According to a recent article published in the Lancet, increasing the dose of Gleevec® (imatinib mesylate) reduces the risk of a cancer relapse in patients with gastrointestinal stromal tumors (GIST).
Gastrointestinal stromal tumors (GISTs) are a unique subset of cancers that are most often located in the stomach, but can arise anywhere in the gastrointestinal tract. GISTs arise from the cells of Cajal, or the “pacemaker” cells of the gastrointestinal tissue. Standard treatment for GISTs includes the surgical removal of the cancer, chemotherapy and/or radiation therapy. However, GISTs tend to be aggressive in nature and resistant to radiation and chemotherapy, with only 4.8% of cases responding to chemotherapy. Patients with advanced GIST have an average survival of 9 to 20 months following standard treatment.
The majority of GISTs have a mutation (alteration) within a protein called KIT. KIT is involved in biological processes that facilitate the growth and multiplication of healthy cells. Normally, this growth process is kept under strict control; however, KIT mutations involved with GISTs lead to excessive, uncontrolled multiplication of cancer cells.
Gleevec® is a biologic agent that has been approved by the FDA for the treatment of GISTS and chronic myelogenous leukemia. It is currently being evaluated in clinical trials for the treatment of several different types of cancers. One function of Gleevec® involves binding to KIT that contains mutations involved in GISTs. This binding action stops or slows the excessive growth of the cancer cells caused by the mutated KIT and has also been implicated in the direct death of cells containing mutated KIT.
Researchers affiliated with the European Organization of Research and Treatment of Cancer (EORTC) recently conducted a clinical trial to compare different doses of Gleevec® in the treatment of GIST. This trial included 946 patients with advanced GIST who were treated with either a lower dose of Gleevec® (400 mg) or a higher dose of Gleevec® (800 mg) and were directly compared. Approximately one-third of patients had received prior treatment with chemotherapy. Patients whose cancer progressed while being treated with 400 mg of Gleevec® were able to “cross over” and receive 800 mg. Overall, complete and partial disappearances of cancer, disease stabilization, and survival at one year were nearly identical between the two groups of patients. The estimated survival at two years was 74% for patients initially treated with 800 mg and 69% for those treated with 400 mg. In addition, there was an 18% reduced risk of a relapse in patients initially treated with 800 mg.
The researchers concluded that 800 mg of Gleevec® appears superior to 400 mg of Gleevec® in reducing the risk of a relapse and improving survival at 2 years in patients with GIST. However, the researchers caution that absolute improvements are difficult to measure, as patients initially treated with 400 mg were able to cross-over to receive 800 mg upon progression of their disease. Patients with GISTs who are to receive Gleevec® should speak with their physician about the risks and benefits of higher doses of Gleevec®.
Reference: Verweij J, Casali G, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomized trial. Lancet. 2004;364:1127-1134.