Gastrointestinal stromal tumor medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

Overview

The predominant therapy for gastrointestinal stromal tumor(GIST) is surgical resection. Adjunctive chemotherapy/tyrosine Kinase Inhibitor therapy may be required.

Medical Therapy

• The treatment options for GIST include surgical therapy, chemotherapy and tyrosine kinase inhibitor therapy.
• Laparoscopic surgical resection is the first-line treatment for primary and localized GIST. However, with advanced disease where surgery is not an option (unresectable lesions), patients are treated with tyrosine kinase inhibitor therapy.
• Around 95 % patients with GIST stain positive for CD117, around 5-10% have PDGFRA mutation and therefore treated with agents acting against CD117 and PDGFRA.
• Medical therapy is also given as part of pre and post-operative care to reduce the risk of morbidity associated with surgical resection of GIST.
  • Peri-operative fluid resuscitation and transfusion preferably with ringer lactate and urinary Foley's catheter to monitor fluid intake/output.
  • Diet and nutrition: Specific peri-operative diet and nutrition (multivitamin and mineral supplements) may given either through a Ryle's tube or a peripheral/central line.
  • Antibiotics cover: Patients with signs and symptoms of bowel perforation or infarction should be treated with intravenous antibiotic prophylaxis to prevent surgical wound infection and sepsis.
  • Pain and deep venous thrombosis prophylaxis: Appropriate pain control (NSAID or morphine) and prophylaxis for DVT (heparin) may be given as a precautionary therapy in patients complaining of pain or breathlessness.

Chemotherapy

• The advent of molecular genetics has drastically changed the management and outlook of patients with GIST.
• The use of tyrosine kinase inhibitors are the drug of choice for medical management of patients with GIST.
  • Prior to use of tyrosine kinase inhibitors, conventional chemotherapy were not effective in treating patients with GIST.
  • Cells with MRP1 (multidrug resistance protein-1) and MDR-1 (multidrug resistance-1) gene produce P-glycoprotein that led to increased expression of cellular efflux pumps and prevented conventional chemotherapy agents to attain appropriate therapeutic levels.

Tyrosine Kinase Inhibitor Therapy

• Imatinib is a selective tyrosine kinase inhibitor(TKI) effective against KIT, PDGFRA, and chronic myelogenous leukemia specific BCR-ABL protein.
• The tyrosine kinase inhibitor (TKI) imatinib mesylate is used as the first-line treatment for unresectable lesions (such as large primary GIST, metastatic or recurrent GIST).
• Surgery is associated with greater morbidity and mortality in patients with unresectable lesions.
• The benefit of TKI is largely evident from the fact that median survival rates have gone from less than 2 years to more than 5 years with the use of imatinib therapy.
• Recent studies also recommend the use of imatinib to decrease the recurrence rate in patients undergoing resection for primary GIST.
• Imatinib is also used to shrink tumor prior to surgery.
  • 1.1 Tyrosine kinase inhibitor (TKI)
  • 1.1.1 Unresectable lesions such as large primary GIST, metastatic or recurrent GIST.
    • Preferred regimen (1): Imatinib 400 mg to 800 mg PO q24h

    Note (1):For unresectable lesions the treatment is usually life long.

    Note (2):Use of 800 mg daily dose has been observed with significant improvement in patients with KIT exon 9 mutation.

    Note (3):Patients resistant to 400 mg imatinib should have their dose increased to 800 mg PO q24h.

    • Alternative regimen (1): Sunitinib 50 mg PO q24h

    Note (1):Sunitinib is given in 6 weeks cycle (with intake for 4 weeks and abstinence for 2 weeks).

    Note (2):Sunitinib has both antiangiogenic and anti-tumor effects.

  • 1.1.2 Adjuvant therapy after resection
    • Preferred regimen (1): Imatinib 400 mg PO q24h

    Note (1):For Adjuvant therapy after resection the recommended duration of treatment is 3 years.

Drug side effects

Common side effects of imatinib therapy include:

• Fluid retention
• Diarrhea
• Nausea
• Fatigue
• Muscle cramps
• Abdominal pain
• Rash
• Mild (macrocytic) anemia

Common side effects associated with sunitinib therapy include the following:

• Fatigue
• Nausea and vomiting
• Anemia
• Neutropenia
• Diarrhea
• Abdominal pain
• Mucositis
• Anorexia
• Skin or hair discoloration
• Hypothyroidism (thyroid function monitoring with TSH is generally recommended to detect subclinical hypothyroidism)

References

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