Practical management of tyrosine kinase inhibitor-associated side effects in GIST

Patients diagnosed with advanced gastrointestinal stromal tumor (GIST) are currently treated with oral tyrosine kinase inhibitors (TKIs). Imatinib mesylate is the standard first-line treatment, and sunitinib malate is administered second-line for patients who are intolerant or progress on imatinib. Imatinib has recently been approved for adjuvant treatment of GIST patients who have a significant risk for relapse. In both the metastatic and adjuvant settings, patients may be on these TKIs for many years. Low plasma imatinib levels have been reported to be associated with a short median time to progression of advanced GIST, stressing the importance of maintaining optimal drug levels. We summarize management of the most frequent and clinically significant adverse effects of imatinib and sunitinib in the treatment of GIST in the context of current guidelines, published literature, and the experience of three large GIST referral centers. The adverse events reviewed include nausea and vomiting, diarrhea, skin rash, musculoskeletal complaints, fatigue, hemorrhage, edema, hand-foot skin reaction, skin and hair discoloration, mucositis, hypertension, cardiac toxicity, hypothyroidism, liver transaminase changes, and hematological toxicity of imatinib and sunitinib. Potential drug-drug interactions with each respective agent are also discussed. With prudent use of supportive care measures, many side effects can be managed without dose reduction or interruption of treatment. On the other hand, individualized tailoring of the dose is often required to manage severe toxicity, such as painful hand-foot skin reactions, fatigue, hepatotoxicity, or cardiac toxicity. Management of many TKI-related adverse effects require further evaluation in prospective clinical trials.