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. However, with advanced disease where surgery is not an option (unresectable lesions), or to prevent recurrence of disease, patients are treated with tyrosine kinase inhibitor therapy. Imatinib 400 mg to 800 mg PO q24h is the drug of choice for patients with unresectable lesions and also as an adjuvant therapy to prevent recurrence following resection. Patients resistant to imatinib are treated with sunitinib 50 mg PO q24h. Medical therapy such as fluid resuscitation, antibiotics cover, deep venous thrombosis prophylaxis should also be given to decrease perioperative morbidity associated with resection of GIST.
Medical Therapy
- The treatment options for gastrointestinal stromal tumor (GIST) include surgical therapy, chemotherapy and tyrosine kinase inhibitor therapy.
- Laparoscopic or endoscopic 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.
- 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 or normal saline may be given along with 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 (DVT) 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 tyrosine kinase inhibitors are the drug of choice for medical management of patients with GIST.[1]
- Prior to use of tyrosine kinase inhibitors, conventional chemotherapy were not effective in treating patients with GIST.[2]
- 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.[3][4][5]
- In addition, around 95 % patients with GIST stain positive for mutated CD117 (KIT) and 5-10% for mutated PDGFRA. These patients may be treated with agents acting against CD117 and PDGFRA (tyrosine kinase inhibitor therapy).
- 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:[6]
- 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
References
- ↑ Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H (2002). "Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors". N. Engl. J. Med. 347 (7): 472–80. doi:10.1056/NEJMoa020461. PMID 12181401.
- ↑ Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, Patel S, McCarter MD, Polikoff JA, Tan BR, Owzar K (2009). "Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial". Lancet. 373 (9669): 1097–104. doi:10.1016/S0140-6736(09)60500-6. PMC 2915459. PMID 19303137.
- ↑ Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Sarlomo-Rikala M, Nilsson B, Sihto H, Monge OR, Bono P, Kallio R, Vehtari A, Leinonen M, Alvegård T, Reichardt P (2012). "One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial". JAMA. 307 (12): 1265–72. doi:10.1001/jama.2012.347. PMID 22453568.
- ↑ Demetri GD, von Mehren M, Antonescu CR, DeMatteo RP, Ganjoo KN, Maki RG, Pisters PW, Raut CP, Riedel RF, Schuetze S, Sundar HM, Trent JC, Wayne JD (2010). "NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors". J Natl Compr Canc Netw. 8 Suppl 2: S1–41, quiz S42–4. PMC 4103754. PMID 20457867.
- ↑ Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG (2006). "Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial". Lancet. 368 (9544): 1329–38. doi:10.1016/S0140-6736(06)69446-4. PMID 17046465.
- ↑ Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ (2000). "Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor". Blood. 96 (3): 925–32. PMID 10910906.