Joint Hospital Surgical Grand Round (25 Jan 2014)Lok Hon Ting (Prince of Wales Hospital)

Treatment for localized disease

Asymptomatic, < 2cm lesion Endoscopic USG

1. interval endoscopic assessment, currently no evidence-based surveillance policy available

2. 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

Principle of SurgeryWide local resection (R0 resection)

Extended lymphadenectomy not requiredPrevalence of lymph node metastasis ~1%

Avoid tumor rupture Tumor rupture decreased peritoneal recurrence-free interval from 31 months to

11 monthsCancer 1992 Mar 15;69(6): 1334 – 41

Nearly all patients develop abdominal metastasis after rupture of GISTBr J Surg 2010 Dec;97(12):1854–9.

Laparoscopic approach feasible

Challenges in the treatment of GISTRecurrenceMetastatic diseaseLocally advanced disease

Imatinib mesylate

Tyrosine kinase inhibitorBlocks 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.

Imatinib as Adjuvant TherapyACOGSOG 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

Imatinib as Adjuvant TherapyDuration of adjuvant beyond 3 years?

EORTC 62024 trial PERSIST-5 trialOn-going trials with interim report suggesting benefits with an

extended duration of adjuvant imatinib

Giant Gastric GIST in 2001M/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

Giant Gastric GIST in 2001Dramatic 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

Giant Gastric GIST in 2010F/37

12 x 9.5 x 13cm Gastric GIST with splenic artery encasement

Imatinib 400mg daily for 7 months

Giant Gastric GIST in 2010Significant 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

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

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%

Pre-op Target therapy + Surgery for metastatic GISTWhy surgery in metastatic GIST

1. Symptomatic tumor (bleeding/obstruction) as palliation2. Single progressive disease3. Decreasing tumor load decrease risk of secondary resistance

to target therapy

Pre-op Target therapy + Surgery for metastatic GIST

ConclusionAdvances 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

What is GISTSoft 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%)

DiagnosisEndoscopy: 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

Benign versus malignantRisk 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)