota S, Science 1998)
2002 – Imatinib Mesylate (GLEEVEC®) approved for advanced and metastatic GIST (previously used for CML)

4. INCIDENCE of GIST tumors
Most common mesenchymal tumor/sarcoma of the GI tract. Cell of origin is Interstitial cells of Cajal.
Estimated annual incidence in US about 3.2 – 7/million.
Many previously misdiagnosed as leiomyosarcoma of the stomach
NIH and SEER age-adjusted incidence shown to increase from per 100,000 in to in 2002

5. GIST : Recurrence After Complete Resection
Recurs in >40% of patients – most will die from disease.
Predominant site is intra-abdominal
— Liver: 2/3
— Local
— Peritoneal

6. Therapy: Historical Perspective
Before 2000, surgery only effective therapy for 10 or 20 disease.
Even today, no cure without surgery
Radiation, chemotherapy, IORT, intraop hyperthermic chemotherapy ineffective

7. Imatinib: Patient Selection ACOSOG Z9001: Phase II trial
All R0, >3cm, c-kit positive
Adjuvant IM for 1-3 years
Median follow-up 19.7 months
Recurrence free survival (RFS) – 98 vs 83%
RFS regardless of size (especially high risk)
DeMatteo, Lancet 2009

8. Metastatic/Recurrent GIST
Current standard-of-care IM
Failure or progression on initial IM therapy:
Treat with increased IM dosage or switch to second and third generation TKIs i.e. sunitinib, Regorafinib
NCCN task force - continued IM therapy to limit growth of sensitive clones

9. Principles Of Surgery For Metastatic Primary In Era Of Imatinib
Initial treatment with imatinib
Resect only with:
a. relapse after initial response
b. if global progression, surgery unhelpful c. resect single imatinib-resistant clone

10. Principles Of Surgery For Recurrent Disease In Era Of Imatinib
Resect isolated liver met with long disease free interval
treat local recurrences initially with imatinib then surgery for resectable active clones
Questionable role of debulking

11. AIM
We aimed to explore whether surgery combined with preoperative TKI in patients with metastatic/recurrent GIST improves PFS and OS
This was compared with standard-of-care IM therapy alone
Surgical resection group was further categorized to either TKI responsive or progressive.

12. Search Strategy & Study Selection
DATABASES SEARCHED
PubMed
MEDLINE
EMBASE
SCOPUS
Cochrane Central Trials Registry

13. Progression Free Survival (PFS)
Meta-analysis showed increased PFS at 1 and 3-years
For TKI followed by surgery group (RR=0.58, 95% CI:0.36 – 0.94; RR=0.55, 95% CI:0.35 – 0.88, p = 0.02)
For TKI responsive group (RR=0.25, 95% CI:0.16 – 0.38; RR=0.60, 95% CI:0.48 – 0.74; p<0.001)

14. 1-YR PFS: Outcomes following TKI therapy with or without Curative Intent Surgery
TKI+ Surgery vs. TKI alone
TKI + Surgery: responsive vs. progressive disease

15. 3-YR PFS: Outcomes following TKI therapy with or without Curative Intent Surgery
TKI+ Surgery vs. TKI alone
TKI + Surgery: responsive vs. progressive disease

16. Meta-analysis showed increased OS at 1 and 3-years
Overall Survival (OS)
Meta-analysis showed increased OS at 1 and 3-years
For TKI followed by surgery group (RR=0.27, 95% CI:0.10 – 0.74; RR=0.55, 95% CI:0.21 – 0.54; p<0.01)
For TKI responsive group (RR=0.14, 95% CI:0.08 – 0.27; RR=0.24, 95% CI: ; p <0.001)

17. 1-YR OS: Outcomes following TKI therapy with or without Curative Intent Surgery
TKI+ Surgery vs. TKI alone
TKI + Surgery: responsive vs. progressive disease

18. 3-YR OS: Outcomes following TKI therapy with or without Curative Intent Surgery
TKI+ Surgery vs. TKI alone
TKI + Surgery: responsive vs. progressive disease

19. LIMITATIONS Most included studies were retrospective
All included studies did not report on genetic and immunochemical testing outcomes of the tumor.
Survival difference amongst large volume, educational centers vs. community based health care centers need to be studied to examine its impact on the observed the difference.

20. CONCLUSION
Surgical resection improves PFS and OS at 1 and 3-years in metastatic/recurrent GIST, especially in TKI responsive patients.
Randomized controlled trials are needed to examine the optimum timing and long term outcomes of surgery in these patients.

21. No Conflict of Interest – Approved by all included authors
2015 Faculty Disclosure Slide
No Conflict of Interest – Approved by all included authors