Gastrointestinal Stromal Tumor Management

Pharmacological therapy

Preoperative or Neoadjuvant Therapy  

Preoperative or neoadjuvant therapy should be considered with locally advanced gastrointestinal stromal tumors with genotype sensitive disease in certain anatomical locations (eg esophageal, esophagogastric junction, duodenum, rectum) if a multivisceral resection is required to resect all gross tumor or in patients with significant comorbidities and are not fit for surgery.  

Preoperative Imatinib may be beneficial as primary treatment for patients with gastrointestinal tumors which are resectable with negative margins and with significant morbidity. Baseline imaging is recommended before starting preoperative Imatinib. Neoadjuvant therapy is also considered only if surgical morbidity can be reduced by downsizing the tumor preoperatively.  

The following neoadjuvant therapies are preferred for resectable disease with significant morbidity:

• Imatinib for KIT or PDGFRA mutations excluding PDGFRA mutations which are insensitive to Imatinib and PDGFRA D842V
• Avapritinib for gastrointestinal stromal tumor with PDGFRA exon 18 mutations which are insensitive to Imatinib including PDGFRA D842V

The following neoadjuvant therapies are useful in certain conditions:

• NRTK-directed therapies (eg Entrctinib, Larotrectinib) for tumors with NTRK fusion-positive gastrointestinal stromal tumor
• Sunitinib for SDH-deficient tumors
• Dabrafenib plus Trametinib for BRAF V600E-mutated gastrointestinal stromal tumor

Maximal response to neoadjuvant therapy may take ≥6 months. Imatinib should be continued until maximal response (defined as no further improvement between 2 successive CT scans) in patients with disease responding to therapy.

Chemotherapy  

Prior to Therapy  

Prior to chemotherapy, assess the present disease state for treatment monitoring purposes. Inform and discuss with the patient the duration of treatment required by the condition including the course of possible disease progression and explain that the tumor cannot be cured. Determine the cardiac status and assure that there is no myocardial infarction within the last 2 months. Advise that physical activity should not be severely limited. Laboratory tests (ie liver function tests [LFTs], complete blood count [CBC], etc) may be requested.  

Tyrosine Kinase Inhibitors (TKIs)  

TKIs are the standard-of-care therapy for patients with advanced or metastatic gastrointestinal stromal tumor. It is the first-line therapy for unresectable primary gastrointestinal stromal tumor. It can be used as a follow-up therapy for unresectable primary gastrointestinal stromal tumors with response or with stable disease. Switching to alternative TKI is recommended in patients with performance status 0-2 with generalized (widespread, systemic) progression on Imatinib or Avapritinib.  

Imatinib  

Imatinib is a selective inhibitor of KIT protein tyrosine kinase. It is the recommended treatment for a gastrointestinal stromal tumor that is unresectable and/or metastatic. It is also used as an adjuvant therapy for patients with a high-risk of relapse and for ruptured tumors during surgery. It is also the preferred adjuvant therapy for patients with significant risk of recurrence (intermediate or high if the patient has an Imatinib-sensitive mutation) after complete resection of gastrointestinal stromal tumor without neoadjuvant therapy. It must be noted that at least 36 months of postoperative Imatinib should be considered in patients with high-risk gastrointestinal stromal tumor.  

Imatinib is also the preferred adjuvant therapy in patients with complete resection of gastrointestinal stromal tumor with neoadjuvant therapy with Imatinib and significant risk of recurrence (intermediate or high-risk). A longer duration of therapy is beneficial for patients with gastrointestinal stromal tumors with KIT mutations. It increases the survival rate of patients with metastatic and/or unresectable gastrointestinal stromal tumors. When Imatinib is used pre-operatively, a PET scan should be used to assess the response. Imatinib should be stopped if intolerable side effects occur and restart once toxicity resolves. For less severe toxicity, consider decreasing the dose.  

Regorafenib  

Regorafenib is a multikinase inhibitor with activity against KIT, PDGFRA, vascular endothelial growth factor receptor (VEGFR), and other mutations. It is a third-line agent for patients unresponsive to both Imatinib and Sunitinib. It is indicated for patients with previous treatment with ≥3 kinase inhibitors including Imatinib and for patients with SDH-deficient tumors. It is shown to prolong progression-free survival in a prospective placebo-controlled randomized trial.  

Ripretinib  

Ripretinib inhibits both KIT and PDGFRA kinases. It is an alternative therapy for gastrointestinal stromal tumors with PDGFRA exon 18 mutations which are insensitive to Imatinib and previously treated with Avapritinib and Dasatinib.  

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• Entrectinib or Larotrectinib for NRTK gene fusion-positive gastrointestinal stromal tumor
• Imatinib/Binimetinib, Pazopanib, Regorafenib or Sunitinib for SDH-deficient gastrointestinal stromal tumor
• Dabrafenib plus Trametinib for BRAF V600E mutations

The preferred second-line chemotherapeutic agents for unresectable, progressive, or metastatic disease include Sunitinib, and Ripretinib for patients intolerant to second-line Sunitinib. Other recommended second-line chemotherapeutic agent includes Dasatanib for patients with PDGFRA D842V mutation or other PDGFRA exon 18 mutations which are Imatinib-insensitive or Avapritinib-resistant. The preferred third-line chemotherapeutic agent is Regorafenib for patients who progressed on Imatinib and Sunitinib. The fourth-line chemotherapeutic agent is Ripretinib for patients with advanced gastrointestinal stromal tumor and previously treated with ≥3 kinase inhibitors including Imatinib.

Other chemotherapeutic agents used after progression on approved therapies:

• Avapritinib
• Cabozantinib
• Everolimus plus TKI (eg Imatinib, Regorafenib, Sunitinib)
• Nilotinib
• Pazopanib
• Ponatinib
  • With activity against advanced gastrointestinal stromal tumor especially in patients with KIT exon 11 mutant disease
• Ripretinib dose escalation to twice a day
• Sorafenib

Other chemotherapeutic agents used in certain conditions after progression on approved therapies:

• Ripretinib 150 mg daily for gastrointestinal stromal tumor which progresses after Avapritinib and Dasatinib therapy
• Ripretinib dose escalation to 150 mg twice a day for gastrointestinal stromal tumor which progresses after Avapritinib and Dasatinib therapy

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Nonpharmacological

Observation

Observation may be considered for gastrointestinal stromal tumors with SDH deficiency or NF1 mutations without KIT/PDGFRA mutations as most of these tumors have an indolent behavior. It is recommended in the following patients:

• With completely resected tumor without neoadjuvant therapy and with low-risk disease or non-Imatinib sensitive tumors
• With completely resected tumors after neoadjuvant therapy with Avapritinib, Larotrectinib, Entrectinib, Sunitinib, or Dabrafenib plus Trametinib

Surgery

Complete surgical excision is the standard treatment of localized or potentially resectable gastrointestinal stromal tumors. It is the initial management of small gastrointestinal stromal tumors that are <2 cm with high-risk EUS or biopsy features. It is recommended for gastrointestinal stromal tumors which are resectable with minimal morbidity. It is also recommended for tumors ≥2 cm, and with signs of malignancy and increasing size.  

Segmental or wedge resection is often performed to obtain negative margins. Wide local resection with a 1- to 2-cm margin is done for most tumors. A laparoscopic approach may be considered in tumors located in the anterior wall of the stomach, jejunum, and ileum, or the greater curvature. Tumors located in the colon may require hemicolectomy while tumors located in the rectum and anus will require abdominoperineal resection of the anus and rectum.  

Sphincter-sparing surgery and esophagus-sparing surgery should be considered for rectal and gastroesophageal junction gastrointestinal stromal tumor, respectively. Surgery is usually performed after 6-12 months of neoadjuvant therapy. Surgery may be warranted in unresectable or metastatic gastrointestinal stromal tumors if there is limited disease progression unre­sponsive to Imatinib or a locally advanced previously unresectable tumor that had a good response to TKI preoperatively. It is also warranted in the management of symptomatic bleeding, obstruction, or perforation.  

Lymphadenectomy is often not indicated but resection of pathologically enlarged nodules should be considered in patients with SDH deficient gastrointestinal stromal tumors or known translocation-associated gastrointestinal stromal tumors.  

Peritoneal cytoreduction and/or liver metastasectomy may be indicated in the following patients with metastatic gastrointestinal stromal tumor:

• Stage IV disease after a favorable response to systemic therapy when performed by an experienced surgeon
• Unifocal disease progression which is refractory to TKI therapy when other disease sites have a favorable response to therapy
• Low-volume multifocal progressive disease which is safely resectable
• Management of symptomatic bleeding, obstruction, or perforation

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Radiation Therapy

Interventional Radiology  

Interventional radiology is an option for patients with limited progression after standard Imatinib dose or Avapritinib resistance.  

Ablation  

Ablation involves the application of thermal or nonthermal therapies to a tumor to achieve cell death. Thermal ablation techniques include cryoablation, radiofrequency ablation (RFA), microwave ablation, laser ablation, and high-intensity focused ultrasound (HIFU). While nonthermal techniques include irreversible electroporation (IRE).  

The choice of modality is based on the tumor size, location, and adjacent critical structures to optimize the treatment effect while limiting potential adverse effects. This can include the target lesion in addition to a margin of radiographically normal tissue to ensure complete local treatment. To protect adjacent critical structures during percutaneous ablation, adjacent passive and active thermoprotective techniques (eg hydrodissection) may be used. Intraoperative ablation may be complementary to surgery to achieve complete response in patients with metastases which are otherwise inoperable.  

Ablation may be considered in patients with disease progression on conventional therapy with TKIs, and patients with unresectable metastases or with medical comorbidities prohibiting surgical resection. Absolute contraindications to image-guided ablation include those with active infection in the planned treatment area, inability to displace or protect adjacent critical structures, and uncorrectable coagulopathy.  

Cryoablation  

In cryoablation, tissue destruction results from the induction of extreme hypothermia.  

Radiofrequency Ablation (RFA)  

In RFA, tissue destruction results from the induction of extreme hyperthermia.  

Irreversible Electroporation (IRE)  

IRE causes permanent cellular membrane injury.  

Catheter-Directed Therapies  

Catheter-directed therapies allow minimally invasive treatment of liver disease in select patients including patients unable to tolerate surgical resection or with lesions not amenable to surgery. It is indicated in patients with disease progression on TKI therapy, those with unresectable liver-dominant metastases or patients with medical comorbidities prohibiting surgical resection. The absolute contraindications include active infection in the planned treatment area, decompensated liver failure, and uncorrectable coagulopathy.  

Transarterial Embolization (TAE)  

TAE involves delivery of embolic agents within the hepatic arteries supplying liver tumors to achieve vessel stasis. It may be considered for patients with hepatic metastases refractory to Imatinib or Imatinib and Sunitinib.  

Transarterial Chemoembolization (TACE)  

TACE consists of conventional TACE and drug-eluting bead TACE (DEB-TACE). Conventional TACE involves targeted infusion of chemotherapeutic agents in addition to embolic agents and Lipiodol into tumoral blood supply. DEB-TACE involves drug delivery through embolic beads loaded with chemotherapeutic agents. TACE is an effective and well-tolerated treatment in patients with gastrointestinal stromal tumors with hepatic metastases unresponsive to TKIs.  

Transarterial Radioembolization (TARE)  

TARE uses beta particle emitting microspheres by yttrium-90 decay to induce tumoricidal effects through local brachytherapy. This can be performed with either glass or resin microspheres. TARE is a safe and effective therapy option for patients with hepatic metastases unresponsive to TKIs. 

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