Elsevier

Human Pathology

Volume 33, Issue 5, May 2002, Pages 466-477
Human Pathology

GIST Symposium
Clinical management of gastrointestinal stromal tumors: Before and after STI-571*,**,*

https://doi.org/10.1053/hupa.2002.124122Get rights and content

Abstract

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. Until recently, surgery has been the only effective therapy for GIST. However, even after complete resection of tumor, many patients still eventually die of disease recurrence. Conventional chemotherapy and radiation therapy have been of limited value. Within the last few years, it was discovered that most GISTs have a gain-of-function mutation in the c-kit proto-oncogene. This results in ligand-independent activation of the KIT receptor tyrosine kinase and an unopposed stimulus for cell growth. STI-571 is a small molecule that selectively inhibits the enzymatic activity of the ABL, platelet-derived growth factor receptor, and KIT tyrosine kinases and the BCR-ABL fusion protein and is a landmark development in cancer therapy. Its clinical development marks a new era of rational and targeted molecular inhibition of cancer that emanates from direct collaborations between scientists and clinicians. It provides proof of the principle that a specific molecular inhibitor can drastically and selectively alter the survival of a neoplastic cell with a particular genetic aberration. The advent of STI-571 has markedly altered the clinical approach to GIST. It has proven to be effective in metastatic GIST and is also under investigation as a neoadjuvant and adjuvant therapy. HUM PATHOL 33:466-477. Copyright 2002, Elsevier Science (USA). All rights reserved.

Section snippets

Primary disease

The exact incidence of GIST in the United States is unknown at this time, because until very recently many of these cases were considered benign neoplasms or leiomyosarcoma. However, the estimated incidence of GIST is at least 1,000 new cases per year, and the actual incidence is probably much higher if very small (<1 cm) lesions found incidentally during laparotomy for other reasons are included. The awareness of GIST has increased because of the routine use of CD117 immunohistochemical

Development of STI-571

The application of STI-571 represents a major paradigm shift in cancer therapy—targeting the specific molecular abnormalities crucial in the etiology of cancer. In contrast, most anticancer therapies developed over the past 50 years have been essentially nonspecific. Cytotoxic agents generally function by interfering with cell machinery common to both neoplastic and normal cells (e.g., DNA synthesis). Consequently, conventional chemotherapeutic agents lack selectivity, have a narrow therapeutic

Correlative studies

The advent of STI-571 has revolutionized the clinical management of patients with primary and metastatic GIST, but our understanding of the genetic aberrations in GIST is just beginning to evolve. The 2 fundamental correlative questions regarding STI-571 use are (1) whether the type of c-kit mutation predicts sensitivity to STI571 and (2) what biologic mechanisms mediate tumor resistance to the agent

Current use of STI-571 and future considerations

STI-571 has quickly become the first-line agent for metastatic GIST. Patients who respond may become candidates for surgical resection. Patients with stable disease may remain on the agent until disease progression becomes evident. Patients who become refractory to STI-571 are eligible for more traditional palliative therapy, such as hepatic artery embolization, radiation, or surgical debulking and/or intraperitoneal chemotherapy. The combination of STI-571 and conventional therapeutic

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    *

    Based on presentations given at the National Institutes of Health Workshop on Gastrointestinal Stromal Tumors, Bethesda, MD, April 2 and 3, 2001.

    **

    Supported in part by the Northwest Health Foundation (M.H.), VA Merit Review program (M.H.), and National Cancer Institute (grant CA94503) (R.D.).

    *

    Address correspondence and reprint requests to Ronald P. DeMatteo, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.

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