eMedicine Specialties > Oncology > Carcinomas of the Gastrointestinal Tract

Gastric Gastrointestinal Stromal Tumors: Treatment & Medication

Author: Michael A Choti, MD, MBA, Jacob C Handelsman Professor of Surgery, Professor of Oncology and Engineering, Johns Hopkins University School of Medicine
Coauthor(s): Matthew Hueman, MD, Fellow in Surgical Oncology, The Johns Hopkins Hospital; Instructor, Department of Surgery, The Johns Hopkins School of Medicine
Contributor Information and Disclosures

Updated: Jun 4, 2009

Treatment

Medical Care

Current data suggest a major role for the tyrosine-kinase inhibitor, imatinib mesylate (STI-571, Gleevec), for patients with GISTs.10,22,23 Despite such a major role, no standard regimen for adjuvant therapy presently exists for GISTs. The optimal duration of treatment with imatinib remains unknown and observation after margin-negative resection of primary GIST remains acceptable. While recurrence-free and progression-free survival have clearly been increased with the use of imatinib in both the adjuvant and advanced/metastatic settings, overall survival has not been proven to be improved in either setting.
 
On December 19, 2008, the Food and Drug Administration (FDA) approved imatinib mesylate as adjuvant therapy to prevent recurrence of primary GIST. This FDA approval was based on the phase III double-blind placebo-controlled randomized controlled multicenter trial ACOSOG Z9001, which revealed a 97% versus 83% 1-year recurrence-free survival benefit to imanitib.10,24 This trial enrolled patients with 3 cm or greater KIT -positive GIST who were treated with imatinib or placebo for one year; the trial results did not stratify by mitotic rate or tumor location. 

The current recommendation by the NCCN (www.nccn.org) is to consider prescribing imatinib in the adjuvant setting in any patient with intermediate-risk or high-risk GIST and to treat for at least 12 months (given the design of the Z9001 trial, see above).16 In the metastatic/advanced setting, the NCCN recommends continuous use of imatinib until clear evidence of progression. For progressive disease, the dose of imatinib may be increased for patients with acceptable performance status (ECOG 0-2) or therapy may be switched to sunitinib. Sunitinib is a newer tyrosine-kinase inhibitor that has been shown to provide significant clinical benefit in imatinib-resistant advanced GIST.

  • Initially, numerous trials confirmed the activity of imatinib in metastatic or advanced GIST, demonstrating substantial tumor responses in such patients.
    • As the result of these substantial tumor responses in several trials, the Food and Drug Administration (FDA) approved imatinib mesylate for metastatic GIST on February 1, 2002. This approval occurred under accelerated approval regulations and under the orphan drug program. The orphan drug program provides financial incentives for drugs developed to treat rare diseases (ie, diseases that affect <200,000 patients).
    • Imatinib was used in patients with chronic myeloid leukemia (CML). CML is characterized by a balanced translocation between chromosomes 9 and 22 (the Philadelphia chromosome) and this abnormality results in the production of the BCR-ABL fusion protein. This BCR-ABL protein has uncontrolled tyrosine-kinase activity and imatinib was found to induce a near-complete response in virtually all patients treated in the chronic phase of CML. In 2001, a New England Journal of Medicine case report of a patient with rapidly progressive metastatic GIST who had a dramatic response to imatinib started the targeted therapy revolution of GIST.22
    • The initial approval of imatinib for the treatment of GIST was based upon a study of 147 patients with unresectable or metastatic GIST who received daily oral imatinib. While no patient had complete disappearance of tumor, 56 patients (38%) had reduction in tumor size by 50% or greater (partial response).
    • The subsequent development of imatinib mesylate has revolutionized the treatment of GISTs. After numerous clinical trials, 55-80% of patients with metastatic GIST achieve a partial response or stable disease while receiving imatinib. The adverse reactions of imatinib are manageable and include edema, rash, diarrhea, nausea, abdominal pain, and fatigue.
    • Currently, the standard dose of imatinib in both adjuvant therapy and in therapy of advance disease is 400 mg by mouth daily.
    • Imatinib shows the highest activity in GISTs who contain the mutation in exon 11 of c-KIT and less activity in GISTs who contain the mutation in exon 9 or who are wild-type. Subset analysis  suggests that patients whose GIST contains exon 9 mutations may benefit from a higher dose of imatinib (? 800 mg daily) then the standard dose (400 mg daily), but this remains to be proven.
      • Phase I clinical trials determined that the maximum tolerated dose (MTD) of imatinib is 800 mg/d. Imatinib comes in 100 mg tablets and can thus be given in graduated doses (100, 200, 300, 400, 500, 600, 700, 800 mg) while monitoring treatment responses. Patients who have had their dose reduced due to severe toxicities have been observed to have a response with a dose as low as 100 mg of imatinib. Importantly, clinical trials have determined the efficacy of commonly prescribed doses (400 mg, 600 mg, and 800 mg). In general, doses below 300 mg should be avoided.
      • In the United States, the FDA recommended starting dosage of imatinib (Gleevec), as of December, 2008, is 400 mg/d for patients with unresectable and/or metastatic, malignant GIST and for patients receiving adjuvant Gleevec. Increasing the dose up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in particular in patients with exon 9 mutations (given the subset analysis that suggested an improved response in this cohort of patients). Clinical indications include clear signs or symptoms of disease progression at a lower dose; dose escalation in this setting is only justified in the absence of severe adverse drug reactions. As the new data on exon 9 response is reviewed, it is possible that the benefit preliminarily attributed to an increased dose of imatinib (800 mg daily divided bid) in these patients may not ultimately be borne out in the final analysis.
      • The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day.
      • Patients who become resistant to imatinib often develop secondary mutations. A 2009 study examined why threonine is always replaced by isoleucine and explained with a combination of in vitro and molecular modeling analyses that only Ile is naturally selected as a resistance mutant in gastrointestinal stromal tumors treated with imatinib.25
  • Other agents with tyrosine-kinase inhibitory activity are also showing significant promise for the treatment of GISTs, and especially in the treatment of GISTs with resistance to imatinib. Dasatinib (BMS-354825) is currently being studied in clinical trials.26 In January 2006, the FDA approved sunitinib malate (SU-11248, Sutent) for the treatment of patients with GISTs whose disease has progressed or who are unable to tolerate treatment with imatinib. While studying the treatment in patients, sunitinib was shown at interim analysis to delay the median time-to-tumor progression (TTP) of GISTs to 27 weeks as compared with 6 weeks for patients who did not receive the drug.

Surgical Care

Despite the proven success of imatinib and other newer tyrosine-kinase inhibitors, surgical resection remains the treatment of choice and offers the only chance for cure from GIST.27,28,29,30,31,32 The main operative principle is resection of the tumor with negative microscopic margins. Wide resection of the tumor (eg, 2 cm margin) has not been shown to improve outcomes and expert consensus is that such dogmatic adherence to a particular width of margin is not necessary or recommended.

  • For small gastric tumors, wedge resection is adequate, if technically possible.33 Larger tumors necessitate subtotal or total gastrectomy. Enucleation should be avoided because predicting malignant potential preoperatively is difficult, even in benign-appearing lesions.
  • For locally invasive tumors, en bloc resection of adjacent involved organs, such as colon, spleen, or liver, may be indicated.
  • Routine lymphadenectomy is not indicated, as lymph node involvement is very rare.
  • Recurrence and survival are not associated with the type of resection (wedge resection versus any type of gastrectomy) provided that a complete resection (R0) is performed.
  • Direct every effort at avoiding tumor rupture during the operation. Tumor rupture is associated with a worse prognosis because of peritoneal seeding.
  • In cases of disseminated disease, consider palliative resection because long-term survival has been reported in certain cases.
  • Also consider resection in patients with recurrent disease, manifested as a solitary lesion in the liver or peritoneal cavity. Published reports of liver resection for hepatic metastasis from gastric and other GISTs suggest a survival benefit in selected patients.
  • In the advent of effective therapy for metastatic GIST disease with imatinib,34 there may be a role for cytoreductive surgery (R0 or R1 resection) in the setting of recurrent metastatic disease confined to the abdomen.35
    • Patients should have been on at least 6 months of tyrosine-kinase inhibitor therapy (eg, imatinib) and have either stable or partially responsive disease during this period. A significant minority of these patients require liver resections (40%) and the majority require multivisceral resection, including bowel resections, peritonectomy, and/or omentectomy (60%). Even after such aggressive resection, R1 resections (microscopically positive resections) are the rule, R0 resections are rare, and about 5% of patients still have bulky disease remaining.
    • Up to 70% of patients able to undergo an R0/R1 resection in the setting of stable or partially responsive disease enjoy a progression-free survival as long as 4 years after the initiation of imatinib therapy.36
  • Because adequate resection for small malignant GISTs can be achieved by wedge resection, minimally invasive surgery techniques can be considered in selected cases. In recent years, numerous published reports of laparoscopic resection of gastric GISTs have demonstrated the feasibility and safety of this technique.37,38,39,40,41,42,43

Medication

The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.

Tyrosine-Kinase Inhibitors

Agents with strong tyrosine-kinase inhibition activity of the bcr-abl abnormality in all cell-cycle phases of gastric tumor cells.


Imatinib mesylate (Gleevec)

Specifically designed to inhibit tyrosine-kinase activity of the bcr-abl kinase in GI stromal tumors. These tumors are characterized by expression of the product of the proto-oncogene c-kit and often harbor gain-of-function KIT mutations, leading to ligand-independent kinase activation. Gleevec inhibits ABL, KIT, and PDGFR tyrosine kinase.

Adult

400 mg PO qd with food; may increase to 800 mg/d divided bid in absence of adverse effects for patients with advanced or metastatic GIST who progress through lower 400 mg daily dose; consider higher dose for patients with exon 9 mutations as they might have improved outcome at higher dose

Pediatric

Not established

CYP3A4 inhibitors (ketoconazole increases distribution of imatinib); CYP3A4 substrates (simvastatin increases maximum concentration of imatinib by a 2- to 3.5-fold factor); CYP3A4 inducers (phenytoin decreases AUC by approximately one fifth of typical AUC); likely to increase blood levels of drugs that are substrates of CYP2C9, CYP2D6, and CYP3A4/5

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Dose must be reduced if edema or anemia occur, transaminases or bilirubin become elevated, or grade 3-4 neutropenia or thrombocytopenia develop

Multikinase inhibitors

Elicit actions via multiple tyrosine-kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression.


Sunitinib malate (SU-11248, Sutent)

Multikinase inhibitor that targets several tyrosine-kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression. Inhibits platelet-derived growth factor receptors (ie, PDGFR-alpha, PDGFR-beta), vascular endothelial growth factor receptors (ie, VEGFR1, VEGFR2, VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell-line–derived neurotrophic factor receptor (RET).
Indicated for persons with GISTs whose disease has progressed or who are unable to tolerate treatment with imatinib (Gleevec). Delays median time to tumor progression.

Adult

Standard dose: 50 mg PO qd on a schedule of 4 wk on treatment followed by 2 wk off treatment, then repeat cycle
Dose modification: Increase or reduce dose in 12.5-mg increments based on individual safety and tolerability
Coadministration with potent CYP4503A4 inhibitors: Minimum dose of 37.5 mg PO qd during treatment phase of cycle
Coadministration with CYP4503A4 inducers: Maximum dose of 87.5 mg PO qd during treatment phase of cycle

Pediatric

Not established

Potent CYP4503A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations; CYP4503A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) may decrease plasma concentrations; St John's wort induces metabolism and decreases plasma concentrations unpredictably (do not take concurrently)

Documented hypersensitivity; concurrent administration with St John's wort

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Common adverse effects include diarrhea, skin discoloration, mouth irritation, weakness, and altered taste; may cause fatigue, hypertension, bleeding, swelling, and hypothyroidism; in clinical trials, decreased left ventricular ejection fraction to below lower limits of normal in 15% of patients (monitor for CHF and discontinue if clinical manifestations of CHF develop); may cause hemorrhagic events that may include epistaxis or rectal, gingival, GI, genital, or wound bleeding

More on Gastric Gastrointestinal Stromal Tumors

Overview: Gastric Gastrointestinal Stromal Tumors
Differential Diagnoses & Workup: Gastric Gastrointestinal Stromal Tumors
Treatment & Medication: Gastric Gastrointestinal Stromal Tumors
Follow-up: Gastric Gastrointestinal Stromal Tumors
Multimedia: Gastric Gastrointestinal Stromal Tumors
References
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Further Reading

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Keywords

gastric gastrointestinal stromal tumors, gastric GISTs, malignant gastric stromal tumors, gastric leiomyosarcomas, gastrointestinal stromal tumors, GISTs, gastric GIST, fibrosarcoma, angiosarcoma, hemangiopericytoma, gastric smooth muscle tumors, intestinal smooth muscle tumors

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Contributor Information and Disclosures

Author

Michael A Choti, MD, MBA, Jacob C Handelsman Professor of Surgery, Professor of Oncology and Engineering, Johns Hopkins University School of Medicine
Michael A Choti, MD, MBA is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Surgeons, American Hepato-Pancreato-Biliary Association, American Society of Clinical Oncology, American Surgical Association, Association for Academic Surgery, International Hepato-Pancreato-Biliary Association, Society for Surgery of the Alimentary Tract, Society of Surgical Oncology, and Society of University Surgeons
Disclosure: Nothing to disclose.

Coauthor(s)

Matthew Hueman, MD, Fellow in Surgical Oncology, The Johns Hopkins Hospital; Instructor, Department of Surgery, The Johns Hopkins School of Medicine
Matthew Hueman, MD is a member of the following medical societies: American Association for Cancer Research, American College of Surgeons, American Hepato-Pancreato-Biliary Association, American Society of Clinical Oncology, Association for Academic Surgery, and Society of Surgical Oncology
Disclosure: Nothing to disclose.

Medical Editor

Robert C Shepard, MD, FACP, Associate Professor of Medicine in Hematology and Oncology at University of North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International
Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physician Executives, American College of Physicians, American Federation for Clinical Research, American Federation for Medical Research, American Medical Association, American Medical Informatics Association, American Society of Hematology, Association of Clinical Research Professionals, Eastern Cooperative Oncology Group, European Society for Medical Oncology, Massachusetts Medical Society, and Society for Biological Therapy
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

 
 
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