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Tyrosine Kinase-Targeted Therapy Effective Against Gastrointestinal Stromal Tumours

Imatinib mesylate is an effective treatment for metastatic gastrointestinal stromal tumours (GISTs) and may serve as a model for the use of other tyrosine kinase targeted therapies in GIST and other more common cancers, according to an American review.

These rare tumours are found in the stomach wall and small bowel, and occasionally in the mesentery, omentum, or retroperitoneum. They are defined as mesenchymal neoplasms with CD117 (KIT) expression, and are often positive for CD34.

Partial gastrectomy or bowel resection is the standard treatment approach for primary GIST, but is contraindicated in metastatic disease unless the primary disease is symptomatic. Moreover, standard chemotherapy agents yield a less than 5% response rate in patients with metastatic GIST, highlighting the need for new treatment options for metastatic disease.

Robert G. Maki, MD, PhD, at the Memorial Sloan-Kettering Cancer Centre, New York, United States, reviewed the use of the KIT tyrosine kinase inhibitor imatinib mesylate in the treatment of GISTs.

Imatinib mesylate is currently the only drug proven effective for patients with metastatic GIST. Moreover, imatinib has demonstrated superior efficacy over chemotherapy, proving to be palliative in 60% or more of patients with metastatic disease.

The latest data available regarding the use of imatinib in the management of GIST were provided by 2 phase III studies presented at the 2003 American Society of Clinical Oncology meeting. Both studies randomised metastatic GIST patients to receive either 400 mg/day or 800 mg/day imatinib.

The study conducted in the United States enrolled 746 patients with metastatic GIST. One year survival rates were estimated at about 85% with either dosing regimen. Moreover, progression-free survival was about 70% in both arms.

In contrast, the study based in Europe and Australasia that enrolled 946 patients found that the higher dosing regimen had a superior progression-free survival rate. Survival comparisons were unavailable for analysis.

The most common side effects associated with imatinib in these and previous studies are mild peripheral or periorbital oedema, nausea, rash, muscle spasms or cramping, diarrhoea, fatigue, neutropaenia, and anaemia. Most side effects are mild to moderate, with grade 3 or 4 toxicity occurring in less than one-third, and most are generally manageable.

Furthermore, drug interactions have been noted between imatinib and warfarin, food containing grapefruit or grapefruit juice, and antiseizure medications.

The use of imatinib in the adjuvant or neoadjuvant setting is still unclear; though a number of studies are underway.

In addition, the potential use of other tyrosine kinase inhibitors and agents affecting the KIT pathway are also under investigation for the treatment of primary and metastatic GISTs, and may be useful in other more common cancers.

Curr Treat Options Gastroenterol 2004 Feb;7:1:13-17. "Gastrointestinal Stromal Tumors Respond to Tyrosine Kinase-targeted Therapy"

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