| Aspect | Key Points |
|---|---|
| Definition | Most common mesenchymal tumor of the GI tract, arising from interstitial cells of Cajal (pacemaker cells of gut). |
| Epidemiology | Rare: ~1–2% of GI malignancies. Median age ~60s. Stomach most common site (60%), then small intestine (30%), colon/rectum, esophagus. |
| Pathophysiology / Molecular biology | – KIT mutations (~75–80%) → constitutive activation of KIT (CD117). – PDGFRA mutations (~5–10%), most common D842V (imatinib-resistant). – SDH-deficient, NTRK, BRAF, NF1: rarer subtypes. Pharmacist pearl: Mutation testing essential before therapy. |
| Presentation | GI bleeding, abdominal pain, palpable mass, incidental imaging finding. Metastases often to liver and peritoneum (rarely lymph nodes). |
| Diagnosis | – Histology: spindle cell (most common), epithelioid, or mixed. – Immunohistochemistry: CD117 (KIT+) and DOG1+. |
| Prognostic factors | Tumor size, mitotic index, site (gastric better than small bowel), and mutational status. |
| Localized disease | – Surgery is curative if resectable. – Adjuvant imatinib (400 mg PO daily) recommended for ≥3 years in high-risk disease (based on size, mitotic rate, site, and mutation). |
| Metastatic/Unresectable disease (standard sequence) | 1. Imatinib 400 mg daily (800 mg for KIT exon 9 mutation). 2. Sunitinib (50 mg daily, 4 weeks on/2 off, or continuous 37.5 mg) after imatinib progression or intolerance. 3. Regorafenib (160 mg daily, 3 weeks on/1 off). 4. Ripretinib (150 mg daily, continuous) after ≥3 prior TKIs. 5- Avapritinib (300 mg daily) for PDGFRA exon 18 mutations (esp. D842V), which are resistant to imatinib. |
| Other settings | – Neoadjuvant imatinib: to shrink borderline resectable tumors. – Lifelong TKI often needed in metastatic disease. |
| Pharmacist considerations | – Mutation testing drives therapy (KIT/PDGFRA). – Adherence to oral TKIs is critical for disease control. – CYP3A4 interactions common with all TKIs (azole antifungals, macrolides, anticonvulsants, etc.). – Toxicities & monitoring: <ul><li>Imatinib: edema, rash, GI upset, hepatotoxicity, cytopenias.</li><li>Sunitinib: HTN, hand-foot, hypothyroidism, cardiotoxicity, mucositis.</li><li>Regorafenib: hepatotoxicity, hand-foot skin reaction, HTN, diarrhea.</li><li>Ripretinib: alopecia, myalgia, fatigue, skin toxicity.</li><li>Avapritinib: cognitive effects, intracranial bleeding (monitor mental status).</li></ul> |
| Monitoring summary | – LFTs: all TKIs (esp. imatinib, regorafenib). – CBC: imatinib, avapritinib. – BP: sunitinib, regorafenib. – Ejection fraction / cardiac: sunitinib if risk factors. – Skin/hand-foot checks: regorafenib, ripretinib. – Neurocognitive assessment: avapritinib. |
Pharmacist Key Takeaways (BPS-level)
- Always confirm mutation status → imatinib standard unless PDGFRA D842V (use avapritinib).
- Treatment sequence matters: imatinib → sunitinib → regorafenib → ripretinib.
- Oral TKIs = long-term adherence + interaction management.
- Supportive care & monitoring differ by TKI:
- Imatinib → edema, cytopenias.
- Sunitinib → HTN, hypothyroid.
- Regorafenib → hepatotoxicity, HFSR.
- Ripretinib → alopecia, myalgia.
- Avapritinib → cognitive effects, bleeding.
Would you like me to make a side-by-side TKI comparison table (Imatinib, Sunitinib, Regorafenib, Ripretinib, Avapritinib) so you have a quick reference for mechanism, dosing, key toxicities, and monitoring?
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