Surgical Management of Metastatic Gastrointestinal Stromal Tumors

Treatment with the tyrosine kinase inhibitor (TKI), imatinib is the standard first-line treatment for metastatic gastrointestinal stromal tumors (GISTs). Unfortunately, acquired c-kit mutations cause secondary resistance to imatinib in a median of 18–24 months. Sunitinib and regorafenib are multi-kinase inhibitors that can be used as second-line or third-line therapy in imatinib-resistant or -intolerant GISTs, respectively. Ripretinib (a switch-control tyrosine kinase inhibitor) has recently been approved for fourth-line treatment in metastatic GIST. The TKI avapritinib has been approved for metastatic GIST harboring the imatinib-resistant PDGFRA exon 18 mutation. Although TKI therapies have revolutionized the treatment of metastatic GISTs, they cannot cure metastatic GISTs. Therefore, cytoreductive surgery is of considerable interest and has been accordingly investigated. Retrospective non-randomized studies demonstrated the feasibility and safety of continuous TKI therapy and surgical resection. Most studies demonstrate response to TKI therapy, completeness of resection, extent of disease, and surgical complexity as predictors of outcomes. Most TKIs can be stopped shortly before surgery and restarted shortly after. There is no known survival benefit from debulking operations or R2 resections and this should not be considered. However, debulking/palliative surgery may be necessary for patients with complications of hemorrhage, pain, or intestinal obstruction. SDH-deficient GISTs have an indolent natural history despite metastatic disease and may be another uncommon subgroup that would benefit from surgical debulking (R2 resection). At the time of operation, care should be taken to avoid tumor rupture. After surgical resection, patients should resume tyrosine kinase inhibitor (TKI) therapy as soon as possible and be monitored for disease progression. In all patients with metastatic GIST, the decision to pursue metastasectomy for GIST should be made in a multidisciplinary setting and be individualized according to patient age, comorbidities, functional status, symptoms, mutation status, extent of disease, completeness of resection, TKI response, and goals of the patient.