Landmark discovery 1998 Majority of GIST have oncogenic gain-of-function mutations of the KIT receptor tyrosine kinase Hirota S et al. Science 1998;279:577–580. 2001 Imatinib (Gleevec) KIT tyrosine kinase inhibitor (TKI) Joensuu et al. N Engl J Med 2001;1052:1052–1056.
Investigations CXR OGD EUS look for size, irregular borders, echogenic foci, cystic spaces Gastrointest Endosc 2003;57: 469–474. Med Clin North Am 2005;89:139–158, viii. Contrast CT for size and anatomical location determine features of GIST – well vascularized, necrotic centre, heterogeneous appearance PET identify metastatic disease monitor response to medical tx
Risk Stratification of GIST Miettinen et al. Am J Surg Pathol 2005;29:52 – 68. ClassificationSizeMitotic rate (/50 HPF) Prognosis Benign≤ 2cm≤ 5No tumor related mortality Very low malignant potential 2-10cm< 5< 3% recurrence Uncertain or low malignant potential ≤ 2cm> 5No reported recurrence Low to moderate malignant potential > 10cm or 2-5cm ≤ 5 or > 5 12-15% High malignant potential> 5cm> 549-86%
Localized GIST Goal of operation Complete macroscopic resection with an intact pseudocapsule Negative microscopic margin (R0 resection) If tumor rupture associated with high risk of intraabdominal dissemination of tumor cells and recurrence However, no additional benefit of wide resection of gastric GIST to obtain generous negative resection margin
Nature of GIST Metastatic spread peritoneal cavity liver uncommonly regional lymph nodes Large GISTs tend to displace rather than invade adjacent organs Miettinen et al. Am J Surg Pathol 2005;29:52–68.
Time response to Imatinib Verweij et al. Lancet 2004;364(9440):1127 – 1134.
Overall survival using Imatinib Verweij et al. Lancet 2004;364(9440):1127 – 1134.
Response Overall disease control in 70-85% of patient Median progression-free survival is 20- 24 months Overall survival time following imatinib therapy > 36 months
Primary resistance / Secondary resistance Do not achieve stable disease Progress within 6 months of initial objective response Develop one or more sites of disease progression after 6 months of measurable benefit
Imatinib then surgery Recommended timing: 1. when maximal response to TKI observed 2. after at least 6 months of TKI treatment Optimal time interval from start of TKI to surgery is unclear Minimal tumor shrinkage noted after 9 months of imatinib DeMatteo et al. Ann Surg 2007;245(3):347–352.
Resection rates during surgery for advanced GIST after TKI therapy High rate of R0/ R1 after TKI therapy
Surgical candidates ongoing response limited disease progression evolving necrosis or impending emergency Non surgical candidates generalized progression
Surveillance Surveillance CT thorax/ abdomen/ pelvis q3- 6months for 1 st 5 years, then annually PET not routinely needed Chandrajit et al. J Gastrointest Surg (2008) 12:1592–1599