JUNE 2003

PET documents Gleevec's tumor-fighting power

ACRIN trial will calculate speed of measurable response

By: Charles Bankhead

Boston researchers have discovered, almost accidentally, that FDG-PET can identify signs of dramatic response within days of the first dose of the signal transduction inhibitor imatinib (Gleevec) in patients with advanced gastrointestinal stromal tumors (GIST). Comparing baseline and one-month follow-up PET studies of a patient with sarcoma treated with imatinib, Dr. Annick Van den Abbeele was surprised to see no visible evidence of disease on the follow-up scan.

"My first reaction was that I was looking at the wrong patient," said Van den Abbeele, director of nuclear medicine at Dana-Farber Cancer Institute. "When I realized the study was from the correct patient, my second reaction was that we had a false-negative study. I had never seen a response that impressive in a patient with that type of tumor."

Later the same day, the scenario was repeated in baseline and one-month PET studies of a patient with a large liver mass who had also been treated with imatinib. The follow-up scan showed no evidence of FDG uptake, despite a residual mass on CT.

"That's when I realized we were on to something," Van den Abbeele said.

She subsequently learned that the patients were the first two GIST patients in the U.S. to be treated with imatinib. The promising results of a clinical trial of imatinib for advanced GIST, in which they were enrolled, were reported last year (NEJM 2002;347:472-480).

As a PET specialist, Van den Abbeele was intrigued by the role the imaging modality could play in GIST patients treated with imatinib. Additional clinical experience has suggested that FDG-PET can identify very early on which patients are responding to therapy. Nonresponders can be switched to an alternative that might work better.

The Dana-Farber investigators found that a decrease in a tumor's standard uptake value (SUV) to less than 2.5 within 21 to 40 days of starting imatinib predicts long-term response. An SUV of 2.5 or greater predicts poor response or progression. A marked decrease in SUV is also seen more frequently in GIST patients who have a mutation in exon 11 of the c-kit growth factor receptor gene. The mutation has previously been shown to predict a favorable response to imatinib.

Observations from the original GIST trial have led to a PET-based companion study to a new clinical trial of neoadjuvant imatinib therapy for advanced GIST. Sponsored

by the Radiation Therapy Oncology Group and the American College of Radiology Imaging Network (ACRIN), the PET study will test the limits of the imaging modality's ability to detect early responses to therapy. The ACRIN trial will determine whether prognostically important metabolic changes can be detected within 24 hours to one week of beginning therapy.

"The metabolic changes occur extremely quickly," Van den Abbeele said. "We have studied patients within the first 24 hours after ingestion of a single Gleevec pill, and we have been able to demonstrate a signaling switch-off in metabolic activity that early. That precedes by a long time what can be seen on CT or MRI."

In addition to evaluating the prognostic potential of early PET-detected changes in tumor metabolic activity, the ACRIN trial includes tumor biopsies at baseline and immediately prior to surgical resection. Analysis of the biopsy tissue should help provide a better understanding of why FDG-PET appears to be such a sensitive predictor of response.