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



# Introduction
Tyrosine kinase inhibitors (TKIs), such as imatinib, suni tinib, and regorafenib, have significantly improved the overall survival of patients with gastrointestinal stromal tumors (GISTs). Their widespread use in clinical practice has provided evidence and experience from which we now may gain practical insight on further improving TKI efficacy and safety.
Maintaining continued drug administration at a suffi cient dose is crucial for good efficacy. For GIST patients undergoing TKI therapy, the management of TKIasso ciated side effects is equally important. Fortunately, the symptoms of TKIassociated side effects are unique and can be exploited in the design of more effective and safe management protocols. The Chinese Society of Surgeons for Gastrointestinal Stromal Tumor of the Chinese Medical Doctor Association organized an expert panel discussion involving GISTtreating clinical doctors representing the various systemic components affected in our patient population including doctors from gastrointestinal sur gery, medical oncology, cardiology, dermatology, neph rology, endocrinology, and ophthalmology. All treatment recommendations in this article are graded according to the Grades of Recommendation Assessment, Devel opment and Evaluation (GRADE) system, which is widely accepted to make evidencebased recommendations [bib_ref] GRADE guidelines: 3. Rating the quality of evidence, Balshem [/bib_ref]. The final grade for the quality of evidence by the GRADE system is in .
This consensus guideline is intended to provide evi dence and experiencebased expert recommendations on the management of TKIassociated side effects in GIST patients, in order to improve the efficacy and safety of TKI therapy. All the TKIsassociated side effects are summarized in .

## Tki-associated side effects

## Edema and fluid retention
Edema is one of the most common adverse events (AEs) experienced by GIST patients undergoing TKI therapy. For imatinib, in particular, edema reportedly affects 74.1% of patients [bib_ref] Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors, Demetri [/bib_ref] ; in contrast, edema is rare and usually mild in patients receiving sunitinib. The TKI induced condition, in general, presents most frequently in the periorbital area or lower limbs.
Although there are reports of controlling the periorbital edema by limiting salt intake or administering topical phenylephrine or diuretics [bib_ref] Practical management of patients with chronic myeloid leukemia receiving imatinib, Deininger [/bib_ref] (GRADE moderate), most cases of periorbital edema require no specific treatments. For patients with mild generalized or peripheral edema, it is important to perform regular weighing and monitoring to detect any event of unexpected weight gain or serious fluid retention [bib_ref] Practical management of tyrosine kinase inhibitor-associated side effects in GIST, Joensuu [/bib_ref] (GRADE moderate). Patients with more than a 3kg weight gain in 1 wk should be counseled to reduce salt intake (GRADE low). When supportive measures result in control of symptoms, reducing the dose of imatinib is not necessary (GRADE moderate). Development of severe fluid retention, including pul monary edema, pleural or pericardial effusion, and as cites or rapid weight gain, warrants prompt initiation or increased dose of a diuretic (GRADE moderate), although the risk of instigating electrolyte depletion necessitates a careful implementation of this approach. Regardless, imatinib should be discontinued in cases of severe fluid retention, and can be restarted once the edema is under control; diuretic therapy should be maintained through out [bib_ref] Indications for imatinib mesylate therapy and clinical management, Guilhot [/bib_ref] (GRADE moderate).
Fluid retention may aggravate or cause heart failure. Patients with past histories of cardiac disease, cardiac failure, or renal impairment and associated risk factors should be monitored closely (GRADE moderate). Timely assessment will help to ensure initiation of proper treat ments for patients as they present symptoms and signs of cardiac and/or renal failure (GRADE moderate).

## Gastrointestinal aes
Nausea and vomiting are the most common early AEs presenting in GIST patients treated with imatinib, suni tinib, or regorafenib [bib_ref] Efficacy evaluation of imatinib in the treatment of patients with gastrointestinal stromal..., Zong [/bib_ref]. The nausea and vomiting are often related, and most cases are reported as mild or moderate (grades 12). These AEs may be caused by the drugs' ability to induce release of neurotransmitters from the gastrointestinal tract and chromaffin cells, exciting the vagus nerves and sympathetic nerves and stimulating the vomiting center.
A prospective study of TKItreated GIST patients reported in the literature identified vomiting as a remar kably common AE. Imatinibtreated GIST patients have a reported incidence of nausea at 52.4% (1.4% representing grades 34) and of vomiting at 12.9% (0.7% representing grades 34) [bib_ref] Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors, Demetri [/bib_ref]. For regorafenib, the reported nausea incidence is 16% (1% representing grades 34) [bib_ref] GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal..., Demetri [/bib_ref] ; and, for sunitinib, the reported nausea incidence is 24% (1% representing grades 34) and vomiting in cidence is 16% (1% representing grades 34) [bib_ref] Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour..., Demetri [/bib_ref].
No special treatments are required when nausea and vomiting are mild or moderate. Dietary adjustment (GRADE moderate), however, can be used. In such cases, patients are advised to take a light diet consisting of acidic foods, fruit juices, etc., and to avoid eating sweet and greasy foods (GRADE moderate). If the AEs are grade 3 or 4, reducing dosage or suspending the drug administration is required. In such cases, more severe nausea and vomiting can be controlled effectively with antiemetic medications (GRADE high), such as metoclopramide, chlorpromazine, 5hydroxytryptamine (5HT3) receptor blockers, and dexamethasone, among others. The TKI treatment can be reinstituted when the symptoms improve to grade 1.
Diarrhea is another common gastrointestinal side effect of the TKIs. While this AE is known to be dose dependent, its underlying mechanisms remain to be fully elucidated [bib_ref] A safety evaluation of imatinib mesylate in the treatment of gastrointestinal stromal..., Ben Ami [/bib_ref]. The reported occurrence rate of diar rhea in patients treated with imatinib is 44.9% (2% representing grades 34) [bib_ref] Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors, Demetri [/bib_ref] , with regorafenib is 40% (5% representing grade 3) [bib_ref] GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal..., Demetri [/bib_ref] , and with sunitinib is 29% (3% representing grades 34) [bib_ref] Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour..., Demetri [/bib_ref]. For mild to moderate diarrhea (grades 12), the drug dose does not need to be reduced but dietary adjustment is required. Patients are recommended a light, easily digestible, vitaminrich, low fiber, highprotein diet, avoiding cold, spicy, and greasy foods (GRADE moderate).
In general, probiotics can be given occasionally to adjust the intestinal flora (GRADE moderate). For those patients whose diarrhea symptoms cannot be controlled or exacerbate, the TKI treatment should be suspended, and the patients should be given probiotics, berberine, montmorillonite, loperamide hydrochloride, and fluid and electrolyte support (GRADE high). The TKI treatment can be reinstituted when the symptoms improve to grade 1. At this point, the initial dosage can be reduced, if necessary.

## Skin rash
Skin rash reportedly occurs in approximately 15% of GIST patients treated with sunitinib, presenting as mild symptoms; in contrast, up to 35% of GIST patients treated with imatinib experience skin rash (approximately 10% representing grades 34) [bib_ref] Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial, Verweij [/bib_ref]. For patiens taking imatinib, the likelihood of developing skin rash increases with increased 800 mg/d dose having a reported rash December 14, 2018|Volume 24|Issue 46| WJG|https://www.wjgnet.com

## 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 The grade for the quality of evidence by the Grades of Recommendation Assessment, Development and Evaluation system presents as erythematous and maculopapular lesions and may occur at any point throughout the treatment administration, but often occurs during the first week.
The forearms or trunk are often affected, and may show pruritic and desquamated skin [bib_ref] Practical management of patients with chronic myeloid leukemia receiving imatinib, Deininger [/bib_ref]. The skin rash may also be more common in female patients [bib_ref] Adverse cutaneous reactions to imatinib (STI571) in Philadelphia chromosome-positive leukemias: a prospective..., Valeyrie [/bib_ref]. Severe cases may rarely lead to toxic epidermal necrolysis or Stevens Johnson syndrome [bib_ref] Practical management of patients with chronic myeloid leukemia receiving imatinib, Deininger [/bib_ref]. The most common sunitinibrelated skin AE is dry skin (xerosis), reported in up to 16% of the treated GIST incidence of 46.6% [bib_ref] Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial, Verweij [/bib_ref]. While the underlying mechanism of these cutaneous reaction remains unclear, the high prevalence and dose dependence (of imatinib) suggest an association with a pharmacologic effect rather than a patient's hyper sensitivity. Inhibition of various metabolic pathways mediated by tyrosine kinases, such as ckit and platelet derived growth factor receptor (PDGFR), could be involved in the pathophysiology of the adverse skin reactions [bib_ref] Adverse cutaneous reactions to imatinib (STI571) in Philadelphia chromosome-positive leukemias: a prospective..., Valeyrie [/bib_ref]. Imatinibinduced skin rash commonly patients. The less frequent events of sunitinibinduced rash can present as inflammatory follicular papules on the face and/or the trunk, or as a seborrheic dermatitis like eruption similar to those associated with epidermal growth factor receptor (EGFR) inhibitors, but milder [bib_ref] Dermatological reactions to the multitargeted tyrosine kinase inhibitor sunitinib, Rosenbaum [/bib_ref]. Rough or dry skin can be managed with observation (without treatment) or with treatment using topical lotions (GRADE moderate). In imatinib patients with mild to moderate rash, symptoms can be relieved with antihistamines and topical lotions. Steroids can be applied in patients with an inadequate response [bib_ref] Practical management of patients with chronic myeloid leukemia receiving imatinib, Deininger [/bib_ref] (GRADE moderate). For recurrent grade 3 skin rash, dose inter ruption or reductions of imatinib should be required, along with oral steroid treatment, until the symptoms subside (GRADE high). The imatinib reinstitution should be initiated at low dosage. In those rare patients who experience severe skin reactions (e.g., StevensJohnson syndrome), the imatinib administration should be inter rupted (GRADE high). These patients can be treated with prednisone (starting at 1 mg/kg and tapering up to 20 mg/d, as needed), and the imatinib can be gradually reintroduced in the absence of alternative treatment options [bib_ref] Practical management of patients with chronic myeloid leukemia receiving imatinib, Deininger [/bib_ref] (GRADE moderate).
It is worth noting that after reinstitution of an inter rupted TKI drug, the patient may again develop a rash. A few patients will have drug hypersensitivity syndrome, exfoliative dermatitis, and bullous epidermolysis, possibly to a lifethreatening extent, and need extramedical attention.

## Ophthalmological complications
Periorbital edema is the most common ocular side effect associated with imatinib, reported in up to 70% of trea ted GIST patients [bib_ref] Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors, Demetri [/bib_ref]. Dermal dendrocytes found in the periocular soft tissue express the tyrosine kinases ckit and PDGFR. Through the inhibition of PDGFR, imatinib may decrease the interstitial pressure and increase transcapillary transport, causing edema [bib_ref] Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary..., Pietras [/bib_ref] [bib_ref] Severe periorbital edema secondary to STI571 (Gleevec), Esmaeli [/bib_ref]. Epiphora occurs in nearly 20% of imatinibtreated GIST patients, representing the second most common ocular side effect of this drug [bib_ref] Ocular side-effects associated with imatinib mesylate (Gleevec), Fraunfelder [/bib_ref]. Postulated mechanisms for epiphora include conjunctival chemosis resulting in ocular surface irritation and the overproduction of tears, lacrimal pump dysfunction due to periorbital edema, blockage of the puncta by conjunctival chalasis, and secretion of the medication in the tear film [bib_ref] The ophthalmological complications of targeted agents in cancer therapy: what do we..., Ho [/bib_ref]. Hemor rhage in the conjunctiva reportedly affects up to 11% of imatinibtreated GIST patients and occurs in the absence of marrow suppression or in those with systemic bleeding tendency [bib_ref] Human conjunctival mast cells: expression of Fc epsilonRI, c-kit, ICAM-1, and IgE, Stahl [/bib_ref] [bib_ref] Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of..., Qiu [/bib_ref]. Genetic polymorphisms of EGFR, SLC22A1, SLC22A5, and ABCB1 may influence the imatinibinduced periorbital edema and conjunctival hemorrhage [bib_ref] Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of..., Qiu [/bib_ref]. Sightthreatening complications affecting the optic nerve, macula, and retina are uncommon but do occur with imatinib. Imatinib has been shown to compromise the survival of retinal ganglion cells in vitro, via the inhibition of the PDGFR signaling pathway [bib_ref] Imatinib induces apoptosis by inhibiting PDGF-but not insulin-induced PI 3-kinase/Akt survival signaling..., Biswas [/bib_ref]. Other rare ophthalmological complications of imatinib include optic disc edema and optic nerve dysfunction, recurrent optic neuritis, cystoid macular edema, and retinal edema .
Most of the reported cases of periorbital edema and epiphora improve with topical steroids and systemic diuretics [bib_ref] Ocular side effects associated with imatinib mesylate and perifosine for gastrointestinal stromal..., Dogan [/bib_ref] (GRADE moderate). Surgical procedures, in the form of debulking excessive skin, fat, and edema, are required occasionally to resolve blurring eyesight resulting from periorbital swelling [bib_ref] Periorbital edema secondary to imatinib mesylate, Mcclelland [/bib_ref] (GRADE low). For conjunctival hemorrhage, most cases spontaneously recover or improve with topical steroids [bib_ref] Conjunctival hemorrhagic events associated with imatinib mesylate, Radaelli [/bib_ref] (GRADE mode rate). Disc edema and optic nerve dysfunction regress after cessation of the medication [bib_ref] Imatinib induces apoptosis by inhibiting PDGF-but not insulin-induced PI 3-kinase/Akt survival signaling..., Biswas [/bib_ref] (GRADE moderate).
Macular edema and retinal edema subside with cessation of the medication, and optic neuritis improves with sys temic steroids [bib_ref] Optic disc edema as a possible complication of Imatinib mesylate (Gleevec), Kwon [/bib_ref] (GRADE moderate).

## Hypertension
Hypertension affects 11% or more of sunitinibtrea ted GIST patients (approximately 3% representing grades 34), whereas it occurs rarely during imatinib treatment [bib_ref] Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour..., Demetri [/bib_ref] [bib_ref] Angiogenesis factors and preeclampsia, Dechend [/bib_ref]. Meanwhile, the incidence of sunitinib induced hypertension in the Chinese GIST population is high, up to 28.8%; however, more severe cases, grades 34, remain low, at 3.4% [bib_ref] Clinical evaluation of continuous daily dosing of sunitinib malate in patients with..., George [/bib_ref]. Several mechanisms of sunitinibinduced hypertension have been identified, and these include activation of the endothelin axis, suppres sion of renin, decreased glomerular filtration rate, and increased sodium and water retention by the kidney . Baseline blood pressure should be recorded before sunitinib therapy. The blood pressure monitoring is re commended to occur on a daily schedule during the sunitinib treatment, especially in the early period of treatment or for patients with a history of hypertension. In any case, hypertension management should involve antihypertensive agents, with a goal of achieving either normal blood pressure or grade 1 blood pressure (< 130/80 mmHg). Use of vasodilatory antihypertensive agents such as angiotensinconverting enzyme inhibitors (ACEIs, and including captopril, enalapril, benazepril, and gilazapril) as well as angiotensin II receptor antagonists (ARAs, and including losartan potassium, valsartan, irbesartan, and telmisartan) are suggested for control of vascular endothelial growth factor receptor (VEGFR) inhibitorassociated hypertension of grade 2 or higher. Since some calcium channel blockers, such as diltiazem, verapamil, nitrendipine, and nifedipine, will increase suni tinib blood concentration (by inhibiting CYP450 3A4) or cause PR interval prolongation, they are not suggested for controlling high blood pressure caused by sunitinib or regorafenib [bib_ref] Angiogenesis inhibitors and hypertension: an emerging issue, Sica [/bib_ref] (GRADE high).
Generally, management of hypertension does not need dose reduction or interruption of sunitinib. In cases of severe hypertension (systolic blood pressure > 200 mmHg or diastolic blood pressure > 110 mmHg), sunitinib therapy should be temporarily ceased until the hypertension is under control (GRADE moderate).

## Hand-foot syndrome
The AE of handfoot syndrome (HFS) can occur during sunitinib or regorafenib treatment, but has seldom been reported in GIST patients undergoing imatinib therapy. HFS rates for the first two drugs are 13.5%25% for sunitinib and 56% for regorafenib at 4 wk into the TKI treatment administration [bib_ref] GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal..., Demetri [/bib_ref] [bib_ref] Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour..., Demetri [/bib_ref] , and it is one of the most frequent reasons for dose reduction of these TKIs. The main manifestations of TKIinduced HFS include bilateral palmarplantar erythema accompanying dysesthesia, skin peeling, and pain (which can lead to dysfunction in daily activities and walking); moreover, a localized skin hyperkeratosis, especially at plantar site, may develop accompanied by callous [bib_ref] Dermatological reactions to the multitargeted tyrosine kinase inhibitor sunitinib, Rosenbaum [/bib_ref].
The mechanism underlying TKIinduced HFS is not clear. HFS occurs in skin sites rich in eccrine glands, such as the palms and soles, due to a portion of the TKI being excreted in sweat. Two hypotheses proposed to explain the handfoot skin reaction include direct skin toxicity of TKIs in general, and poor repair of repeated small traumas in hands and feet due to VEGFR and PDGFR inhibiting activity of sunitinib in particular [bib_ref] Practical management of tyrosine kinase inhibitor-associated side effects in GIST, Joensuu [/bib_ref]. Patient education is the first step of HFS manage ment. Patients need to be able to recognize the clinical symptoms of HFS before receiving TKI treatment, to facilitate treatment at the earliest stage possible. Topical creams, keratolytic creams, or emollients can be useful to decrease HFSrelated keratosis. Sufferers of TKIinduced HFS should be encouraged to use pressureabsorbing insoles and comfortable shoes or gloves when performing various activities. Analgesics may also be necessary to control HFSrelated pain, until symptoms subside [bib_ref] Sunitinib malate in the treatment of renal cell carcinoma and gastrointestinal stromal..., Desai [/bib_ref] (GRADE moderate). Administration of recombinant hu man fibroblast growth factor and/or recombinant human epidermal growth factor can help the recovery of skin da mage (GRADE low).
In cases of grade 2 or 3 HFS, the TKI treatment should be temporarily interrupted. In severe cases of HFS, the TKI dosage must be reduced permanently. A study of HFS, sunitinib, and dosage showed an asso ciation between 50 mg/d (4 wk on, followed by 2 wk off) and severe AE cases, as compared to the schedule of 37.5 mg/d continuous therapy [bib_ref] GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal..., Demetri [/bib_ref] (GRADE moderate).

## Fatigue
Fatigue is a common AE of all three TKIs used in GIST patients, but it can be easily ignored since it is often accompanied by other symptoms. Yet, fatigue has se rious impact on quality of life [bib_ref] Chronic fatigue is the most important factor limiting health-related quality of life..., Efficace [/bib_ref]. The incidence of fatigue is similar among the three TKIs, reportedly 34.7% with imatinib (all cases grade 12) [bib_ref] Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors, Demetri [/bib_ref] , 39% with regorafenib (2% of cases representing grade 3) [bib_ref] GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal..., Demetri [/bib_ref] , and 34% with sunitinib (5% of cases representing grade 3) [bib_ref] Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour..., Demetri [/bib_ref]. While the mechanisms of TKIinduced fatigue are not entirely clear, they are apparently complex. Among the hypothesized mechanisms are 5hydroxy tryptamine neurotransmitter disorder, proinflammatory cytokine accumulation, and neuromuscular function degradation [bib_ref] The role of cytokines in cancer-related fatigue, Kurzrock [/bib_ref] [bib_ref] Cytokines and their relationship to the symptoms and outcome of cancer, Seruga [/bib_ref].
Cases of TKIinduced fatigue that are mild to mode rate generally require no special treatment. However, if the fatigue reaches grade 3 or higher, active treatments should be initiated; these include reducing dosage or suspending administration of the drug, exercise inter vention (such as yoga) [bib_ref] Yoga for improving health-related quality of life, mental health and cancerrelated symptoms..., Cramer [/bib_ref] (GRADE low), massage, and acupuncture [bib_ref] Massage therapy for symptom control: outcome study at a major cancer center, Cassileth [/bib_ref] [bib_ref] Therapeutic massage and healing touch improve symptoms in cancer, Post-White [/bib_ref] (GRADE low). But caution should be taken for affected patients with bone metastases, throm bocytopenia, anemia, fever or active infections, etc. Psychological intervention and nutritional support can also be applied (GRADE low). Pharmacologic intervention with modafinil can be used in severe cases of fatigue (GRADE low), but this management strategy appears to be ineffective for mild to moderate cases [bib_ref] Modafinil Moderates the Relationship Between Cancer-Related Fatigue and Depression in 541 Patients..., Conley [/bib_ref].

## Proteinuria
VEGF signaling pathway inhibitors are currently widely applied, as targeted therapy, for treating renal cancer, colorectal cancer, ovarian cancer and other advanced malignancies. The main role of these chemotherapeutic agents is to inhibit angiogenesis, and this chemotherapy approach includes use of monoclonal antibodies (such as bevacizumab) and small orally active TKIs (such as axitinib, sunitinib, and sorafenib). Proteinuria is one of the most frequently observed AEs of VEGF/VEGFR inhibitors.
The reported incidence rate of proteinuria has varied among different studies, according to differences in cha racteristics of the study population and tumor type under VEGF/VEGFR inhibitor treatment. In these cases, grade 1 proteinuria is defined as urinary protein of < 1.0 g in 24 h, grade 2 as urinary protein of 1.03.4 g in 24 h, and grade 3 as  3.5 g in 24 h. The highest risk of se vere proteinuria was reported in patients with renal cell carcinoma (RCC), and the lowest risk is by patients with colorectal cancer [bib_ref] A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for..., Yang [/bib_ref]. The exact incidence of proteinuria in patients treated with small orally active VEGF TKIs is still undetermined. In trials with sorafenib, 21%63% of the patients have presented asymptomatic mild proteinuria. Severe protei nuria cases have been reported in up to 6.5% of RCC patients [bib_ref] VEGF signalling inhibition-induced proteinuria: Mechanisms, significance and management, Izzedine [/bib_ref]. VEGF signaling inhibitioninduced proteinuria is typically asymptomatic and depends on dosage and time [bib_ref] Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial..., Zhu [/bib_ref]. Incidence of proteinuria is also related to tumor type, kidneyassociated chronic disease, druginduced renal toxicity, and patient characteristics.
The mechanism underlying TKIrelated proteinuria is not completely understood. There are few accepted theories. The first of such involves the role of VEGF in maintaining the glomerular filtration barrier, providing cytoprotection to the glomerular capillary endothelial cells. Inhibition of this protective effect through sunitinib induced VEGF inhibition may, then, lead to proteinuria. A second theory involves the role of VEGF in down regulating tight junction proteins on podocytes, thereby reducing kidney filtration function [bib_ref] Plethora of agents, plethora of targets, plethora of side effects in metastatic..., Schmidinger [/bib_ref]. A third theory is based on VEGF signaling inhibition resulting in sup pression of nephrin and leading to nephritic syndrome and glomerular thrombotic microangiopathy [bib_ref] Practical management of tyrosine kinase inhibitor-associated side effects in GIST, Joensuu [/bib_ref]. No guidelines exist for managing patients with suni tinibspecific proteinuria. Prior to beginning sunitinib therapy, all patients should undergo complete medical historytaking, physical examination, urinalysis, and urine sediment analysis. Currently, the majority of clinical researchers recommend ACEI or ARA therapy, which may reduce mild proteinuria (GRADE moderate). Antihypertensive drugs should be taken if the AE is accompanied by hypertension [bib_ref] Proteinuria reduction and progression to renal failure in patients with type 2..., Atkins [/bib_ref] (GRADE moderate).
The Kidney Disease Outcomes Quality Initiative re commends ACEIs or ARAs as firstline therapy for VEGF associated proteinuria(GRADE moderate). Discon tinuation of sunitinib is recommended for patients with urinary protein levels > 3 g in a 24h period (GRADE high). The sunitinib treatment can be restarted when the urinary protein level falls below that threshold [bib_ref] VEGF signalling inhibition-induced proteinuria: Mechanisms, significance and management, Izzedine [/bib_ref] (GRADE high). The tumor and patient conditions should also be considered, as well as results of riskbenefit trend evaluation. Finally, it is crucial to obtain the informed consent of patients for this management.

## Stomatitis
Targeted therapyrelated stomatitis is characterized by pain, edema, erythema, ulcers, burning sensation when ingesting sour and spicy foods, and even anatomical dysfunction, such as difficulty in speech or dysphagia and loss of taste. Since the pathogenesis of stomatitis is associated with blockade of the VEGFR signaling path way, this AE is rare during imatinib treatment but is common during sunitinib or regorafenib treatment. The reported incidence rates of stomatitis associated with sunitinib vary widely in the literature, ranging from 5% to 40.4% [bib_ref] Risk of mucocutaneous toxicities in patients with solid tumors treated with sunitinib:..., Abdel-Rahman [/bib_ref] [bib_ref] Oral adverse events in cancer patients treated with VEGFRdirected multitargeted tyrosine kinase..., Yuan [/bib_ref]. In the GRID phase III trial (evaluating regorafenib in metastatic GISTs), however, stomatitis occurred in 38% of the treatment group, with only 2% developing grade 3 or above [bib_ref] GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal..., Demetri [/bib_ref]. TKIinduced stomatitis is usually grade 1 or 2, and sometimes presents without definitive evidence or signs. The onset usually occurs within the first 1.9 mo of treat ment [bib_ref] Oral adverse events in cancer patients treated with VEGFRdirected multitargeted tyrosine kinase..., Yuan [/bib_ref].
Most of the cases do not need a dose modification or TKI withdrawal. Since stomatitis may lead to a decline in treatment compliance and the development of sepsis, it is necessary to pay attention to and help strengthen the patient's oral care by improving their oral hygiene, avoiding irritant food intake, and using mouth rinses (such as sodium bicarbonate); topical or systemic analgesics may be administered if necessary (e.g., viscous lidocaine, benzocaine, or benzydamine) [bib_ref] Practical management of tyrosine kinase inhibitor-associated side effects in GIST, Joensuu [/bib_ref] (GRADE moderate).
If oral fungal infection is suspected, nystatin is recom mended (rinse 4 times a day for 10 d). If grade 3 or 4 stomatitis occurs, the frequency of rinse application should be increased to 812 or more times per day (GRADE moderate). If there is no improvement after 1 wk, the TKI should be temporarily discontinued until the stomatitis attenuates to grade 1, then the drug could be resumed at the same dose (GRADE moderate).

## Cardiotoxicity
TKIrelated cardiac toxicity may present as asymptomatic QT interval prolongation, decreased left ventricular ejection fraction (LVEF), congestive heart failure, acute coronary syndrome, and myocardial infarction. Imatinib related cardiac toxicity is rare. The incidence of heart failure in imatinibtreated GIST patients reported in the literature ranges from 0.5% to 1.7%, and cases are usually represented by the elderly (over 65 years old) with cardiac risk factors [bib_ref] Congestive heart failure is a rare event in patients receiving imatinib therapy, Atallah [/bib_ref] [bib_ref] In reply to 'Cardiotoxicity of the cancer therapeutic agent imatinib mesylate', Hatfield [/bib_ref]. The mechanism underlying imatinibinduced cardiotoxicity may involve myocardial toxicity caused by cAbl inhibition [bib_ref] Cardiotoxicity of the cancer therapeutic agent imatinib mesylate, Kerkela [/bib_ref]. The rate of cardiac toxicity in sunitinibtreated GIST patients is higher than that of imatinib treatment, and the incidence of heart failure is reported to be 2.7%15% , which needs to be paid more attention. The possible mechanisms of this sunitinibinduced cardiotoxicity include abnormality of mitochondrial energy metabolism induced by 5' ade nosine monophosphateactivated protein kinase (AMPK) inhibition in cardiac myocytes [bib_ref] Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase, Kerkela [/bib_ref] , and decreased myo cardial adaption to afterload stress caused by inhibition of the PDGFR signaling pathway in cardiac myocytes. For regorafenib therapy, there is limited data on cardiac AEs. Although, in the GRID phase III trial, there was one (0.8%) case of cardiac AE, it was grade 5 (cardiac arrest) [bib_ref] GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal..., Demetri [/bib_ref]. Cardiac function evaluation should be considered when patients present signs of dyspnea and fatigue during the TKI therapy period. Patients with a history of coronary disease should undergo echocardiographic baseline LVEF measurement prior to sunitinib treatment and should be closely monitored for blood pressure and LVEF during the entire course of treatment. Hypertension should be treated with therapy including an ACE inhibitor (GRADE high). Patients with symptoms of chronic heart failure should be treated with ACE inhibitors and diuretics (GRADE high). In patients with a definitive diagnosis of heart failure, the sunitinib administration should be inter rupted (GRADE high). Each patient needs to be assessed individually when the cardiac function has stabilized, with consideration given to available alternative treatments and the tradeoff between the cardiac and GISTrelated risks. Reinstitution of sunitinib should start at a reduced dose (GRADE moderate).
For those patients with LVEF reduction to less than 50% during sunitinib treatment and without clinical symp toms of heart failure, the options include: (1) interruption of sunitinib treatment for several weeks; (2) sunitinib dose reduction; and (3) initiation of cardiac medication accompanied by close monitoring of cardiac function [bib_ref] Practical management of tyrosine kinase inhibitor-associated side effects in GIST, Joensuu [/bib_ref] (GRADE moderate).

## Hypothyroidism
The incidence of hypothyroidism caused by sunitinib is higher. Clinical or subclinical hypothyroidism repor tedly occurs in 53%85% of GIST patients taking suni tinib . The mechanism of sunitinibinduced hypothyroidism is not yet clear. Although studies have shown that during the sunitinib treatment, the thyroid uptake rate of I 123 is reduced. Most of such AE cases return to normal uptake Li J et al . Management of TKI-associated AEs rate after treatment completion, suggesting that the possible mechanism of this hypothyroidism involves an obstacle in the thyroid gland's ability to uptake iodine [bib_ref] A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine..., Mannavola [/bib_ref]. Some researchers have theorized that destruction of the thyroid gland by sunitinib is the main pathogenic me chanism of the related hypothyroidism [bib_ref] Thyrotoxicosis during sunitinib treatment for renal cell carcinoma, Grossmann [/bib_ref]. In addition, sunitinib has been shown to inhibit thyroid peroxidase activity and to reduce thyroid hormone synthesis [bib_ref] Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase..., Wong [/bib_ref] , which may support development of hyperthyroidism. It has also been suggested that the antiangiogenic effect of sunitinib may cause the observed decrease in the density of thyroid capillaries [bib_ref] Sunitinib induces hypothyroidism with a markedly reduced vascularity, Makita [/bib_ref] , leading to a toxic effect on the thyroid gland. In vitro experiments have also provided insights into the potential pathogenic mechanisms, and sunitinib was found to inhibit the transfection rear rangement/papillary adenocarcinoma kinase (RET/PTC) of the cell proliferation signaling pathway [bib_ref] Effect of sunitinib on growth and function of FRTL-5 thyroid cells, Salem [/bib_ref] , which plays an important role in maintaining normal thyroid physio logical function [bib_ref] An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent..., Kim [/bib_ref] and can induce hypothyroidism.
Thyroid dysfunction caused by sunitinib is more frequent in the early stage of treatment and most ca ses present transient thyrotoxicosis, manifesting as fatigue exacerbation and palpitation. However, as the treatment cycle is extended, the risk of hypothyroidism increases, and patients present with such symptoms as chills, drowsiness, and even myxedema coma. The mean duration of sunitinibinduced hypothyroidism is 50 wk. Sometimes, the clinical manifestations alone may not be sufficient to diagnose hypothyroidism in time and accurately. Thus, it is necessary to monitor thyroid function regularly in GIST patients undergoing sunitinib treatment. A number of studies have found that the median progressionfree survival in patients with sunitinibinduced hypothyroidism is longer than in those who retained normal thyroid function. Therefore, some scholars [bib_ref] Unanswered questions regarding the management of sunitinib-induced hypothyroidism, Garfield [/bib_ref] [bib_ref] Therapy management with sunitinib in patients with metastatic renal cell carcinoma: key..., Castellano [/bib_ref] have suggested thyroid function as an indicator of the efficacy of sunitinib in the treatment of GIST.
For GIST patients who are to receive sunitinib the rapy, thyroid function should be assessed before the treat ment initiation. For those with a past history of thyroid disease, the level of thyroidstimulating hormone (TSH) should be monitored during the treatment course [bib_ref] Sunitinib malate in the treatment of renal cell carcinoma and gastrointestinal stromal..., Desai [/bib_ref] [bib_ref] Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors, Desai [/bib_ref] [bib_ref] Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib, Rini [/bib_ref] ; yet, the optimal TSH monitoring frequency and time have not been determined. Sunitinibinduced thyroid toxicity is usually not accompanied by clinical symptoms and is selflimiting (GRADE moderate). It is usually unnecessary to modify the dose or interrupt the administration of suni tinib (GRADE moderate). If severe symptoms of thyro toxicosis develop or the patient presents with thyroid crisis, sunitinib should be discontinued and intervention measures should be taken (GRADE high). Patients with severe hypothyroidism can be treated with thyroid hor mone replacement therapy, and the most commonly used alternative drug is sodium levothyroxine (GRADE high).

## Hepatotoxicity and nephrotoxicity
Liver transaminase elevations are observed with TKI treatment [bib_ref] Practical management of tyrosine kinase inhibitor-associated side effects in GIST, Joensuu [/bib_ref] [bib_ref] Efficacy evaluation of imatinib in the treatment of patients with gastrointestinal stromal..., Zong [/bib_ref]. Abnormal liver transaminase levels have been observed in about 5.4% of GIST patients receiving imatinib (2.7% representing grades 3 and 4) [bib_ref] Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors, Demetri [/bib_ref] , and each case of imatinibinduced acute severe hepatotoxicity needs to be addressed seriously as it could cause hepatic failure or even death [bib_ref] Imatinib mesylate-induced acute liver failure in a patient with gastrointestinal stromal tumors, Tonyali [/bib_ref]. Liver function, as evidenced by measures of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin, should be assessed before treatment initiation and should be monitored perio dically during the treatment period.
GIST patients with elevated AST/ALT levels should be monitored closely. Mild elevations can be monitored without administration of specific therapies or dose reduc tion. For patients with persistent grade 2 toxicity [AST/ ALT at 2.5 to 5fold upper limit of normal (ULN) value], a complete workup to determine the cause of abnormal liver function is necessary (GRADE moderate). In pa tients with ongoing grade 2 toxicity, detailed evaluation is needed to determine dose reduction or interruption [bib_ref] Practical management of patients with chronic myeloid leukemia receiving imatinib, Deininger [/bib_ref] (GRADE moderate). The current management of grade 3 or higher elevations in transaminases (AST/ALT at > 5fold ULN) is to interrupt the TKI treatment (GRADE high). When the liver functions return to grade 1 or less (AST/ ALT at < 2.5fold ULN or bilirubin at < 1.5fold ULN), the TKI administration can be reinstituted, but at a reduced dose (GRADE moderate). Specifically, the daily dose of imatinib should be reduced from 400 mg to 300 mg. The incidence of severe hepatotoxicity in sunitinibtreated patients is less than that in the imatinibtreated, and for sunitinib the dose can be decreased by 12.5 mg daily from the original dose when reinstituting the treatment [bib_ref] Sunitinib malate in the treatment of renal cell carcinoma and gastrointestinal stromal..., Desai [/bib_ref] (GRADE low).
Hepatitis B is one of the most important public health issues in China, with almost 7.2% of China's population being chronically infected [bib_ref] Epidemiology of Hepatitis B Virus Infection in China: Current Status and Challenges, Yan [/bib_ref] [bib_ref] Epidemiological serosurvey of hepatitis B in China--declining HBV prevalence due to hepatitis..., Liang [/bib_ref]. Considering the high prevalence of chronic hepatitis B in China, oncologists are likely to face patients who suffer from both GISTs and hepatitis B virus (HBV) infection. HBV reactivation is a wellrecognized risk in patients with chronic HBV infection during chemotherapy and immunosuppressant therapy . HBV reactivation can be severe and po tentially fatal. There have been some reports of HBV reactivation in patients receiving imatinib . HBV scree ning tests should be performed before receiving TKIs [bib_ref] Hepatitis B reactivation in patients receiving targeted therapies, Chang [/bib_ref] [bib_ref] ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on..., Reinwald [/bib_ref] (GRADE low). Prophylactic antiviral treatment should be offered to HBsAgpositive patients during treatment (GRADE low). In addition, HBV virus load of antiHBc positive, HBsAgnegative patients could be monitored to assess the eventual reactivation of the occult disease [bib_ref] ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on..., Reinwald [/bib_ref] (GRADE low).
Nephrotoxicity has been observed rarely in GIST pa tients treated with TKIs. However, its monitoring should still be applied vigilantly during longterm treatment with TKIs, which may cause decline in kidney function. Cases of TKIrelated acute kidney injury, chronic kidney disease, proteinuria, and nephrotic syndrome have been reported [bib_ref] Estimated glomerular filtration rate changes in patients with chronic myeloid leukemia treated..., Yilmaz [/bib_ref]. The monitoring of renal function should begin at treatment initiation and continue on a periodic schedule throughout the treatment course. When im paired kidney function is detected, it is necessary to consult a kidney specialist and evaluate the value of con tinuing TKI treatment (GRADE low).

## Hair disorder
A pooled analysis of AEs experienced by GIST patients treated with TKIs revealed that the incidence of hair disorder is about 14%. The hair disorders reported have included discoloration, trichomegaly, hypertrichosis, alo pecia, and madarosis. Compared with imatinibtreated patients, sunitinibtreated patients experience hair dis coloration during treatment at a much more frequent rate (15.2%) [bib_ref] Persistent cutaneous hyperpigmentation after tyrosine kinase inhibition with imatinib for GIST, Alexandrescu [/bib_ref]. Some researchers have reported that inhibition of kit pathway may reduce hair pigmentation. The functions of tyrosinase and tyrosinaserelated protein 1, which are related to melanin synthesis, have been found to be impaired in TKItreated patients as well(GRADE high).
GIST patients receiving TKI treatment should be in formed of the possibility of developing an uneven hair pig mentation AE. It is also necessary for patients to know that hair disorders associated with sunitinib are mostly mild and generally selflimiting, and that the AE will at tenuate after cessation of treatment [bib_ref] GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal..., Demetri [/bib_ref] (GRADE high).

## Interstitial lung disease
Interstitial lung disease is a relatively rare AE during the TKI treatment of patients with GIST. However, once diagnosed, patients with TKIinduced interstitial lung dis ease need close medical attention and appropriate treat ment. The incidence of interstitial lung disease among TKItreated GIST patients is still unclear, due to a lack of research on this topic. According to a Japanese study of 5000 patients with chronic myeloid leukemia and 500 patients with GISTs receiving imatinib treatment, the overall incidence of interstitial lung disease was 0.5% and that in GIST patients was 0.8% [bib_ref] Twenty-seven cases of druginduced interstitial lung disease associated with imatinib mesylate, Ohnishi [/bib_ref]. The collective literature, albeit limited, suggests that interstitial lung disease may affect Asians more than other races and males more than females [bib_ref] Imatinib-induced interstitial lung disease and sunitinib-associated intra-tumour haemorrhage, Loong [/bib_ref]. In addition, a history of interstitial lung disease is a risk factor for development of this AE during TKI therapy [bib_ref] Hypersensitivity pneumonitis related to imatinib mesylate, Bergeron [/bib_ref]. The mechanisms of TKIinduced interstitial lung dis ease remain debatable. The main hypotheses for such involve a hypersensitivity reaction, the pharmacological action of the TKI itself, and induced pulmonary fibrosis and inflammatory cell infiltration upon inhibition of PDGFRA [bib_ref] Drug-induced pneumonitis associated with imatinib mesylate in a patient with idiopathic pulmonary..., Yamasawa [/bib_ref] [bib_ref] Druginduced interstitial lung disease in tyrosine kinase inhibitor therapy for non-small cell..., Min [/bib_ref]. The symptoms are usually unspecific and present a few months into the treatment; these include fever of unknown origin, cough, dyspnea, hypo xemia, and hypereosinophilia. Chest Xray, computed tomography (CT), and highresolution CT may help to diagnose the interstitial lung disease. The typical CT characteristics are groundglass opacity, irregular lining or reticular areas of formation with bronchiectasis and bronchiolectasis.
The success of treating TKIinduced interstitial lung disease depends on rapid and correct diagnoses. When a TKItreated GIST patient presents with symptoms of interstitial lung disease (with possible infection or other causative factors excluded) and diagnosis of the disease is made, physicians should immediately dis continue the TKI treatment and treat patients with time ly and sufficient corticosteroids, and antibiotics when necessary [bib_ref] Tyrosine Kinase Inhibitor-Induced Interstitial Lung Disease: Clinical Features, Diagnostic Challenges, and Therapeutic..., Shah [/bib_ref] (GRADE moderate). Although the severity of TKIinduced interstitial lung disease varies, it usually responds well to corticosteroid therapy [bib_ref] Tyrosine Kinase Inhibitor-Induced Interstitial Lung Disease: Clinical Features, Diagnostic Challenges, and Therapeutic..., Shah [/bib_ref] (GRADE mo derate). After the symptoms have been relieved and imaging examination shows improvement of the disease condition, the physician should switch the patient to other drug regimens for treating the GIST. However, if no other therapies are available and the TKI is still ef fective, it should be continued under close monitoring. In such cases, the ratio of risk and benefit should be assessed carefully and the patients should be followed intensively [bib_ref] Tyrosine Kinase Inhibitor-Induced Interstitial Lung Disease: Clinical Features, Diagnostic Challenges, and Therapeutic..., Shah [/bib_ref] (GRADE moderate).

## Hematological side effects
Anemia: Anemia is very common in GIST patients, both at the time of diagnosis and during the course of TKI treat ment, especially for imatinib and when administered at high dosage (800 mg/d). A reported 16.7% of imatinib treated patients present with grade 34 anemia [bib_ref] Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels..., Blanke [/bib_ref] , as compared to only 6.2% of sunitinibtreated patients [bib_ref] Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour..., Demetri [/bib_ref]. GIST patients may have irondeficiency anemia due to chronic gastrointestinal hemorrhage prior to surgery or small bowel resection. Meanwhile, gastrectomy and small bowel resection will cause vitamin B12 or folate defi ciency, leading to megaloblastic anemia. Theoretically, TKIs may also inhibit KITexpressing hematologic stem cells in the bone marrow.
Serum iron, ferritin, and transferrin levels, total iron binding capacity, folic acid, vitamin B12, and bilirubin should be detected in patients with GISTs. For patients with mild anemia (grade 1: blood hemoglobin  95 g/L), TKI interruption or other treatments are not necessary. For patients with grade 2 or higher anemia (blood he moglobin level < 94 g/L), treatment regimens vary ac cording to the anemia cause. For example, oral ferrous sulfate or intravenous administration of iron is suggested for patients with iron deficiency anemia, and vitamin B12 and folate are suggested for patients with megaloblastic anemia (GRADE high).
A high risk of thromboembolic events and high mor tality rate from erythropoietin and darbepoetin alfa ane mia therapies was found by metaanalyses [bib_ref] Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including..., Bohlius [/bib_ref] [bib_ref] Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis..., Bohlius [/bib_ref]. As such, these drugs are only indicated when, after careful evaluation, the advantages outweigh the disadvantages. Red blood cell transfusion is only indicated for patients with acute hemorrhage or severe anemia, since its ef fects are transient and accompanied by transfusion associated risks, such as transfusion reaction, virus transmission, and iron overload (GRADE high). The TKI dose does not need to be adjusted to address an anemia AE. Acute anemia should be evaluated for presence of hemorrhage in the gastrointestinal tract or peritoneal cavity caused by the GIST itself, and emergency surgery should be considered. Once bleeding is under control, the initial dose of imatinib, sunitinib, or other TKIs can be reinstituted.
Neutropenia: Neutropenia is common in patients under going TKI therapy. The majority of these AEs are of grades 12. The rate of grades 34 neutropenia is around 7% with imatinib treatment and 10% with sunitinib treatment. Regardless of grade, the AE usually appears during the first 6 wk of treatment and remains stable afterwards [bib_ref] Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors, Demetri [/bib_ref] [bib_ref] Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour..., Demetri [/bib_ref] [bib_ref] Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial, Verweij [/bib_ref].
For patients with grades 12 TKIinduced neutropenia, the TKI treatment can be continued at the initial dose and no specific management needs to be considered. If grades 34 neutropenia appear, administration of gra nulocyte colonystimulating factor (GCSF) is indicated and the TKI treatment should be suspended until the neutrophil count exceeds 1.5  10 6 /L, at which time the initial daily dose should be reinstituted (GRADE high). Dose reduction of the TKI may be carried out in patients who experience repeated episodes of severe neutropenia (grades 34) or febrile neutropenia; for example, the dose of imatinib could be reduced from 400 mg daily to 300 mg daily or of sunitinib from 50 mg per day to 37.5 mg per day (GRADE high). Studies of GCSF treatment in a mouse model of neutropenia indicated that the GCSF may decrease the effect of antiVEGF therapy [bib_ref] G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy..., Shojaei [/bib_ref]. These bench laboratory experimental results suggest that clinical administration of GCSF and other granulocyte growth factors in combination with antiVEGF therapies, such as sunitinib and regorafenib, should be carefully evaluated (GRADE moderate).
Thrombocytopenia: Thrombocytopenia is rarely ob served in GIST patients receiving imatinib treatment (all grades: 6.3%; grade 3: 1.3%), but it is commonly seen in patients undergoing sunitinib therapy (all grades: 15.2%; grades 34: 5.7%) [bib_ref] Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors, Demetri [/bib_ref] [bib_ref] Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour..., Demetri [/bib_ref] [bib_ref] Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial, Verweij [/bib_ref]. For patients with mild or moderate TKIinduced throm bocytopenia (grades 12), the TKI treatment can be continued at the initial dose and no specific treatment is needed. However, if the patient's blood platelet count falls below 50  10 9 /L, recombinant human thrombopoietin (TPO) or interleukin11 is indicated and the TKI treat ment should be interrupted until the platelet count rises above 75  10 9 /L, when it can be reinstituted at the initial daily dose (GRADE high). Dose reduction of TKIs may be carried out in patients with repeated episodes of severe thrombocytopenia (grades 34). The dose of imatinib at reinstitution can be reduced from 400 mg/d to 300 mg/ d, and of sunitinib from 50 mg/d to 37.5 mg/d (GRADE high).

# Conclusion
The AEs of TKI treatment are different in each GIST patient. Clinicians need to comprehensively assess the therapy's purpose and efficacy, the patient's tolerance, the types and severities of potential (and developed) AEs. Such assessments before TKI treatment initiation should be done with respect to the need for providing timely and effective treatment, so that the optimal efficacy of TKI treatment can be achieved and the patient's quality of life can be most protected and/or improved.
[fig] 2: Summary of tyrosine kinase inhibitor-associated side effects 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. [/fig]