Research Stretches Survival for GIST Patients

LAS VEGAS — Gastrointestinal stromal tumors, long an enigma, are revealing their secrets and their vulnerabilities in the face of revolutionary discoveries about their origins, speakers said at a multidisciplinary general session of the spring meeting of the American College of Surgeons.

Complete resection remains the initial treatment of choice for these often fatal tumors, but advances in their characterization and therapy are providing a more optimistic outlook for patients whose survival was once measured in months rather than years.

“These tumors were miscategorized for 20 years,” said Dr. Stanley W. Ashley, vice chairman of surgery at Brigham and Women's Hospital and professor of surgery at Harvard Medical School, Boston.

In the late 1990s, Japanese researchers discovered that approximately 75%–80% of gastrointestinal stromal tumors (GISTs) have mutations in the c-kit gene.

This advance meant that tumors previously classified as leiomyomas, leiomyosarcomas, and leiomyoblastomas could be correctly recognized as GISTs. Further study revealed that 5%–10% of GISTs have a closely related mutation in the PDGFRA gene, while approximately 12%–15% are unrelated to these mutations and therefore characterized as “wild type” or “wild card” GISTs.

GISTs are now recognized as the most common sarcomas of the gastrointestinal tract and account for an official 0.2% of GI malignancies, “but that's changing” as the incidence increases, Dr. Ashley said.

Autopsy studies suggest that small GISTs exist in much of the population, with triggering genetic mechanisms likely responsible for turning these benign, incidental lesions into the “bad actors” they can become.

An important therapeutic turning point was the approval in 2002 of imatinib (Gleevec) for unresectable and/or metastatic GISTs, which drove median survival rates for these patients from “at best, 19 months” to about 58 months, said Dr. Martin McCarter, associate professor of surgery at the University of Colorado, Denver.

Adding nuance to basic understanding, Dr. Christopher Corless, chief of surgical pathology at Oregon Health and Science University, Portland, and others have begun to further characterize mutations according to exons within the c-kit and PDGFRA genes.

“We've come to think of GIST not as a single, unique entity, [but] rather as a family of tumors broken down by type of kit mutation or type of receptor alpha mutation,” Dr. Corless said at the meeting.

Exon 11 mutations, for example, occur in GISTs seen throughout the GI tract and are quite sensitive to Gleevec, as are “wild type” tumors. Exon 9 mutations, however, occur only in tumors arising from the duodenum, jejunum, ileum, and right colon—”never in the stomach,” he said. They respond to Gleevec in standard doses in only about 35%–40% of cases, which suggests to some the need to increase the dosage given to patients with this mutation.

And exon 18 mutations in the PDGFRA gene, seen in tumors arising in the stomach and omentum, appear to be 100% resistant to Gleevec—at least in vivo—which makes these patients potential candidates for sunitinib, which has been approved for salvage therapy and is marketed as Sutent.

Dr. McCarter recommends that advanced tumors be biopsied, then treated with one of the tyrosine kinase inhibitors for 3–6 months. Surgery should be performed while the tumor is still responding. Selective resection may be considered if focal resistance to the drug is detected.

For patients with suspected GISTs small enough to be resected, biopsy should be skipped, suggested Dr. Ashley. The best tool for preoperative planning is the CT scan, although endoscopic ultrasound-guided fine-needle aspiration has been used in the upper GI tract.

Once macroscopic disease has been resected (with negative microscopic margins, if possible), size (greater or less than 2 cm for intestinal tumors, and greater than or less than 5 cm for stomach tumors) and mitotic count determine prognosis and risk of recurrence.

Although tyrosine kinase inhibitors are approved only for advanced disease, neoadjuvant therapy is recommended by some.

“If it's less than 5 cm, proceed with surgery,” opined Dr. Ashley, who added that although Gleevec has greatly improved survival for some patients, it is “no match for the response you get with surgery.”

Dr. McCarter advised prudence in discussing prognosis with patients who have unresectable or metastatic GISTs, despite the advances made in understanding these lesions.

“It's important to point out that cure is still unlikely for those with metastatic GIST,” he said. Significant differences in progression-free survival still mean that most patients can expect a “lifetime of chemotherapy.”

Almost all patients with unresectable disease develop new mutations during the course of their treatment, he said.

CT is the best preoperative planning tool for gastrointestinal stromal tumors, the most common sarcomas of the GI tract. Courtesy Dr. Martin McCarter

LAS VEGAS — Gastrointestinal stromal tumors, long an enigma, are revealing their secrets and their vulnerabilities in the face of revolutionary discoveries about their origins, speakers said at a multidisciplinary general session of the spring meeting of the American College of Surgeons.

Complete resection remains the initial treatment of choice for these often fatal tumors, but advances in their characterization and therapy are providing a more optimistic outlook for patients whose survival was once measured in months rather than years.

“These tumors were miscategorized for 20 years,” said Dr. Stanley W. Ashley, vice chairman of surgery at Brigham and Women's Hospital and professor of surgery at Harvard Medical School, Boston.

In the late 1990s, Japanese researchers discovered that approximately 75%–80% of gastrointestinal stromal tumors (GISTs) have mutations in the c-kit gene.

This advance meant that tumors previously classified as leiomyomas, leiomyosarcomas, and leiomyoblastomas could be correctly recognized as GISTs. Further study revealed that 5%–10% of GISTs have a closely related mutation in the PDGFRA gene, while approximately 12%–15% are unrelated to these mutations and therefore characterized as “wild type” or “wild card” GISTs.

GISTs are now recognized as the most common sarcomas of the gastrointestinal tract and account for an official 0.2% of GI malignancies, “but that's changing” as the incidence increases, Dr. Ashley said.

Autopsy studies suggest that small GISTs exist in much of the population, with triggering genetic mechanisms likely responsible for turning these benign, incidental lesions into the “bad actors” they can become.

An important therapeutic turning point was the approval in 2002 of imatinib (Gleevec) for unresectable and/or metastatic GISTs, which drove median survival rates for these patients from “at best, 19 months” to about 58 months, said Dr. Martin McCarter, associate professor of surgery at the University of Colorado, Denver.

Adding nuance to basic understanding, Dr. Christopher Corless, chief of surgical pathology at Oregon Health and Science University, Portland, and others have begun to further characterize mutations according to exons within the c-kit and PDGFRA genes.

“We've come to think of GIST not as a single, unique entity, [but] rather as a family of tumors broken down by type of kit mutation or type of receptor alpha mutation,” Dr. Corless said at the meeting.

Exon 11 mutations, for example, occur in GISTs seen throughout the GI tract and are quite sensitive to Gleevec, as are “wild type” tumors. Exon 9 mutations, however, occur only in tumors arising from the duodenum, jejunum, ileum, and right colon—”never in the stomach,” he said. They respond to Gleevec in standard doses in only about 35%–40% of cases, which suggests to some the need to increase the dosage given to patients with this mutation.

And exon 18 mutations in the PDGFRA gene, seen in tumors arising in the stomach and omentum, appear to be 100% resistant to Gleevec—at least in vivo—which makes these patients potential candidates for sunitinib, which has been approved for salvage therapy and is marketed as Sutent.

Dr. McCarter recommends that advanced tumors be biopsied, then treated with one of the tyrosine kinase inhibitors for 3–6 months. Surgery should be performed while the tumor is still responding. Selective resection may be considered if focal resistance to the drug is detected.

For patients with suspected GISTs small enough to be resected, biopsy should be skipped, suggested Dr. Ashley. The best tool for preoperative planning is the CT scan, although endoscopic ultrasound-guided fine-needle aspiration has been used in the upper GI tract.

Once macroscopic disease has been resected (with negative microscopic margins, if possible), size (greater or less than 2 cm for intestinal tumors, and greater than or less than 5 cm for stomach tumors) and mitotic count determine prognosis and risk of recurrence.

Although tyrosine kinase inhibitors are approved only for advanced disease, neoadjuvant therapy is recommended by some.

“If it's less than 5 cm, proceed with surgery,” opined Dr. Ashley, who added that although Gleevec has greatly improved survival for some patients, it is “no match for the response you get with surgery.”

Dr. McCarter advised prudence in discussing prognosis with patients who have unresectable or metastatic GISTs, despite the advances made in understanding these lesions.

“It's important to point out that cure is still unlikely for those with metastatic GIST,” he said. Significant differences in progression-free survival still mean that most patients can expect a “lifetime of chemotherapy.”

Almost all patients with unresectable disease develop new mutations during the course of their treatment, he said.

CT is the best preoperative planning tool for gastrointestinal stromal tumors, the most common sarcomas of the GI tract. Courtesy Dr. Martin McCarter

LAS VEGAS — Gastrointestinal stromal tumors, long an enigma, are revealing their secrets and their vulnerabilities in the face of revolutionary discoveries about their origins, speakers said at a multidisciplinary general session of the spring meeting of the American College of Surgeons.

Complete resection remains the initial treatment of choice for these often fatal tumors, but advances in their characterization and therapy are providing a more optimistic outlook for patients whose survival was once measured in months rather than years.

“These tumors were miscategorized for 20 years,” said Dr. Stanley W. Ashley, vice chairman of surgery at Brigham and Women's Hospital and professor of surgery at Harvard Medical School, Boston.

In the late 1990s, Japanese researchers discovered that approximately 75%–80% of gastrointestinal stromal tumors (GISTs) have mutations in the c-kit gene.

This advance meant that tumors previously classified as leiomyomas, leiomyosarcomas, and leiomyoblastomas could be correctly recognized as GISTs. Further study revealed that 5%–10% of GISTs have a closely related mutation in the PDGFRA gene, while approximately 12%–15% are unrelated to these mutations and therefore characterized as “wild type” or “wild card” GISTs.

GISTs are now recognized as the most common sarcomas of the gastrointestinal tract and account for an official 0.2% of GI malignancies, “but that's changing” as the incidence increases, Dr. Ashley said.

Autopsy studies suggest that small GISTs exist in much of the population, with triggering genetic mechanisms likely responsible for turning these benign, incidental lesions into the “bad actors” they can become.

An important therapeutic turning point was the approval in 2002 of imatinib (Gleevec) for unresectable and/or metastatic GISTs, which drove median survival rates for these patients from “at best, 19 months” to about 58 months, said Dr. Martin McCarter, associate professor of surgery at the University of Colorado, Denver.

Adding nuance to basic understanding, Dr. Christopher Corless, chief of surgical pathology at Oregon Health and Science University, Portland, and others have begun to further characterize mutations according to exons within the c-kit and PDGFRA genes.

“We've come to think of GIST not as a single, unique entity, [but] rather as a family of tumors broken down by type of kit mutation or type of receptor alpha mutation,” Dr. Corless said at the meeting.

Exon 11 mutations, for example, occur in GISTs seen throughout the GI tract and are quite sensitive to Gleevec, as are “wild type” tumors. Exon 9 mutations, however, occur only in tumors arising from the duodenum, jejunum, ileum, and right colon—”never in the stomach,” he said. They respond to Gleevec in standard doses in only about 35%–40% of cases, which suggests to some the need to increase the dosage given to patients with this mutation.

And exon 18 mutations in the PDGFRA gene, seen in tumors arising in the stomach and omentum, appear to be 100% resistant to Gleevec—at least in vivo—which makes these patients potential candidates for sunitinib, which has been approved for salvage therapy and is marketed as Sutent.

Dr. McCarter recommends that advanced tumors be biopsied, then treated with one of the tyrosine kinase inhibitors for 3–6 months. Surgery should be performed while the tumor is still responding. Selective resection may be considered if focal resistance to the drug is detected.

For patients with suspected GISTs small enough to be resected, biopsy should be skipped, suggested Dr. Ashley. The best tool for preoperative planning is the CT scan, although endoscopic ultrasound-guided fine-needle aspiration has been used in the upper GI tract.

Once macroscopic disease has been resected (with negative microscopic margins, if possible), size (greater or less than 2 cm for intestinal tumors, and greater than or less than 5 cm for stomach tumors) and mitotic count determine prognosis and risk of recurrence.

Although tyrosine kinase inhibitors are approved only for advanced disease, neoadjuvant therapy is recommended by some.

“If it's less than 5 cm, proceed with surgery,” opined Dr. Ashley, who added that although Gleevec has greatly improved survival for some patients, it is “no match for the response you get with surgery.”

Dr. McCarter advised prudence in discussing prognosis with patients who have unresectable or metastatic GISTs, despite the advances made in understanding these lesions.

“It's important to point out that cure is still unlikely for those with metastatic GIST,” he said. Significant differences in progression-free survival still mean that most patients can expect a “lifetime of chemotherapy.”

Almost all patients with unresectable disease develop new mutations during the course of their treatment, he said.

CT is the best preoperative planning tool for gastrointestinal stromal tumors, the most common sarcomas of the GI tract. Courtesy Dr. Martin McCarter