Journal reports on clinical trial patient No. 1

Someone had to be first. In the case of gastrointestinal stromal tumor treated with STI571, (now Gleevec) the first patient was a woman in Finland. She began taking the drug in March 2000, four months before the clinical trial of STI571 for GIST would begin at three cancer centers in the United States.

The following are excerpts from the case report published in the April 5 New England Journal of Medicine, used here with permission.

In October 1996, a 50-year-old, previously healthy woman presented with mild abdominal discomfort and a large mass in the upper abdomen. Surgeons subsequently removed two tumors, 6.5 and 10 centimeters in diameter, from the stomach. Also, the greater omentum and mesocolic peritoneum were removed because of the presence of multiple metastatic nodules 1 to 2 millimeters in diameter. Tests revealed the masses as GIST.

In February 1998, the woman again underwent surgery. This time recurrent tumors in the left upper abdomen, two liver metastases, and multiple small intra-abdominal metastases were removed. In September that same year, six more liver metastases and an ovarian metastasis were removed.

From November 1998 to March 1999, the woman was given seven cycles of chemotherapy for additional liver metastases. Doctors used mesna, doxorubicin, ifosfamide and dacarbazine. There was no clinical response.

In March 1999, the cancer had progressed. A metastasis that was obstructing the large bowel and 45 smaller metastases were surgically removed. Again, the patient was treated with chemotherapy. Between April 1999 and February 2000, she was given thalidomide and interferon alfa. The therapy was unsuccessful; by February 2000 the liver metastases were progressing in size and number, and several new intra-abdominal and mesenteric metastases were found by magnetic resonance imaging (MRI).

That was when the doctors at Helsinki University Central Hospital turned to a new compound – STI571.

Treatment was started in March 2000, with four 100 mg capsules of STI571 given once daily. This dose was based on evaluations of the safety and tolerability of STI571 in patients with chronic myeloid leukemia.

Toxicity was assessed at follow-up visits every two to four weeks, and blood-cell counts and blood chemical values were analyzed every one to two weeks.

The response was measured with dynamic MRI, positron-emission tomography (PET), and serial needle biopsies of a liver metastasis.

The day before the start of treatment, doctors measured eight large liver metastases and came up with a combined size of 112.5 square centimeters. On subsequent MRI scans, the size was as follows: 67 square centimeters after two weeks of treatment, 54 square centimeters at one month, 42 square centimeters at two months, 36 square centimeters at four months, 33 square centimeters at 5½ months, and 28 square centimeters at eight months. No new lesions appeared, and six of the 28 liver metastases disappeared.

As of February 2001, all tumors continued to respond to treatment, and the patient remained clinically well.

STI571 was well tolerated. No drugrelated adverse effects on the liver, kidneys, or heart were observed. All of the main subjective adverse effects were mild and consisted of an increased frequency of bowel movements, occasional muscle cramps in the legs, and slight ankle edema.

Editor’s note: The Life Raft Group Newsletter thanks the New England Journal of Medicine for permission to reprint the case study, and the authors of the study: Drs. Heikki Joensuu, Peter J. Roberts, Maarit Sarlomo-Rikala, Leif C. Andersson, Pekka Tervahartiala, David Tuveson, Sandra L. Silberman, Renaud Capdeville, Sasa Dimitrijevic, Brian Druker and George D. Demetri.