Treatment Protocols

Treatment protocols for gastrointestinal stromal tumors (GISTs) are provided below, including those for limited-stage disease and persistent or metastatic disease.

Limited-stage disease with possible resection

Surgery is the primary treatment for localized or potentially resectable GISTs. Patients with a small GIST (< 2 cm) may be treated with endoscopic surveillance if high-risk features are absent; high-risk endoscopic ultrasound features include the following^{[1, 2, 3]}:

An irregular border
Cystic space
Ulceration
Echogenic foci
Heterogeneity

Neoadjuvant therapy^{[4, 5]}:

Neoadjuvant imatinib therapy is preferred for marginally resectable tumors or patients with comorbidities for surgery^[6]
Neoadjuvant therapy is aimed at reducing tumor size, which may facilitate complete surgical resection.
Treatment should continue until the time of maximal response, which is typically no more than 10-12 months.^[7]
The usual dose of imatinib is 400 mg PO daily. In patients with a known exon 9 KIT mutation, a dose of 800 mg PO daily can be considered if tolerated.^[8]
Neoadjuvant imatinib will be less effective and is therefore not recommended in cases of a platelet-derived growth factor receptor–alpha (PDGFRA) D842V mutation or a succinate dehydrogenase (SDH)–deficient or neurofibromatosis (NF)-related GIST^{[9, 10, 11]}

Adjuvant therapy for high-risk patients^[12]:

Imatinib is also approved for adjuvant therapy in patients with GISTs
Imatinib 400 mg PO daily for 3 years following complete gross resection of CD117-positive GIST has shown an improvement in overall survival and recurrence-free survival compared with a treatment duration of 1 year^{[13, 14]}
Extending adjuvant imatinib to 5 years has been shown to continue preventing (or delaying) recurrences, but nearly half of those treated discontinued the imatinib early due to toxicity.^{[15, 16]}
Adjuvant imatinib will be less effective and is therefore not recommended in cases of a PDGFRA D842V mutation or an SDH-deficient or NF-related GIST.^{[9, 10, 11]}

Persistent or metastatic disease

The primary treatment for metastatic GISTs is imatinib. Surgery may be indicated in patients who have locally advanced or previously unresectable disease after a positive response to preoperative imatinib, or with limited disease progression on systemic therapy.^[1]

Recommended therapy:

Imatinib 400 mg PO daily^{[17, 18, 19, 20]}: For patients with a known KIT exon 9 mutation, dose can be escalated to 800 mg (400 mg PO BID)^[8]
Progression of disease on imatinib 400 mg PO daily: May escalate dose to 800 mg (400 mg PO BID daily) as tolerated
In patients with a known PDGFRA D842V mutation conferring imatinib resistance, sunitinib is a reasonable option. Some data indicate that dasatinib may have some activity in this population, as well.^[21]
In patients with an SDH-deficient or NF-related GIST, imatinib is not recommended because of resistance.^{[10, 11]} In this situation, sunitinib or regorafenib would be options.^{[22, 23]}
Sunitinib 50 mg PO daily for 4 wk, then 2 wk off (4/2 schedule); efficacy and better tolerance have been reported with off-label continuous dosing at 37.5 mg PO daily^{[24, 25]}
Regorafenib: 160 mg PO daily for the first 21 days of each 28-day cycle; indicated for locally advanced, unresectable GISTs that no longer respond to imatinib or sunitinib^[23]
Avapritinib: 300 mg PO daily continued until disease progression or unacceptable toxicity; indicated for unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutations, including PDGFRA D842V mutations^{[26, 27]}
Ripretinib: 150 mg PO daily continued until disease progression or unacceptable toxicity; indicated for advanced GISTs for patients previously treated with 3 or more kinase inhibitors ^[28]

Progressive disease

Options are limited for patients with progressive disease whose GISTs are resistant to both imatinib, sunitinib, and regorafinib. Possible approaches include the following^[29]

Enrollment in a clinical trial
Rechallenging patients with imatinib and sunitinib if all other options have failed
Use of sorafenib, dasatinib, or nilotinib, for patients who do not receive clinical benefits from imatinib and sunitinib

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