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 has also been 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]}

Progressive disease

See the list below:

Options are limited for patients with progressive disease whose GISTs are resistant to both imatinib, sunitinib, and regorafinib.
Other options include the use of sorafenib, dasatinib, or nilotinib for patients who do not receive clinical benefits from imatinib and sunitinib
Patients continuing to progress should be recommended to enroll in clinical trials
Some studies recommend rechallenging patients with imatinib and sunitinib if all other options have failed

Sepe PS, Brugge WR. A guide for the diagnosis and management of gastrointestinal stromal cell tumors. Nat Rev Gastroenterol Hepatol. 2009 Jun. 6(6):363-71. [Medline].
Palazzo L, Landi B, Cellier C, et al. Endosonographic features predictive of benign and malignant gastrointestinal stromal cell tumours. Gut. 2000 Jan. 46(1):88-92. [Medline]. [Full Text].
Sato S, Tsujinaka T, Yamamoto K, Takahashi T, Kishi K, Imamura H, et al. Primary surgery as a frontline treatment for synchronous metastatic gastrointestinal stromal tumors: an analysis of the Kinki GIST registry. Surg Today. 2015 Nov 26. [Medline].
Andtbacka RH, et al. Surgical resection of gastrointestinal stromal tumors after treatment with imatinib. Ann Surg Oncol. 2007. 14(1):14-24.
Eisenberg BL, Harris J, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol. 2009 Jan 1. 99(1):42-7. [Medline]. [Full Text].
Demetri GD, von Mehren M, Antonescu CR, DeMatteo RP, et al. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw. 2010 Apr. 8 Suppl 2:S1-41; quiz S42-4. [Medline].
Tirumani SH, Shinagare AB, Jagannathan JP, Krajewski KM, Ramaiya NH, Raut CP. Radiologic assessment of earliest, best, and plateau response of gastrointestinal stromal tumors to neoadjuvant imatinib prior to successful surgical resection. Eur J Surg Oncol. 2014. 40:420-8.
Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 2008. 26:5360-5367.
Hirota S, Ohashi A, Nishida T, Isozaki K, Kinoshita K, Shinomura Y, et al. Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology. 2003. 125:660.
Hanrich MC et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003. 21:4342-4349.
Mussi C et al. Therapeutic consequences from molecular biology gor gastrointestinal stromal tumor patients affected by neurofibromatosis type 1. Clin Cancer Res. 2008. 14:4550-4555.
Huang HY, Li CF, Huang WW, et al. A modification of NIH consensus criteria to better distinguish the highly lethal subset of primary localized gastrointestinal stromal tumors: a subdivision of the original high-risk group on the basis of outcome. Surgery. 2007 Jun. 141(6):748-56. [Medline].
Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Mar 28. 373(9669):1097-104. [Medline].
Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012 Mar 28. 307(12):1265-72. [Medline]. [Full Text].
Blanke CD et al. Duration of Adjuvant Therapy for Patients With Gastrointestinal Stromal Tumors: Where Is Goldilocks When We Need Her?. JAMA Oncology. 2016. 2:721-722.
Chandrajit P. et al. Extended treatment with adjuvant imatinib (IM) for patients (pts) with high-risk primary gastrointestinal stromal tumor (GIST): The PERSIST-5 study. Journal of Clinical Oncology. May 2017. 35:11009.
Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004 Sep 25-Oct 1. 364(9440):1127-34. [Medline].
Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008 Feb 1. 26(4):620-5. [Medline].
Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008 Feb 1. 26(4):626-32. [Medline].
Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002 Aug 15. 347(7):472-80. [Medline].
Trent JC at al. A phase II study of dasatinib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST). Journal of Clinical Oncology. 2011. 29:15suppl:10006.
Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006 Oct 14. 368(9544):1329-38. [Medline].
Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26. 381(9863):295-302. [Medline].
Hsu CC, Wu CE, Chen JS, Tseng JH, Chiang KC, Liu YY, et al. Imatinib escalation or sunitinib treatment after first-line imatinib in metastatic gastrointestinal stromal tumor patients. Anticancer Res. 2014 Sep. 34 (9):5029-36. [Medline].
Li J, Gao J, Hong J, Shen L. Efficacy and safety of sunitinib in Chinese patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors. Future Oncol. 2012 May. 8 (5):617-24. [Medline].
Heinrich M, von Mehren M, Jones RL, Bauer S, Yoon-Koo K, Schöfski P, et al. Avapritinib is highly active and well-tolerated in patients with advanced GIST driven by a diverse variety of oncogenic mutations in KIT and PDGFRA. Presented at Connective Tissue Oncology Society 2018 Annual Meeting. Rome, IT. 2018 Nov 15. [Full Text].
Bauer S, George S, Yoon-Koo K, Tap WD, Zhou T, Picazio N, et al. An open-label, randomized, phase 3 study of avapritinib vs regorafenib in patients with locally advanced metastatic or unresectable gastrointestinal stromal tumors. Presented at the Annual congress of the European Society for Medical Oncology (ESMO). Munich, Germany. 2018 Oct 19-23. [Full Text].