Management of GIST Dr Kwan Ming Wa Tuen Mun Hospital

Contents Mainly concern about Oncogensis Oncogensis Surgical treatment Surgical treatment Targeted therapy Targeted therapy

Introduction GIST the most common Sarcoma of the GI tract the most common Sarcoma of the GI tract derived from the Interstitial cells of Cajal derived from the Interstitial cells of Cajal

Oncogenesis of GIST Gene expression Signal-Transduction ATP  ADP Signal-Transduction ATP  ADP Plasma Membrane Signal Molecule KIT Receptor Earl W. Sutherland (Nobel Prize – 1971) Mutated KIT receptor become autonomous and cell proliferation become uncontrolled

Understanding of the oncogenesis is the key to the advances of diagnosis and targeted therapy

Differentiation of GIST from smooth muscle tumour KITCD34Desmin GIST+60-70%rare Smooth muscle tumour _10-15%+

Targeted therapy (Glivec) Gene expression ATP  ADP Plasma Membrane Autonomous KIT Receptor Autonomous KIT Receptor Competitive inhibition of Tyrosine Kinase

Clinical features of GIST Incidence Worldwide 10-20/ million Worldwide 10-20/ million Tuen Mun ~13 cases/ year Tuen Mun ~13 cases/ year Median age at 60 Sex ratio 1:1

Location of GIST Siteworldwide Tuen Mun stomach % 55% Small intestine 20-40%29% Colon and rectum 5-15%8% esophagus<5%2% others5-7%7%

Presentation GI Bleeding the most common presenting symptom the most common presenting symptom Mass effect when tumour is large enough when tumour is large enough Small GIST Usually found incidentally Usually found incidentally

Symptoms related to gastric GIST in TuenMun

Preoperative biopsy Not advocated GIST is highly vascular and friable Risk of bleeding Risk of bleeding Risk tumour rupture Risk tumour rupture Risk tumour dissemination and early recurrence Risk tumour dissemination and early recurrence

Imaging for diagnosis and staging CT scan, endoscopy and EUS are commonly used to diagnose GIST A well circumscribed, vascular mass associated with stomach/ intestine A well circumscribed, vascular mass associated with stomach/ intestine Staging primary GIST CT scan and CXR is sufficient CT scan and CXR is sufficient metastasis is usually confined to peritoneum and the liver metastasis is usually confined to peritoneum and the liver For complicated disease, PET-CT Recurrent disease/ extraperitoneal metastasis Recurrent disease/ extraperitoneal metastasis

Surgery The primary treatment for resectable GIST The goal is complete resection of the mass without disruption of the pseudocapsule

GIST generally displace rather than infiltrating the surrounding structure Achieving negative margin is usually possible

Dissection of lymph node does not prolong survival or delay recurrence Connolly EM, Br J Surg 2003 Sammiian L, Am Surg 2004

Type of operation for gastric GIST in Tuen Mun

Outcome of gastric GIST resection in TMH

Outcome after complete resection 5yr survival (overall) : 48-65% Poor outcome is associated with Big tumour size (>5cm) Big tumour size (>5cm) High mitotic figure (>5/50HPF) High mitotic figure (>5/50HPF)

Example of excising a big GIST

1 year later..

Conventional adjuvant therapy Chemotherapy: refractory Radiotherapy: limited use

Targeted therapy Evidence of benefit in Treatment of advanced GIST Treatment of advanced GIST As adjuvant to primary tumour resection As adjuvant to primary tumour resection

Advanced GIST treated with Glivec U.S./ Finland study (n=147) EORTC study (n=36) Partial response 54%69% Stable disease 28%19% progression14%11%

ACOSOG Z9001: A randomized, double blind study of adjuvant Glivec versus placebo following resection of primary GIST 10 years or until death Design: Primary GIST (≥ 3 cm) Placebo x 1 year Glivec 400mg x 1 year Recurrence Glivec 400mg (or 800mg) x 2 years FOLLOWFOLLOW Complete Gross Resection

Data monitoring committee evaluated data on >600 pts with complete resection of primary GIST At 1 year follow-up, 97% of patients on Glivec arm were free of recurrence compared with 83% of patients on placebo arm Approximately 65% less likely to experience recurrence within two years All patients will be unblinded, and patients in the placebo arm will be offered 1 year of Glivec ACOSOG Trial Prematurely Stopped Due to Superior Rates of Recurrence Free Survival (RFS) with Glivec Available at:

Treatment model NormalNormalPre-CancerPre-Cancer Metastatic Cancer CancerCancer prevention Primary +/- Adjuvant Primary +/- Adjuvant systemic therapy systemic therapy 1st Line 2 rd Line Treatment Stage Treatment Stage

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