NCCN GIST GUIDELINESS

March 23, 2010 (Hollywood, Florida) — Whether or not to delay the use of imatinib mesylate (Gleevec, Novartis) in patients with localized gastrointestinal stromal tumors (GIST) after complete resection is a "$64 million question," said the chair of the National Comprehensive Cancer Network (NCCN) panel on soft-tissue sarcomas.

In a presentation here at the NCCN 15th Annual Conference, George Demetri, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, reviewed a wide variety of changes related to the GIST algorithm in the NCCN's soft-tissue sarcoma guideline.

The changes range from new guidance about managing small gastric GISTs (<2>

There is also new guidance about the use of imatinib.

In patients with primary localized disease and tumors larger than 3 cm, adjuvant therapy with imatinib "for at least 12 months should be considered in patients with intermediate- to high-risk GIST," said Dr. Demetri, reading from a new footnote in the guideline. The new guidance also notes that "the optimal duration [of imatinib] has not yet been determined. Patients at significantly higher risk for disease recurrence may justify a longer course of therapy."

However, Dr. Demetri also pointed out that "these tumors are generally not cured after 1 year of therapy."

Later in the session, an audience member reminded Dr. Demetri of his comment about imatinib not being curative. "If it's not curative, why not wait to see who recurs and give it then?" asked a young oncologist.

"That's a $64 million question," declared Dr. Demetri.

Imatinib has been shown to improve recurrence-free survival in resected patients and is approved by the US Food and Drug Administration (FDA) for the prevention of postoperative recurrence. However, it is not currently known whether adjuvant therapy improves overall survival when given immediately after surgery. Imatinib is also approved for use in the first-line treatment of metastatic GIST.

The NCCN also now advises clinicians to consider preoperative imatinib in localized or potentially resectable GIST "if surgical morbidity would be improved by reducing the size of the tumor."

Very Small Gastric GIST and Other Changes

The NCCN now has a new page in the soft-tissue sarcoma guideline on "very small gastric GISTs" (<2>

"We see a lot of GIST that is tiny," said Dr. Demetri, who called these tumors a "different bird" from the large-sized tumors.

If endoscopic ultrasound reveals high-risk features, such as irregular border, cystic spaces, ulceration, echogenic foci, and heterogeneity, then surgical resection is advised. If not, the guideline says, "consider endoscopic surveillance."

For patients with larger suspected GISTs and potentially resectable disease, expert pathology review after surgery is very important, he added.

"I can think of very few tumors in which pathological evaluation is so important," he continued.

The review must include the "careful and time-consuming" assessment of mitoses and molecular genetic testing, including mutation analysis for KIT and PDGFRA genes.

"Tumor size and mitotic rate are used as guides to predict the malignant potential of GISTs, although it is notoriously difficult to predict the biologic potential of individual cases," states the guideline.

Overall, the pathologic review has "important ramifications for prognosis and possibly treatment," said Dr. Demetri.

Patients with KIT exon 9 mutations might benefit from receiving a "high dose" of imatinib, said Dr. Demetri. The recommendation is based on a recent study reported by Medscape Oncology.

For GIST that is unresectable, recurrent, or metastatic, the new guideline no longer recommends positron emission tomography (PET)-computed tomography (CT) within 3 months of initiating imatinib to monitor the effect of therapy. Instead, CT alone is recommended, with PET as an option if CT results are "ambiguous."

Update on Soft-Tissue Sarcomas

Another "important revision" to the soft-tissue sarcoma guideline is that there has been a "comprehensive update of new molecular pathology discoveries, with clinical relevance for diagnosis and therapy," said Dr. Demetri.

For the NCCN, soft-tissue sarcomas do not include those of the uterus or bone, or dermatofibrosarcoma or pediatric sarcomas. Instead, the guideline is limited to sarcomas of the soft-tissue extremity/trunk and retroperitoneal/abdominal, GIST, and desmoid tumors. Morphologic diagnosis based on microscopic examination of histologic sections remains the gold standard for sarcoma diagnosis, according to the guideline. However, several ancillary techniques are useful in support of morphologic diagnosis, including immunohistochemistry, and cytogenetic and molecular genetic testing.

Dr. Demetri highlighted the potential of a number molecular markers in identifying sarcomas.

There is also a "major ongoing project to continually improve the NCCN guideline for soft-tissue sarcomas" that is related to expanding treatment options for the tumors, said Dr. Demetri.

Currently, there are only 2 chemotherapies approved for use in all sarcomas and only 1 therapy (imatinib) for use in GIST, he noted.

The NCCN is maintaining a comprehensive listing of possible therapeutic options for sarcoma patients using therapeutic agents approved by the FDA for some other indication, but which have potential efficacy in various sarcomas.

The list is based on published literature and academic public presentations, said Dr. Demetri.

Dr. Demetri reports being a consultant to Ariad, Novartis, Pfizer, Genentech, Daiichi-Sankyo, Johnson & Johnson, Kolltan, Plexxikon, and ZioPharm.

National Comprehensive Cancer Network (NCCN) 15th Annual Conference: Presented March 12, 2010.