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First Effective Treatment for Gastrointestinal Sarcoma Seen with Molecular Therapy in Multi-Center Trial of STI-571; Studied at Fox Chase Cancer Center

A new drug, STI-571 or Gleevec (Novartis), that inactivates a protein linked to the growth of some cancers has shown evidence of being effective for an inoperable or advanced form of soft-tissue sarcoma called gastrointestinal stromal tumors (GIST). Although this is not a common tumor, the concept of controlling a cancer by shutting down the molecular activity needed for the tumor's growth may apply to other cancer types. The results of a multi-center clinical trial for GISTs were presented today at the American Society of Clinical Oncology's 2001 Annual Meeting in San Francisco. Fox Chase Cancer Center in Philadelphia, a comprehensive cancer center designated by National Cancer Institute, was one of the four sites involved in the multi-center study. Soft-tissue sarcomas are rare cancers that originate in connective tissue such as muscle and fat.

Gastrointestinal stromal tumors originate in the stroma, the connective tissue that supports the foundation of various organs in the intestinal tract. Normal cells in the gastrointestinal stroma are believed to initiate the contractions basic to the digestive process. Alterations in a gene in these cells called c-KIT can produce inappropriate enzyme activity that leads to the growth of a tumor. In the GIST trial presented at ASCO, 148 patients were enrolled. Of these, 145 were evaluable for side effects and 86 patients were evaluable for response. The patients ranged in age from 18 to 83 years old, with the median age being 54. Fifty-five of the participants had received previous chemotherapy, 16 had received radiation therapy and 94 had had surgery.

To be eligible, patients had to have gastrointestinal stromal tumors that could not be removed surgically or else had spread beyond the original site-tumors considered incurable by the standard treatment combination. They also had to have evidence that the c-KIT protein was expressed by their tumor.

Half the study participants started with a daily dose of 400 milligrams of STI-571 and half received 600 milligrams daily.

Patients on the lower dose whose cancer continued to progress were allowed to switch to the higher dose. An analysis of patients' response to STI 571 found that more than half (59 percent) responded to STI-571.

Patients receiving the higher 600 milligram dosage had a slightly higher response rate (68 percent). However, the difference in response rate has not been shown to be statistically different from the 400 milligram dose. Stable disease was seen in 26 percent of patients and 13 percent had tumors that continued to progress.

"It's important to note that none of the patients who have had an objective response to this drug have shown disease progression," said Dr. Margaret von Mehren, principal investigator for the study at Fox Chase and a co-author of the ASCO paper. "These results validate the concept of molecularly-targeted therapy for an advanced solid tumor." Relatively few patients in the study experienced severe side effects. These included abnormal gastrointestinal bleeding (5 percent), abnormal liver function tests (3 percent), a low number of white cells (neutropenia) in the blood (3 percent), infection (2 percent) and swelling or edema (3 percent).

"What we don't know about STI-571 is whether or not this will actually have an effect on the overall survival of people with this sarcoma," von Mehren said. "This study has only been under way for less than a year now. Many questions remain, but for now we are hopeful."

It is estimated that 5,000 Americans a year develop GISTs, usually in the stomach or small intestine. Although many sarcomas can be treated successfully with a combination of surgery, radiation and chemotherapy, people with GISTs that cannot be completely removed by surgery do not usually respond to standard sarcoma drugs. STI-571, however, has the ability to target the c-kit enzyme; many patients with GIST tumors have been found to have mutations in the gene for this enzyme. The mutation results in c-kit continually giving the cell a growth signal. STI-571 attaches to the targeted enzyme in a way that inhibits its growth activity but leaves normal cells unharmed. Side effects have been much milder than those associated with many chemotherapy agents.

"Before now, people with gastrointestinal stromal tumors had few options," said von Mehren. "STI-571 demonstrates great possibilities." Gleevec was approved by the Food and Drug Administration on May 10, 2001 for treatment of chronic myeloid leukemia (CML). The drug shows promise in the treatment of patients with CML and GIST, according to two New England Journal of Medicine reports published April 5. The journal reported on results of STI-571 treatment for a woman with a gastrointestinal stromal tumor that had recurred in her liver and abdomen with more than 28 tumors. Dramatically, after six months, the largest liver tumors had shrunk by 70 percent, six tumors vanished and no new ones were seen.

That one-person study led to two multi-center trials to see if STI-571's promise would hold true for other people with GIST. A grant from the drug's manufacturer, Novartis Pharmaceuticals, supported the study presented at ASCO. The second study, sponsored by the National Cancer Institute in collaboration with the Southwest Oncology Group and the Eastern Cooperative Oncology Group, is now open to GIST patients at Fox Chase with von Mehren as the principal investigator. von Mehren is the principal investigator for the ECOG study.

Researchers participating in the study presented at ASCO include Dr. George D. Demetri and Dr. David Tuveson, Dana-Farber Cancer Institute in Boston; Dr. Burton Eisenberg, Fox Chase Cancer Center; Dr. Heikki Joensuu, Helsinki University Central Hospital in Finland; Dr. Sasa Dimitrijevic, Novartis Oncology, Basel, Switzerland; Dr. Sandra L. Silberman, Novartis Oncology, East Hanover, N.J.; Dr. Charles D. Blanke, Dr. Brian J. Druker and Dr. Michael Heinrich, Oregon Health Sciences University in Portland; and Peter J. Roberts, University of Turku, Turku, Finland. Dr. Druker was a lead investigator for the previously reported studies of STI-571 in patients with chronic myeloid leukemia.

Fox Chase Cancer Center, one of the nation's first comprehensive cancer centers designated by the National Cancer Institute in 1974, conducts basic and clinical research; programs of prevention, detection and treatment of cancer; and community outreach. For more information about Fox Chase activities, visit the Center's web site at www.fccc.edu.


Fox Chase Cancer Center, part of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence four consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach.  For more information, call 1-888-FOX CHASE or (1-888-369-2427).

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