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Clinical Trial Results

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  • Posted: 06/25/2007
  • Updated: 05/19/2009

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Imatinib (Gleevec®) Reduces Cancer Recurrence in Patients with Surgically Removed GIST

Key Words

Gastrointestinal stromal tumor (GIST); imatinib (Gleevec®). (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)

Summary

Patients with localized gastrointestinal stromal tumors (GIST) who took imatinib (Gleevec®) for one year after surgical removal of the primary tumor were significantly less likely to have a recurrence of their cancer compared to patients who did not receive imatinib treatment. There wasn’t enough evidence to determine whether those on imatinib would also live longer overall.

Source

American Society of Clinical Oncology (ASCO) annual meeting, Chicago, June 4, 2007 (see the meeting abstract). Final results for this trial were published in the Mar. 28, 2009, Lancet; see the journal abstract.

Background

Gastrointestinal stromal tumors (GIST) usually begin in cells in the wall of the stomach or intestines. GIST is a type of soft-tissue sarcoma—a cancer of the soft tissues of the body, which include the muscles, tendons, fat, nerves, and the tissues around the joints. Until recently, surgery was the only treatment available for GIST, which rarely responds to chemotherapy or radiation therapy.

Over 90 percent of GIST cells have mutations in one of two genes, called KIT and PDGFRα. The drug imatinib targets both of these mutated genes. Previous clinical trials have shown that imatinib can kill GIST cells that have spread (metastasized) to other parts of the body and cannot be removed with surgery.

The clinical trial described below tested whether imatinib could extend recurrence-free survival (time until cancer returns) and overall survival in patients with GIST that has not spread outside the area of the original tumor (localized GIST) and has been completely removed by surgery.

The Study

This randomized clinical trial enrolled patients with localized GIST larger than 3 centimeters (a little over an inch) in diameter, who underwent complete surgical removal of their tumor. Patients taking part in the trial had to have tumors that overexpressed the gene KIT.

The investigators randomly assigned patients to receive either one year of imatinib at a dose of 400 milligrams a day or one year of placebo pills after surgery. If the cancer returned in a patient taking the placebo, they started taking imatinib. If the cancer returned in a patient taking imatinib, the investigators doubled the patient’s dose of imatinib.

During the year after treatment ended, patients whose cancer returned either started taking imatinib (if they had been in the placebo group) or restarted taking the drug (if they had been in the imatinib group).

Patients underwent imaging tests every three months for the first two years, then twice a year for the next three years. The investigators compared recurrence-free survival, overall survival, and side effects between the two groups.

The trial was organized by the North American Intergroup, and included patients from 230 participating centers. The lead author of the study was Ronald DeMatteo, M.D., from Memorial Sloan-Kettering Cancer Center. (See the protocol summary.)

Results

Beginning in June 2002, the investigators enrolled 644 patients into the trial. In January 2006, the difference in progression-free survival among patients receiving imatinib was large enough that the trial’s independent study monitoring committee recommended the study be stopped; imatinib was then offered to all participants (see earlier press release).

Seventy-one percent of patients in the placebo group and 67 percent of patients in the imatinib group completed a full year of treatment. Tumor progression was the most common reason for patients in the placebo group to stop treatment, and toxicity (side effects) was the most common reason for stopping treatment in the imatinib group.

After one year of treatment, 97 percent of patients in the imatinib group had not experienced recurrence of their disease, compared to 83 percent of patients in the placebo group. No difference in overall survival could be seen at the time of analysis. It appeared that patients with tumors larger than 10 centimeters (almost 4 inches) benefited more from imatinib than those with smaller tumors.

Limitations

While this trial showed that one year of treatment with imatinib improves progression-free survival for patients with localized GIST, “questions still remain about the appropriate dose, appropriate duration of therapy, the impact of [different gene mutations] and…most importantly…the time to secondary [imatinib] resistance and, therefore, overall survival,” explained Shreyaskumar Patel, M.D., from M.D. Anderson Cancer Center, in a discussion at the ASCO meeting.

Because all patients given imatinib likely will develop resistance to the drug, doctors need to know whether giving imatinib immediately after surgery or waiting until a tumor returns to give the drug has the largest effect on overall survival. The long-term follow-up from this trial cannot answer that question, because all patients were given imatinib immediately after surgery.

“It is still a debate when treating GIST patients with completely resected disease as to whether it is best to start patients out right away [on imatinib], or wait until they progress and then give the drug,” said Barry Anderson, M.D., Ph.D., of the National Cancer Institute’s Cancer Therapy Evaluation Program.

In addition, he explained, two ongoing clinical trials are examining the question of how long a patient should take imatinib, since in this trial the drug was only given for one year. The results of these studies will help doctors plan the most effective treatment regimens for their patients with GIST.

Comments

“Four-hundred milligrams a day of imatinib…for one year is safe and well tolerated after the complete [surgical removal] of a primary gastrointestinal stromal tumor,” summarized DeMatteo, presenting the results at ASCO. “Our data show that recurrence-free survival is increased in patients who take one year of imatinib, but overall survival has not been altered at this time.”

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