Management of Gastrointestinal Stromal Tumor

1. Management of Gastrointestinal Stromal Tumor Joint Hospital Surgical Grand Round (25 Jan 2014) Lok Hon Ting (Prince of Wales Hospital)

2. Treatment for localized disease • Asymptomatic, < 2cm lesion • Endoscopic USG • interval endoscopic assessment, currently no evidence-based surveillance policy available • Standard treatment is surgical excision • Rectal GIST – surgical excision indicated regardless of tumor size because of higher risk of malignancy and local implications for surgery • Symptomatic or > 2cm lesion • Standard treatment is surgical excision

3. Principle of Surgery • Wide local resection (R0 resection) • Extended lymphadenectomy not required • Prevalence of lymph node metastasis ~1% • Avoid tumor rupture • Tumor rupture decreased peritoneal recurrence-free interval from 31 months to 11 months Cancer 1992 Mar 15;69(6): 1334 – 41 • Nearly all patients develop abdominal metastasis after rupture of GIST Br J Surg 2010 Dec;97(12):1854–9. • Laparoscopic approach feasible

4. Challenges in the treatment of GIST • Recurrence • Metastatic disease • Locally advanced disease

5. Imatinib mesylate • Tyrosine kinase inhibitor • Blocks the kinase activity of KIT, arrest proliferation and causes apoptosis • Adverse events in ~20%, • Life threatening tumor hemorrhage in ~5% Joensuu et al. N Engl J Med. 2001; 344:1052.

6. Imatinib as Adjuvant Therapy • ACOGSOG Z9001 study • 713 patients CD117+ve GIST at least 3cm in size • Imatinib 400mg daily for 1 year versus placebo • Improvement in progression-free survival with a median follow-up of 19.7 months Lancet 2009 March 28; 373(9669): 1097 - 1104 • SSG XVIII Study • 785 patients with high risk resected GIST • 36 months versus 12 months duration of Imatinib • superior recurrence-free survival and overall survival with a median follow-up of 54 months • JAMA 2012;307(12): 1265 - 1272 Recurrence-free survival Overall survival

7. Imatinib as Adjuvant Therapy • Duration of adjuvant beyond 3 years? • EORTC 62024 trial • PERSIST-5 trial On-going trials with interim report suggesting benefits with an extended duration of adjuvant imatinib

8. Giant Gastric GIST in 2001 • M/48 • Laparotomy: attempted dissection resulted in massive bleeding  open and close • Post-op complicated with gastrocutaneous fistula • Started Imatinib 400mg daily •  Significant clinical and radiological response • Re-laparotomy offered but refused • Multiple liver metastasis at 22 months and succumbed at 30 months after treatment

9. Giant Gastric GIST in 2001 • Dramatic clinical and radiological response with Imatinib • As evidenced by multiple RCTs with long term follow-up, 83 – 89% of patients either respond or achieve durable stable disease • Imatinib does FAIL • secondary resistance and disease progression occurs at a median time interval of 2 years • Strategy: • ? No surgery in view of inevitable progression • ? Surgery after initial response before it’s too late

10. Giant Gastric GIST in 2010 • F/37 • 12 x 9.5 x 13cm Gastric GIST with splenic artery encasement • Imatinib 400mg daily for 7 months

11. Giant Gastric GIST in 2010 • Significant radiological response • Surgical resection done in July 2010 • Post-op adjuvant Imatinib for 1 year (stopped due to financial reason) • No relapse in latest follow-up

12. Neoadjuvant Imatinib therapy for locally advanced GIST • Median tumour size was 12.2cm (range 5.2 - 30) • Median duration of Imatinib: 8 months • Median tumor size after Imatinib: 6cm • R0 Resection n=48, R1 resection n = 8

13. Neoadjuvant Imatinib therapy for locally advanced GIST • Retrospective analysis of databases of ten EORTC STBSG centers • 161 patients with locally advanced, non-metastatic GISTs who received neo-adjuvant imatinib therapy • 2 patients had disease progression before operation. R0 resection 83%

14. Pre-op Target therapy + Surgery for metastatic GIST • Why surgery in metastatic GIST • Symptomatic tumor (bleeding/obstruction)  as palliation • Single progressive disease • Decreasing tumor load  decrease risk of secondary resistance to target therapy

15. Pre-op Target therapy + Surgery for metastatic GIST

16. Conclusion • Advances in Target Therapy revolutionized the management of Gastrointestinal Stromal Tumor • Combination of target therapy agent and surgery had encouraging outcome in selected patients • New data from on-going clinical researches, mutation analysis and new biological agents (sunitinib, Regorafinib) will probably bring further breakthrough for the management of GIST

17. What is GIST • Soft tissue neoplasm of mesenchymal origin arising in the gastrointestinal tract • Originated from interstitial cell of Cajal • Symptoms depends on site of GIST • Stomach (50 – 60%) • Small Bowel (30 – 35%) • Colon and Rectum (5%) • Esophagus (<1%)

18. Diagnosis • Endoscopy: submucosal tumor • Endoscopic ultrasonography: hypoechoic mass contiguous with muscularis propria or muscularis mucosae • Computed Tomography • Pathological diagnosis • Morphology: Spindle cell (70%), epithelioid (20%), mixed (10%) • Immunohistochemistry: CD 117 (90% cases), DOG1 • 10 – 30%of GISTs are overtly malignant at presentation

19. Benign versus malignant • Risk stratification methods • National institutes of Health consensus criteria (tumor size, mitotic figure) • Armed Forces Institute of Pathology Criteria (tumor size & site, mitotic figure) • Modified NIH (tumor size & site, mitotic figure, history of rupture)