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Published on: February 19, 2022
Surgical Management of Metastatic Gastrointestinal Stromal Tumors
Jennifer A Yonkus1, Roberto Alva-Ruiz1, Travis E Grotz2
1Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, 200 First Street S.W, Rochester, MN, 55905, USA.
Opinion Statement:
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.
Insights
Metastatic gastrointestinal stromal tumors (GISTs) are treated with tyrosine kinase inhibitors (TKIs), but resistance develops. Surgery may be considered alongside TKIs for select GIST patients, but debulking offers no survival benefit.
Area of Science:
- Oncology
- Surgical Oncology
- Pharmacology
Background:
- Metastatic gastrointestinal stromal tumors (GISTs) are primarily treated with tyrosine kinase inhibitors (TKIs) like imatinib, sunitinib, regorafenib, ripretinib, and avapritinib.
- Acquired resistance to TKIs, often due to c-kit mutations, limits long-term efficacy, necessitating alternative or combined treatment strategies.
- While TKIs have improved outcomes, they do not offer a cure for metastatic GISTs, prompting investigation into cytoreductive surgery.
Purpose of the Study:
- To evaluate the role and outcomes of cytoreductive surgery in combination with tyrosine kinase inhibitor (TKI) therapy for metastatic gastrointestinal stromal tumors (GISTs).
- To identify predictors of success for surgical intervention in metastatic GIST patients undergoing TKI treatment.
- To provide guidance on the appropriate selection and management of metastatic GIST patients considered for metastasectomy.
Main Methods:
- Review of retrospective, non-randomized studies assessing the feasibility and safety of combined TKI therapy and surgical resection in metastatic GIST.
- Analysis of factors influencing outcomes, including TKI response, completeness of resection, disease extent, and surgical complexity.
- Examination of specific GIST subtypes, such as SDH-deficient GISTs, and the role of palliative surgery for complications.
Main Results:
- Retrospective studies indicate that continuous TKI therapy combined with surgical resection is feasible and safe for select metastatic GIST patients.
- Key predictors of successful outcomes include response to TKI therapy, achieving a complete resection, extent of disease, and surgical complexity.
- Debulking or R2 resections do not offer survival benefits but may be necessary for symptom palliation (hemorrhage, obstruction, pain).
- SDH-deficient GISTs may represent a subgroup benefiting from surgical debulking due to their indolent nature.
Conclusions:
- Cytoreductive surgery can be a valuable adjunct to TKI therapy for carefully selected metastatic GIST patients, with decisions made in a multidisciplinary setting.
- Individualized treatment plans considering patient factors, disease characteristics, and treatment response are crucial for optimizing outcomes.
- Resuming TKI therapy promptly after surgery and vigilant monitoring for progression are essential components of post-operative management.
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