Chinese consensus on management of tyrosine kinase inhibitor-associated side effects in gastrointestinal stromal tumors

Table 1 The grade for the quality of evidence by the Grades of Recommendation Assessment, Development and Evaluation system

Final grade rank	Definition of grade rank
High	We are very confident that the effect of the study reflects the actual effect
Moderate	We are quite confident that the effect in the study is close to the true effect, but it is also possible that it is substantially different
Low	The true effect may differ significantly from the estimate
Very low	The true effect is likely to be substantially different from the estimated effect

Table 2 Summary of tyrosine kinase inhibitor-associated side effects

Side effects	Relative TKIs	Symptoms	Mechanisms	General management	TKIs - dose reduction or temporary discontinuation
Edema and fluid retention	Imatinib	Frequently in the periorbital area or lower limbs	Inhibiting PDGFR and decreasing the interstitial pressure	Limit salt intake or administer diuretics	Occasionally
Gastrointestinal adverse events	Imatinib, sunitinib, regorafenib	Nause, vomiting, and diarrhea	Inducing release of neurotransmitters, exciting the vagus nerves and sympathetic nerves	Antiemetic medications, Antidiarrhoeal medicine	Seldom
Skin rash	Imatinib, sunitinib	Erythematous and maculopapular lesions	Inhibiting of metabolic pathways mediated by tyrosine kinases	Topical lotions, antihistamines and steroids	Sometimes
Ophthalmological complications	Imatinib	Periorbital edema, epiphora, and hemorrhage in the conjunctiva	Inhibiting PDGFR and decreasing the interstitial pressure, conjunctival chemosis	Steroids and systemic diuretics	Not necessary
Hypertension	Sunitinib, regorafenib	Hypertension	Activating the endothelin axis and suppressing renin	ACEIs, ARAs	Sometimes
Hand-foot syndrome	Sunitinib, regorafenib	Bilateral palmar plantar erythema, skin peeling, and pain	Direct skin toxicity of TKIs, poor repair of small traumas due to VEGFR and PDGFR inhibition	Topical creams, keratolytic creams, emollients, analgesics	Often
Fatigue	Imatinib, sunitinib, regorafenib	Fatigue	5-HT3 neurotransmitter disorder, proinflammatory cytokine accumulation, neuromuscular function degradation	Exercise intervention, nutritional support	Seldom
Proteinuria	Sunitinib, regorafenib	24 h urinary protein increase	VEGF inhibition	ACEIs, ARAs	Sometimes
Stomatitis	Sunitinib, regorafenib	Pain, edema, erythema, ulcers, burning sensation	Blockade of the VEGFR signaling pathway	Oral care, analgesics	Sometimes
Cardiotoxicity	Sunitinib, regorafenib	Q-T interval prolongation, decreased LVEF, etc	AMPK and PDGFR inhibition	ACEIs, diuretics	Often
Hypothyroidism	Sunitinib	Clinical or subclinical hypothyroidism	Destruction of the thyroid gland, inhibiting thyroid peroxidase activity, decreasing the density of thyroid capillaries	Sodium levothyroxine	Don’t need
Hepatotoxicity and nephrotoxicity	Imatinib, sunitinib, regorafenib	Liver transaminase elevation, creatinine elevation	HBV reactivation, VEGF inhibition	Antiviral treatment, diammonium glycyrrhizinate	Sometimes
Hair disorder	Imatinib	Discoloration, trichomegaly, hypertrichosis, alopecia, etc.	Inhibition of kit pathway	No	Don’t need
Interstitial lung disease	Imatinib	fever of unknown origin, cough, dyspnea, hypoxemia	Hypersensitivity reaction, inhibition of PDGFR	Sufficient corticosteroids, antibiotics	Discontiuation permanently in most cases
Hematological side effects	Imatinib, sunitinib, regorafenib	Anemia, neutropenia, thrombocytopenia	Inhibiting KIT-expressing hematologic stem cells	Ferrous sulfate, folate, G-CSF, TPO	Sometimes

TKI: Tyrosine kinase inhibitor; PDGFR: Platelet-derived growth factor receptor; ACEI: Angiotensin-converting enzyme inhibitor; ARA: Angiotensin II receptor antagonist; VEGFR: Vascular endothelial growth factor receptor; 5-HT₃: 5-hydroxytryptamine; AMPK: 5' adenosine monophosphate-activated protein kinase; LVEF: Left ventricular ejection fraction; G-CSF: Granulocyte colony-stimulating factor; TPO: Thrombopoietin.