What are the treatment options for Gastrointestinal Stromal Tumor (GIST)?

GIST Work-up and Treatment

Diagnostic Work-up

All suspected GISTs should be managed by an experienced multidisciplinary team at a specialist center, with the diagnostic approach stratified by tumor size and location. 1

Size-Based Diagnostic Algorithm

Small Gastric/Duodenal Nodules (<2 cm):

• Perform endoscopic ultrasound (EUS) assessment initially 1
• Active surveillance is generally recommended if biopsy is not feasible or yields inadequate material 1
• Surgical/endoscopic resection should be performed if the tumor increases in size or becomes symptomatic 1
• Short-term first assessment at 3 months, then increase follow-up intervals if no growth is evident 1

Rectal Nodules (Any Size):

• All rectal nodules require biopsy or excision after endorectal ultrasound and pelvic MRI, regardless of size 1
• This aggressive approach is mandatory because rectal GISTs have higher progression risk, worse prognosis, and more critical surgical implications compared to gastric GISTs 1
• Dedicated rectal MRI and examination under anesthesia should be considered 1

Tumors ≥2 cm:

• Biopsy or excision is the standard approach due to higher progression risk 1
• For large masses requiring potential multivisceral resection, obtain multiple core needle biopsies via EUS or CT-guided percutaneous approach before surgery 1
• This allows surgical planning, consideration of neoadjuvant treatment, and avoids unnecessary surgery for other diagnoses (lymphomas, mesenteric fibromatosis) 1

Pathological Diagnosis

Immunohistochemistry:

• Diagnosis relies on morphology with CD117 (KIT) and/or DOG1 positivity 1
• Approximately 5% of GISTs are CD117-negative 1
• Mitotic count should be expressed as number of mitoses per 5 mm² total area (not per high-power field to avoid variability) 1

Mutational Analysis:

• Mutational analysis for KIT and PDGFRA is mandatory for all GISTs to confirm diagnosis, guide treatment sensitivity, and inform prognosis 1
• This is particularly critical before initiating neoadjuvant imatinib therapy 1
• Analysis should be centralized in laboratories with expertise and quality assurance programs 1

Staging

Standard staging includes:

• Contrast-enhanced abdominal and pelvic CT scan (preferred for staging and follow-up) 1
• Pelvic MRI for rectal GISTs provides superior preoperative staging 1
• Chest CT or X-rays and routine laboratory testing 1
• PET scan is useful for early detection of tumor response to imatinib when this information is clinically critical 1

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Treatment Approach

Localized Disease

Complete surgical excision with negative margins (R0 resection) is the cornerstone of treatment for localized GIST. 1

Surgical Principles:

• Perform wedge resection when anatomically feasible to preserve function 2
• Avoid tumor rupture and pseudocapsule injury at all costs—rupture dramatically increases peritoneal recurrence risk and automatically places patients in high-risk category 2, 3
• No lymph node dissection is required for standard GISTs (lymphatic spread is extremely rare) 1, 2, 4
• Exception: SDH-mutated GISTs may warrant pickup dissection of enlarged nodes 2, 4
• Use plastic bags for specimen removal to prevent tumor seeding 2

Laparoscopic vs. Open Approach:

• Laparoscopic wedge resection is preferred for gastric GISTs ≤5 cm, offering reduced morbidity with equivalent oncological outcomes 2
• GISTs >5 cm or non-gastric locations have higher rupture risk with laparoscopy and are not routinely recommended for laparoscopic approach 2

Neoadjuvant Therapy:

• Pre-operative imatinib should be considered when immediate resection would be highly morbid (e.g., total gastrectomy, abdominoperineal resection, multivisceral resection) 1
• Mutational analysis is mandatory before initiating neoadjuvant imatinib 1
• Maximal tumor response typically occurs after 6-12 months 1
• PET scan can assess response rapidly (within weeks) to avoid delaying surgery in non-responding disease 1

Rectal GIST Specific Considerations:

• Surgical strategy must be tailored to precise anatomic site and relation to sphincter complex 1
• Approaches include pararectal incisions, transanal approaches (including TAMIS), minimally invasive/robotic surgery, or abdominoperineal resection 1
• Organ-preserving approach should be prioritized when possible 1
• For larger tumors, neoadjuvant imatinib facilitates more marginal excision, especially when tumor demonstrates response 1
• Radiotherapy may be considered when surgery is not feasible, after or in addition to systemic therapy 1

Adjuvant Therapy

High-risk patients should receive 3 years of adjuvant imatinib, provided their tumor is not resistant (particularly excluding PDGFRA exon 18 D842V mutation). 1

Risk Stratification Factors:

• Tumor size, mitotic index, tumor location, and tumor rupture 2, 3

Dosing:

• Standard dose: 400 mg daily 1
• For KIT exon 9 mutations: 800 mg daily is the standard treatment due to significant survival advantage (hazard ratio 0.54) 1

Tumor Rupture/Perforation:

• Adjuvant imatinib is mandatory after resection of ruptured GISTs due to very high risk of peritoneal recurrence 1, 3
• Duration should be at least 3 years, with consideration for lifelong treatment 1, 3
• Tumor spillage from perforation should be documented in detail as it affects risk stratification 3

Advanced/Metastatic Disease

First-Line Treatment:

• Imatinib 400 mg daily is the standard treatment for inoperable and metastatic disease 1
• For KIT exon 9 mutations: 800 mg daily is standard due to superior progression-free survival and overall survival 1
• Treatment should be continued indefinitely, as interruption generally leads to rapid tumor progression 1
• This applies even to patients who previously received adjuvant imatinib without relapse during treatment 1

Second-Line Treatment:

• Sunitinib 50 mg orally once daily on a 4-weeks-on/2-weeks-off schedule is indicated after disease progression on or intolerance to imatinib 5

Third-Line Treatment:

• Regorafenib 160 mg orally once daily for 21 days of each 28-day cycle is standard therapy for patients previously treated with imatinib and sunitinib 1, 6
• Take with a low-fat meal (<600 calories, <30% fat) 6
• Monitor hepatic function closely due to risk of severe and sometimes fatal hepatotoxicity 6

Surgery in Metastatic Disease:

• Surgery as a primary approach to metastatic GIST is not recommended 1
• Cytoreductive surgery may be considered in patients who respond to imatinib, particularly if R0/R1 resection is achievable 7
• Optimal timing is between 6 months and 2 years after starting imatinib 7
• Patients with multifocal progression undergoing surgery generally have poor outcomes 7
• Early surgical intervention should be considered for imatinib-responsive disease, as complete resection is rarely achieved once tumor progression occurs 8

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Follow-up Protocol

For Perforated/High-Risk GISTs:

• Contrast-enhanced CT scans every 3-4 months for the first 2-3 years 3
• Every 6 months for years 4-5 3
• Annually thereafter up to 10 years 3
• Focus surveillance on liver and peritoneum (most common recurrence sites) 4

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Critical Pitfalls to Avoid

• Never underestimate the significance of tumor rupture in risk stratification—this mandates aggressive adjuvant therapy 3
• Do not perform lymph node dissection for standard GISTs (only for SDH-mutated subtype with enlarged nodes) 2, 4
• Avoid direct tumor handling with forceps during surgery—always use plastic bags for specimen removal 2
• Do not delay mutational analysis—it is essential for treatment planning and predicting therapy response 1, 3
• Never treat rectal GISTs the same as gastric GISTs—they require more aggressive initial management regardless of size 1