Newly Diagnosed With GIST: First Steps

This is the first thing to get straight. A gastrointestinal stromal tumor arises from the interstitial cells of Cajal, or their stem cell-like precursors. Those are the pacemaker cells that set the rhythm of the gut wall. It is a sarcoma, not a carcinoma.

The practical consequence is blunt. NCI states that efforts to treat GISTs with conventional cytotoxic chemotherapy were essentially futile. Radiation is rarely used, mostly for symptom relief.

GIST is uncommon. NCI reports over 6,000 new US cases a year, an age-adjusted rate of 6.78 per million over 2001 to 2011. Median age at diagnosis is 65 to 69.

Where they arise, using the approximate distribution the AJCC Cancer Staging Manual gives and NCI reproduces:

• Stomach, 60%.
• Jejunum and ileum, 30%.
• Duodenum, 5%.
• Rectum, 3%.
• Colon, 1%.
• Esophagus, under 1%.

Immunohistochemistry. CD117, the KIT antigen, is positive in about 95% of GISTs. DOG1 is the second stain, and NCI notes it helps separate GIST from other mesenchymal tumors, especially the KIT-negative ones.

Mutation testing. About 85% of GISTs carry a driver change in KIT or PDGFRA. NCI breaks it down:

• KIT overall, 80% of GISTs. Exon 11 accounts for 67%, exon 9 for 10%, and exons 8, 13, and 17 together for 3%.
• PDGFRA, 5% to 8% of GISTs. Exon 18 covers 80% to 90% of those.
• Wild-type GIST, 12% to 15%. This includes SDH-deficient tumors, tumors linked to neurofibromatosis type 1, and others driven by BRAF V600E or NTRK.

This is the single most consequential fact on the page.

Within PDGFRA exon 18 sits the D842V variant, which NCI reports in 62% of PDGFRA-mutant GISTs. It confers resistance to imatinib. NCI states that avapritinib is used as first-line therapy in D842V disease instead.

The exon number also changes dosing. NCI notes that patients with KIT exon 9 variants may benefit from higher-dose imatinib, 800 mg per day rather than the standard 400 mg. It is a decision your oncologist makes from the mutation report and how well you tolerate the drug, so raise it with them rather than changing how many tablets you take.

And it can rule the drug out. NCI states that KIT wild-type tumors and PDGFRA D842V tumors are unlikely to benefit from adjuvant imatinib.

So ask one question before any drug starts: has my tumor been sequenced, and which exon is involved?

Not from a stage number. NCI's prognostic factors are mitotic index, tumor size, tumor location, tumor rupture, and imaging features. Mitotic index is counted as mitoses per 50 high-power fields, which measures how fast cells are dividing.

Location alone shifts the odds. NCI reports that 20% to 25% of gastric GISTs behave aggressively, against 40% to 50% of small intestinal GISTs.

The size-and-mitosis grid makes it concrete. For gastric GISTs with 5 or fewer mitoses per 50 high-power fields, the metastasis rate runs 0% at 2 cm or less, 1.9% above 2 up to 5 cm, 3.6% above 5 up to 10 cm, and 12% above 10 cm.

Change the mitotic rate and the picture changes completely. For gastric GISTs above 5 mitoses per 50 high-power fields, the rate is 16% at 2 to 5 cm, 55% at 5 to 10 cm, and 86% above 10 cm.

Non-gastric tumors are worse at every size. A small intestinal GIST of 2 cm or less with a high mitotic count carries a 50% to 54% risk.

Between 10% and 25% of patients already have metastatic disease at diagnosis.

The goal is complete removal with the pseudocapsule intact and clear microscopic margins. NCI states that wide excision is not necessary, because these tumors are encapsulated. Lymph node removal is generally unnecessary, except in SDH-deficient GIST with enlarged nodes.

NCI reports that laparoscopic surgery shows lower recurrence rates, shorter hospital stays, and lower complication rates.

The thing to avoid is rupture. NCI notes that tumor rupture during surgery markedly worsens recurrence-free survival. If your operative report mentions rupture or spillage, that changes the treatment discussion afterward.

NCI describes endoscopic surveillance as an option for tumors 2 cm or smaller with a mitotic index of 5 or fewer per 50 high-power fields.

If watching is offered, ask what the surveillance interval is and what change would trigger surgery.

Three phase III trials define this, and the duration question was settled by the third.

ACOSOG Z9001 randomized 713 patients with KIT-positive GISTs of 3 cm or larger to imatinib 400 mg daily or placebo for 1 year. One-year recurrence-free survival was 98% against 83%, hazard ratio 0.35. Overall survival did not differ.

EORTC-62024 gave 908 intermediate or high-risk patients 2 years of imatinib or observation. Five-year recurrence-free survival was 69% against 63%. Five-year overall survival was 91.8% against 92.7%, essentially identical.

SSG XVIII compared 1 year against 3 years of imatinib in 400 high-risk patients. At a median of 54 months, recurrence-free survival was 65.6% with 3 years against 47.9% with 1 year, hazard ratio 0.46. Five-year overall survival was 92% against 81.7%, hazard ratio 0.45. In the KIT exon 11 subgroup, 5-year recurrence-free survival was 71.0% against 41.3%.

NCI states that at least 3 years of therapy is generally used in practice. Grade 3 or 4 side effects occurred in 32.8% on the 3-year arm and 20.1% on the 1-year arm, so the cost is real. Trial protocols set one strength for everyone; your own prescription may differ, so take what the label on your bottle says.

NCI describes neoadjuvant imatinib for large tumors, or tumors in hard-to-reach places, that are only marginally removable. Significant shrinkage is often seen.

NCI recommends sequencing before this starts, so a resistant variant is not treated with a drug that will not work.

For resected moderate or high-risk disease, NCI describes abdominal and pelvic imaging every 3 to 6 months.

The quirk is worth knowing. NCI notes that PET imaging can detect imatinib activity much earlier than CT, with reduced tumor avidity seen as soon as 24 hours after the first dose. A GIST that is responding may not look smaller for months, but it can look less active almost immediately.

Call 911 for:

• Vomiting blood, or black tarry stools.
• Sudden severe abdominal pain, or a rigid, tender abdomen.
• Vomiting with no passage of gas or stool, which can mean obstruction.
• Fainting, or a racing heartbeat with weakness.

These can mean a bleed or a perforation. Do not drive yourself, and do not wait for a call back.

Call 911 or get to an emergency department straight away for:

• A temperature of 100.4 °F (38 °C) or higher during cancer treatment, the threshold CDC gives. Fever on chemotherapy is treated as an emergency, not as something to raise at the next appointment.

Call the treating team the same day for:

• New leg swelling, or swelling around the eyes on imatinib.
• Vomiting that stops you keeping the tablet down.

• Was my tumor sequenced, and which gene and exon are involved?
• What is my mitotic count per 50 high-power fields, and my tumor size?
• Was the tumor ruptured during surgery?
• Am I high-risk enough for adjuvant imatinib, and for how many years?
• If imatinib is planned, is 400 mg or 800 mg right for my exon?
• Is there a sarcoma center nearby that sees GIST regularly?

Soft Tissue Sarcoma covers the wider family. Biomarker Testing and Precision Medicine explains the sequencing above. Getting a Second Opinion matters in a tumor this uncommon.

• NCI PDQ — Gastrointestinal Stromal Tumors Treatment (Health Professional Version)
• National Cancer Institute — Infection and Neutropenia during Cancer Treatment