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

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

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)

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 0.028 per 100,000 in 1992 to 0.688 in 2002

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

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

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

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

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

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

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.

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

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)

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

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

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:0.13 - 0.42; p <0.001)

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

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

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.

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.

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