Treatment of gastrointestinal stromal tumor: focus on imatinib mesylate

Gastrointestinal stromal tumor (GIST) is a rare primary neoplasm of the gastrointestinal tract, mesentery, or omentum. In the past, surgery has been the only effective treatment. The diagnosis and treatment of GIST has been revolutionized over the past decade, since expression of the receptor tyrosine kinase KIT was shown to occur on these tumors. Mutations in this proto-oncogene commonly cause constitutive activation of the KIT tyrosine kinase receptor, an important factor in the pathogenesis of the disease. The development of specific tyrosine kinase inhibitors, such as imatinib mesylate, has led to a breakthrough in the treatment of advanced GIST. Treatment with this drug has led to significant improvements in survival, with overall response rates in excess of 80%. Side effects are common, but usually manageable. The success of this drug has led to further trials investigating its use in the pre- and postoperative situation. This review summarizes the current knowledge of GIST and imatinib treatment and possible future developments.

[1]  Peter Lloyd,et al.  Clinical Pharmacokinetics of Imatinib , 2005, Clinical pharmacokinetics.

[2]  E. Targarona,et al.  Laparoscopic Resection of Clinically Suspected Gastric Stromal Tumors , 2006, Surgical innovation.

[3]  C. Ryan,et al.  Surgical treatment of gastrointestinal stromal tumors in the imatinib (STI-571) era. , 2003, Surgery.

[4]  E. Atkinson,et al.  Prognostic factors influencing survival in gastrointestinal leiomyosarcomas. Implications for surgical management and staging. , 1992, Annals of surgery.

[5]  J. Blay,et al.  Erratum: Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Concensus Conference of 20-21 March 2004, under the auspices of ESMO (Annals of Oncology (2005) vol. 16 (566-578)) , 2005 .

[6]  S. Hirota,et al.  Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. , 2003, Gastroenterology.

[7]  C. Antonescu,et al.  Acquired Resistance to Imatinib in Gastrointestinal Stromal Tumor Occurs Through Secondary Gene Mutation , 2005, Clinical Cancer Research.

[8]  D. Michael King The radiology of gastrointestinal stromal tumours (GIST) , 2005, Cancer Imaging.

[9]  O. S. Nielsen,et al.  Exatecan in pretreated adult patients with advanced soft tissue sarcoma: results of a phase II--study of the EORTC Soft Tissue and Bone Sarcoma Group. , 2002, European journal of cancer.

[10]  M. Mazur,et al.  Gastric stromal tumors Reappraisal of histogenesis , 1983, The American journal of surgical pathology.

[11]  C. Sawyers,et al.  Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. , 2001, The New England journal of medicine.

[12]  O. GonzaloMéndez,et al.  Gastric stromal tumors. , 1987, The Nebraska medical journal.

[13]  Haesun Choi,et al.  We should desist using RECIST, at least in GIST. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  K. Min,et al.  Small Intestinal Stromal Tumors With Skeinoid Fibers: Clinicopathological, Immunohistochemical, and Ultrastructural Investigations , 1992, The American journal of surgical pathology.

[15]  C. J. Chen,et al.  KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. , 2001, Cancer research.

[16]  B. Nilsson,et al.  Gastrointestinal stromal tumors: The incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era , 2005, Cancer.

[17]  H. Joensuu Sunitinib for imatinib-resistant GIST , 2006, The Lancet.

[18]  J. Verweij,et al.  Imatinib and gastrointestinal stromal tumors: Where do we go from here? , 2005, Molecular Cancer Therapeutics.

[19]  A. D. Van den Abbeele,et al.  Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  P. Rutkowski,et al.  Risk Criteria and Prognostic Factors for Predicting Recurrences After Resection of Primary Gastrointestinal Stromal Tumor , 2007, Annals of Surgical Oncology.

[21]  J. Kononen,et al.  Prevalence of KIT expression in human tumors. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  A. D. Van den Abbeele,et al.  Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. , 2002, The New England journal of medicine.

[23]  L. Kindblom,et al.  Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. , 1998, The American journal of pathology.

[24]  J. Desai,et al.  Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  M. van Glabbeke,et al.  Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group study. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  G. Demetri,et al.  Clinical management of gastrointestinal stromal tumors: before and after STI-571. , 2002, Human pathology.

[27]  Gerald Antoch,et al.  Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[28]  Jürg Zimmermann,et al.  Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells , 1996, Nature Medicine.

[29]  Sigrid Stroobants,et al.  Update of phase I study of imatinib (STI571) in advanced soft tissue sarcomas and gastrointestinal stromal tumors: a report of the EORTC Soft Tissue and Bone Sarcoma Group. , 2002, European journal of cancer.

[30]  B. Gunawan,et al.  Gastrointestinal stromal tumor (GIST) -- single center experience of prolonged treatment with imatinib. , 2005, Zeitschrift für Gastroenterologie - German Journal of Gastroenterology.

[31]  K. Antman,et al.  Imatinib mesylate--a new oral targeted therapy. , 2002, The New England journal of medicine.

[32]  J. Blay,et al.  KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. , 2006, European journal of cancer.

[33]  C. Ball,et al.  The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. , 2004, The American journal of pathology.

[34]  G. Demetri,et al.  Management of malignant gastrointestinal stromal tumours. , 2002, The Lancet. Oncology.

[35]  P. Parsons,et al.  Immunohistochemical localisation of stem cell factor (SCF) with comparison of its receptor c-Kit proto-oncogene product (c-KIT) in melanocytic tumours , 2004, Virchows Archiv.

[36]  J. Lasota,et al.  Mutations in gastrointestinal stromal tumors – a population‐based study from Northern Norway , 2007, Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS).

[37]  J. Radford,et al.  Response evaluation in gastrointestinal stromal tumours treated with imatinib: misdiagnosis of disease progression on CT due to cystic change in liver metastases. , 2006, The British journal of radiology.

[38]  J. Desai,et al.  Hypothyroidism after Sunitinib Treatment for Patients with Gastrointestinal Stromal Tumors , 2006, Annals of Internal Medicine.

[39]  A. D. Van den Abbeele,et al.  Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to imatinib mesylate. , 2005, Radiology.

[40]  Ikuo Wada,et al.  Multiple small intestinal stromal tumors with skeinoid fibers in association with neurofibromatosis 1 (von Recklinghausen's disease) , 1996, Pathology international.

[41]  Sigrid Stroobants,et al.  Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study , 2001, The Lancet.

[42]  M. Carroll,et al.  CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. , 1997, Blood.

[43]  C. Sakakura,et al.  Long-term survival of a case with multiple liver metastases from duodenal gastrointestinal stromal tumor drastically reduced by the treatment with imatinib and hepatectomy. , 2006, World journal of gastroenterology.

[44]  E. Wiemer,et al.  Activating mutations in c-KIT and PDGFRα are exclusively found in gastrointestinal stromal tumors and not in other tumors overexpressing these imatinib mesylate target genes , 2005, Cancer biology & therapy.

[45]  J Nuyts,et al.  18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). , 2003, European journal of cancer.

[46]  E. Wardelmann,et al.  Association of platelet-derived growth factor receptor alpha mutations with gastric primary site and epithelioid or mixed cell morphology in gastrointestinal stromal tumors. , 2004, The Journal of molecular diagnostics : JMD.

[47]  R. Shlansky-Goldberg,et al.  Sarcomas metastatic to the liver: response and survival after cisplatin, doxorubicin, mitomycin-C, Ethiodol, and polyvinyl alcohol chemoembolization. , 2001, Journal of vascular and interventional radiology : JVIR.

[48]  J. Blay,et al.  Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  M. Debiec‐Rychter,et al.  Chromosomal aberrations in malignant gastrointestinal stromal tumors: correlation with c-KIT gene mutation. , 2001, Cancer genetics and cytogenetics.

[50]  G. Mann,et al.  Gastrointestinal stromal tumour treated with neoadjuvant imatinib , 2005, Journal of Clinical Pathology.

[51]  Markku Miettinen,et al.  Pathology and diagnostic criteria of gastrointestinal stromal tumors (GISTs): a review. , 2002, European journal of cancer.

[52]  L. Sobin,et al.  KIT mutation portends poor prognosis in gastrointestinal stromal/smooth muscle tumors. , 1998, Laboratory investigation; a journal of technical methods and pathology.

[53]  S. Hirota,et al.  Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors. , 1999, Cancer research.

[54]  J. Desai,et al.  Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial , 2006, The Lancet.

[55]  M. Miettinen,et al.  Gastrointestinal stromal tumors--value of CD34 antigen in their identification and separation from true leiomyomas and schwannomas. , 1995, The American journal of surgical pathology.

[56]  J. Blay,et al.  Management of gastrointestinal stromal tumors in the imatinib era: selected case studies. , 2006, The oncologist.

[57]  C. Blanke,et al.  Gastrointestinal stromal tumors and the evolution of targeted therapy. , 2005, Clinical advances in hematology & oncology : H&O.

[58]  Tae Won Kim,et al.  Patterns of progression in gastrointestinal stromal tumor treated with imatinib mesylate. , 2006, Japanese journal of clinical oncology.

[59]  L. Sobin,et al.  Analysis of KIT Mutation and Protein Expression in Fine Needle Aspirates of Gastrointestinal Stromal/Smooth Muscle Tumors , 2000, Acta Cytologica.

[60]  L. Ellis,et al.  Gastrointestinal leiomyosarcoma metastatic to the liver. Durable tumor regression by hepatic chemoembolization infusion with cisplatin and vinblastine , 1995, Cancer.

[61]  K. Shirao,et al.  Phase II clinical study of STI571 in Japanese (Jpn) patients (pts) with malignant gastrointestinal stromal tumors (GIST): results of the B 1201 study. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[62]  J. Fletcher,et al.  Biology of gastrointestinal stromal tumors. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[63]  Haesun Choi,et al.  Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  L. Sobin,et al.  Gastrointestinal Stromal Tumors of the Stomach: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 1765 Cases With Long-term Follow-up , 2005, The American journal of surgical pathology.

[65]  C. Leutner,et al.  Acquired resistance to imatinib in gastrointestinal stromal tumours caused by multiple KIT mutations. , 2005, The Lancet. Oncology.

[66]  S. Sheps,et al.  The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. , 1977, The New England journal of medicine.

[67]  G. Antoch,et al.  Resection of residual disease in patients with metastatic gastrointestinal stromal tumors responding to treatment with imatinib , 2005, International journal of cancer.

[68]  Xin Huang,et al.  Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial , 2006, The Lancet.

[69]  E. Visvardis,et al.  The role of surgery in the management of gastrointestinal stromal tumors (GISTs) in the era of imatinib mesylate effectiveness. , 2005, Surgical oncology.

[70]  S. Hirota,et al.  Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. , 1998, Science.

[71]  I. Judson,et al.  Surgery for gastrointestinal stromal tumour in the post‐imatinib era , 2005, ANZ journal of surgery.

[72]  J. Verweij,et al.  Imatinib pharmacokinetics in patients with gastrointestinal stromal tumour: a retrospective population pharmacokinetic study over time. EORTC Soft Tissue and Bone Sarcoma Group , 2005, Cancer Chemotherapy and Pharmacology.

[73]  Y. Novitsky,et al.  Long-term Outcomes of Laparoscopic Resection of Gastric Gastrointestinal Stromal Tumors , 2006, Annals of surgery.

[74]  L. Sobin,et al.  Diagnosis of gastrointestinal stromal tumors: A consensus approach. , 2002, Human pathology.

[75]  E. van den Berg,et al.  Soft tissue leiomyosarcomas and malignant gastrointestinal stromal tumors: differences in clinical outcome and expression of multidrug resistance proteins. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[76]  Samuel Singer,et al.  PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors , 2003, Science.

[77]  D. Tuveson,et al.  Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. , 2001, The New England journal of medicine.

[78]  J. Crowley,et al.  Dose effect of imatinib (IM) in patients (pts) with metastatic GIST - Phase III Sarcoma Group Study S0033. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[79]  B. Druker,et al.  Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. , 2000, Blood.

[80]  F. Ris,et al.  An audit of surgical management of gastrointestinal stromal tumours (GIST). , 2006, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[81]  J. Trent,et al.  Update on the biology and therapy of gastrointestinal stromal tumors. , 2005, Cancer control : journal of the Moffitt Cancer Center.

[82]  T. Nicol,et al.  Complete hepatic resection of metastases from leiohyosarcoma prolongs survival , 1998, Journal of Gastrointestinal Surgery.

[83]  K. Franssila,et al.  KIT and platelet-derived growth factor receptor alpha tyrosine kinase gene mutations and KIT amplifications in human solid tumors. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[84]  J. Lasota,et al.  Mutations in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. , 1999, The American journal of pathology.

[85]  P. Schnyder,et al.  The value of PET, CT and in-line PET/CT in patients with gastrointestinal stromal tumours: long-term outcome of treatment with imatinib mesylate , 2004, European Journal of Nuclear Medicine and Molecular Imaging.

[86]  L. Sobin,et al.  Gastrointestinal Stromal Tumors of the Jejunum and Ileum: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 906 Cases Before Imatinib With Long-term Follow-up , 2006, The American journal of surgical pathology.

[87]  O. GonzaloMéndez,et al.  Tumores estromales del estómago , 2006 .

[88]  R. DeMatteo,et al.  Gastrointestinal stromal tumor: 5 years later , 2005, Cancer.

[89]  J. Fletcher,et al.  Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor. , 2006, Cancer research.

[90]  Rossella Bertulli,et al.  Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial , 2004, The Lancet.

[91]  J. Blay,et al.  Continuous versus interruption of imatinib (IM) in responding patients with advanced GIST after three years of treatment: A prospective randomized phase III trial of the French Sarcoma Group , 2007 .

[92]  J. Lasota,et al.  Gastrointestinal stromal tumors – definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis , 2000, Virchows Archiv.

[93]  R. DeMatteo,et al.  Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. , 2000, Annals of surgery.

[94]  F. Bertucci,et al.  Acquired resistance to imatinib and secondary KIT exon 13 mutation in gastrointestinal stromal tumour. , 2006, Oncology reports.

[95]  E. Wardelmann,et al.  Polyclonal Evolution of Multiple Secondary KIT Mutations in Gastrointestinal Stromal Tumors under Treatment with Imatinib Mesylate , 2006, Clinical Cancer Research.

[96]  J. Blay,et al.  Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[97]  T. Lehnert,et al.  Treatment of Gastrointestinal Stromal Tumor with Imatinib Mesylate: A Retrospective Single-Center Experience in Heidelberg , 2006, Digestive Diseases.

[98]  K. Owzar,et al.  Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST): A meta-analyis based on 1,640 patients (pts) , 2007 .