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Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 14, 2018; 24(46): 5189-5202
Published online Dec 14, 2018. doi: 10.3748/wjg.v24.i46.5189
Chinese consensus on management of tyrosine kinase inhibitor-associated side effects in gastrointestinal stromal tumors
Jian Li, Ming Wang, Bo Zhang, Xin Wu, Tian-Long Lin, Xiu-Feng Liu, Ye Zhou, Xin-Hua Zhang, Hao Xu, Li-Jing Shen, Jing Zou, Ping Lu, Dong Zhang, Wei-Jun Gu, Mei-Xia Zhang, Jian Pan, Hui Cao, Chinese Society of Surgeons for Gastrointestinal Stromal Tumor of the Chinese Medical Doctor Association
Jian Li, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
Ming Wang, Tian-Long Lin, Hui Cao, Department of Gastrointestinal Surgery, Reiji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
Bo Zhang, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Xin Wu, Department of General Surgery, the General Hospital of the People’s Liberation Army, Beijing 100853, China
Xiu-Feng Liu, Department of Oncology, The Chinese People’s Liberation Army 81st Hospital, Nanjing 210031, Jiangsu Province, China
Ye Zhou, Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Xin-Hua Zhang, Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
Hao Xu, Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 320100, Jiangsu Province, China
Li-Jing Shen, Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, China
Jing Zou, Department of Respirology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, China
Ping Lu, Department of Dermatology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, China
Dong Zhang, Department of Nephrology, The General Hospital of the People’s Liberation Army, Beijing 100853, China
Wei-Jun Gu, Department of Endocrinology, The General Hospital of the People’s Liberation Army, Beijing 100853, China
Mei-Xia Zhang, Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Jian Pan, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
ORCID number: Jian Li (0000-0002-4688-0424); Ming Wang (0000-0002-7029-0950); Bo Zhang (0000-0001-9985-7167); Xin Wu (0000-0002-8935-6075); Tian-Long Lin (0000-0002-8105-4742); Xiu-Feng Liu (0000-0003-3318-3766); Ye Zhou (0000-0002-3020-8238); Xin-Hua Zhang (0000-0002-7689-6830); Hao Xu (0000-0001-5827-1821); Li-Jing Shen (0000-0002-9242-4171); Jing Zou (0000-0002-0364-5205); Ping Lu (0000-0002-9220-2392); Dong Zhang (0000-0002-4446-5374); Wei-Jun Gu (0000-0001-7999-4594); Mei-Xia Zhang (0000-0003-4475-4843); Jian Pan (0000-0002-7009-9689); Hui Cao (0000-0002-2300-5088).
Author contributions: Cao H designed the consensus and revised the final manuscript; Li J, Wang M, Zhang B, Wu X, Lin TL, Liu XF, Zhou Y, Zhang XH, and Xu H collected the data and performed different parts of this article according to different specialties; Shen LJ, Zou J, Lu P, Zhang D, Gu WJ, Zhang MX, and Pan J helped to collect the data and gave comments; Li J and Lin TL integrated the final manuscript. Li J, Wang M, Zhang B, Wu X, Lin TL, Liu XF, Zhou Y, Zhang XH, and Xu H contributed equally to this consensus.
Conflict-of-interest statement: All the authors report no conflicts of interest in this work.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author to: Hui Cao, MD, Chief Doctor, Surgical Oncologist, Department of General Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, No. 160, Pujian Road, Pudong New District, Shanghai 200127, China.
Telephone: +86-21-68383751 Fax: +86-21-58395057
Received: August 23, 2018
Peer-review started: August 23, 2018
First decision: October 5, 2018
Revised: November 4, 2018
Accepted: November 7, 2018
Article in press: November 8, 2018
Published online: December 14, 2018


Tyrosine kinase inhibitors (TKIs) have improved the overall survival of patients with gastrointestinal stromal tumors (GISTs), but their side effects can impact dose intensity and, consequently, the clinical benefit. To date, no guideline or consensus has been published on the TKI-associated adverse reactions. Therefore, the Chinese Society of Surgeons for Gastrointestinal Stromal Tumor of the Chinese Medical Doctor Association organized an expert panel discussion involving representatives from gastrointestinal surgery, medical oncology, cardiology, dermatology, nephrology, endocrinology, and ophthalmology to consider the systemic clinical symptoms, molecular and cellular mechanisms, and treatment recommendations of GISTs. Here, we present the resultant evidence- and experience-based consensus to guide the management of TKI-associated side events in clinical practice.

Key Words: Side effects, Gastrointestinal stromal tumor, Tyrosine kinase inhibitors, Consensus guideline, China

Core tip: This is the first consensus focusing on tyrosine kinase inhibitor (TKI)-associated side effects in gastrointestinal stromal tumors (GISTs). The authors include not only oncologist, oncology surgeon, but also doctors from other relative specialties, such as cardiology, dermatology, nephrology, and endocrinology. The content consists of clinical symptoms, mechanisms, and management. Because except for GISTs, TKIs in this consensus are also used in other tumors, this consensus will be helpful to many oncologists in different specialties.

  • Citation: Li J, Wang M, Zhang B, Wu X, Lin TL, Liu XF, Zhou Y, Zhang XH, Xu H, Shen LJ, Zou J, Lu P, Zhang D, Gu WJ, Zhang MX, Pan J, Cao H, Chinese Society of Surgeons for Gastrointestinal Stromal Tumor of the Chinese Medical Doctor Association. Chinese consensus on management of tyrosine kinase inhibitor-associated side effects in gastrointestinal stromal tumors. World J Gastroenterol 2018; 24(46): 5189-5202
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  • DOI:


Tyrosine kinase inhibitors (TKIs), such as imatinib, sunitinib, 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 sufficient dose is crucial for good efficacy. For GIST patients undergoing TKI therapy, the management of TKI-associated side effects is equally important. Fortunately, the symptoms of TKI-associated 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 GIST-treating clinical doctors representing the various systemic components affected in our patient population including doctors from gastrointestinal surgery, medical oncology, cardiology, dermatology, nephrology, endocrinology, and ophthalmology. All treatment recommendations in this article are graded according to the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system, which is widely accepted to make evidence-based recommendations[1]. The final grade for the quality of evidence by the GRADE system is in Table 1.

Table 1 The grade for the quality of evidence by the Grades of Recommendation Assessment, Development and Evaluation system.
Final grade rankDefinition of grade rank
HighWe are very confident that the effect of the study reflects the actual effect
ModerateWe 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
LowThe true effect may differ significantly from the estimate
Very lowThe true effect is likely to be substantially different from the estimated effect

This consensus guideline is intended to provide evidence- and experience-based expert recommendations on the management of TKI-associated side effects in GIST patients, in order to improve the efficacy and safety of TKI therapy. All the TKIs-associated side effects are summarized in Table 2.

Table 2 Summary of tyrosine kinase inhibitor-associated side effects.
Side effectsRelative TKIsSymptomsMechanismsGeneral managementTKIs - dose reduction or temporary discontinuation
Edema and fluid retentionImatinibFrequently in the periorbital area or lower limbsInhibiting PDGFR and decreasing the interstitial pressureLimit salt intake or administer diureticsOccasionally
Gastrointestinal adverse eventsImatinib, sunitinib, regorafenibNause, vomiting, and diarrheaInducing release of neurotransmitters, exciting the vagus nerves and sympathetic nervesAntiemetic medications, Antidiarrhoeal medicineSeldom
Skin rashImatinib, sunitinibErythematous and maculopapular lesionsInhibiting of metabolic pathways mediated by tyrosine kinasesTopical lotions, antihistamines and steroidsSometimes
Ophthalmological complicationsImatinibPeriorbital edema, epiphora, and hemorrhage in the conjunctivaInhibiting PDGFR and decreasing the interstitial pressure, conjunctival chemosisSteroids and systemic diureticsNot necessary
HypertensionSunitinib, regorafenibHypertensionActivating the endothelin axis and suppressing reninACEIs, ARAsSometimes
Hand-foot syndromeSunitinib, regorafenibBilateral palmar plantar erythema, skin peeling, and painDirect skin toxicity of TKIs, poor repair of small traumas due to VEGFR and PDGFR inhibitionTopical creams, keratolytic creams, emollients, analgesicsOften
FatigueImatinib, sunitinib, regorafenibFatigue5-HT3 neurotransmitter disorder, proinflammatory cytokine accumulation, neuromuscular function degradationExercise intervention, nutritional supportSeldom
ProteinuriaSunitinib, regorafenib24 h urinary protein increaseVEGF inhibitionACEIs, ARAsSometimes
StomatitisSunitinib, regorafenibPain, edema, erythema, ulcers, burning sensationBlockade of the VEGFR signaling pathwayOral care, analgesicsSometimes
CardiotoxicitySunitinib, regorafenibQ-T interval prolongation, decreased LVEF, etcAMPK and PDGFR inhibitionACEIs, diureticsOften
HypothyroidismSunitinibClinical or subclinical hypothyroidismDestruction of the thyroid gland, inhibiting thyroid peroxidase activity, decreasing the density of thyroid capillariesSodium levothyroxineDon’t need
Hepatotoxicity and nephrotoxicityImatinib, sunitinib, regorafenibLiver transaminase elevation, creatinine elevationHBV reactivation, VEGF inhibitionAntiviral treatment, diammonium glycyrrhizinateSometimes
Hair disorderImatinibDiscoloration, trichomegaly, hypertrichosis, alopecia, etc.Inhibition of kit pathwayNoDon’t need
Interstitial lung diseaseImatinibfever of unknown origin, cough, dyspnea, hypoxemiaHypersensitivity reaction, inhibition of PDGFRSufficient corticosteroids, antibioticsDiscontiuation permanently in most cases
Hematological side effectsImatinib, sunitinib, regorafenibAnemia, neutropenia, thrombocytopeniaInhibiting KIT-expressing hematologic stem cellsFerrous sulfate, folate, G-CSF, TPOSometimes
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[2]; in contrast, edema is rare and usually mild in patients receiving sunitinib[3]. 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[4] (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[5] (GRADE moderate). Patients with more than a 3-kg weight gain in 1 wk should be counseled to reduce salt intake[6] (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 pulmonary edema, pleural or pericardial effusion, and ascites 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 throughout[7] (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 treatments 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, sunitinib, or regorafenib[8]. The nausea and vomiting are often related, and most cases are reported as mild or moderate (grades 1-2). 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 TKI-treated GIST patients reported in the literature identified vomiting as a remarkably common AE[9]. Imatinib-treated GIST patients have a reported incidence of nausea at 52.4% (1.4% representing grades 3-4) and of vomiting at 12.9% (0.7% representing grades 3-4)[2]. For regorafenib, the reported nausea incidence is 16% (1% representing grades 3-4)[10]; and, for sunitinib, the reported nausea incidence is 24% (1% representing grades 3-4) and vomiting incidence is 16% (1% representing grades 3-4)[11].

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, 5-hydroxytryptamine (5-HT3) 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[12]. The reported occurrence rate of diarrhea in patients treated with imatinib is 44.9% (2% representing grades 3-4)[2], with regorafenib is 40% (5% representing grade 3)[10], and with sunitinib is 29% (3% representing grades 3-4)[11]. For mild to moderate diarrhea (grades 1-2), the drug dose does not need to be reduced but dietary adjustment is required. Patients are recommended a light, easily digestible, vitamin-rich, low-fiber, high-protein 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 3-4)[13,14]. For patiens taking imatinib, the likelihood of developing skin rash increases with increased 800 mg/d dose having a reported rash incidence of 46.6%[13].

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 hypersensitivity. Inhibition of various metabolic pathways mediated by tyrosine kinases, such as c-kit and platelet-derived growth factor receptor (PDGFR), could be involved in the pathophysiology of the adverse skin reactions[15]. Imatinib-induced skin rash commonly 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[4]. The skin rash may also be more common in female patients[15]. Severe cases may rarely lead to toxic epidermal necrolysis or Stevens-Johnson syndrome[4].

The most common sunitinib-related skin AE is dry skin (xerosis), reported in up to 16% of the treated GIST patients. The less frequent events of sunitinib-induced 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[16].

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[4] (GRADE moderate). For recurrent grade 3 skin rash, dose interruption 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., Stevens-Johnson syndrome), the imatinib administration should be interrupted (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[4] (GRADE moderate).

It is worth noting that after reinstitution of an interrupted 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 life-threatening extent, and need extra-medical attention.

Ophthalmological complications

Periorbital edema is the most common ocular side effect associated with imatinib, reported in up to 70% of treated GIST patients[2]. Dermal dendrocytes found in the periocular soft tissue express the tyrosine kinases c-kit and PDGFR. Through the inhibition of PDGFR, imatinib may decrease the interstitial pressure and increase transcapillary transport, causing edema[17,18].

Epiphora occurs in nearly 20% of imatinib-treated GIST patients, representing the second most common ocular side effect of this drug[19]. 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[20]. Hemorrhage in the conjunctiva reportedly affects up to 11% of imatinib-treated GIST patients and occurs in the absence of marrow suppression or in those with systemic bleeding tendency[21,22]. Genetic polymorphisms of EGFR, SLC22A1, SLC22A5, and ABCB1 may influence the imatinib-induced periorbital edema and conjunctival hemorrhage[22].

Sight-threatening 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[23]. Other rare ophthalmological complications of imatinib include optic disc edema and optic nerve dysfunction, recurrent optic neuritis, cystoid macular edema, and retinal edema[24-26].

Most of the reported cases of periorbital edema and epiphora improve with topical steroids and systemic diuretics[27] (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[28] (GRADE low). For conjunctival hemorrhage, most cases spontaneously recover or improve with topical steroids[29] (GRADE moderate). Disc edema and optic nerve dysfunction regress after cessation of the medication[23] (GRADE moderate). Macular edema and retinal edema subside with cessation of the medication, and optic neuritis improves with systemic steroids[24] (GRADE moderate).


Hypertension affects 11% or more of sunitinib-treated GIST patients (approximately 3% representing grades 3-4), whereas it occurs rarely during imatinib treatment[11,30,31]. Meanwhile, the incidence of sunitinib-induced hypertension in the Chinese GIST population is high, up to 28.8%; however, more severe cases, grades 3-4, remain low, at 3.4%[32]. Several mechanisms of sunitinib-induced hypertension have been identified, and these include activation of the endothelin axis, suppression of renin, decreased glomerular filtration rate, and increased sodium and water retention by the kidney[33-36].

Baseline blood pressure should be recorded before sunitinib therapy. The blood pressure monitoring is recommended 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 angiotensin-converting 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) inhibitor-associated hypertension of grade 2 or higher. Since some calcium channel blockers, such as diltiazem, verapamil, nitrendipine, and nifedipine, will increase sunitinib 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[37,38] (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 hand-foot 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[10,11,39-41], and it is one of the most frequent reasons for dose reduction of these TKIs. The main manifestations of TKI-induced HFS include bilateral palmar-plantar 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[16].

The mechanism underlying TKI-induced 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 hand-foot 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[5].

Patient education is the first step of HFS management. 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 HFS-related keratosis. Sufferers of TKI-induced HFS should be encouraged to use pressure-absorbing insoles and comfortable shoes or gloves when performing various activities. Analgesics may also be necessary to control HFS-related pain, until symptoms subside[42] (GRADE moderate). Administration of recombinant human fibroblast growth factor and/or recombinant human epidermal growth factor can help the recovery of skin damage (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 association 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[10] (GRADE moderate).


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 serious impact on quality of life[43]. The incidence of fatigue is similar among the three TKIs, reportedly 34.7% with imatinib (all cases grade 1-2)[2], 39% with regorafenib (2% of cases representing grade 3)[10], and 34% with sunitinib (5% of cases representing grade 3)[11].

While the mechanisms of TKI-induced fatigue are not entirely clear, they are apparently complex. Among the hypothesized mechanisms are 5-hydroxy tryptamine neurotransmitter disorder, proinflammatory cytokine accumulation, and neuromuscular function degradation[44,45].

Cases of TKI-induced fatigue that are mild to moderate 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 intervention (such as yoga)[46] (GRADE low), massage, and acupuncture[47,48] (GRADE low). But caution should be taken for affected patients with bone metastases, thrombocytopenia, 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[49].


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 characteristics 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 1.0-3.4 g in 24 h, and grade 3 as ≥ 3.5 g in 24 h[50]. The highest risk of severe proteinuria was reported in patients with renal cell carcinoma (RCC), and the lowest risk is by patients with colorectal cancer[51].

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 proteinuria cases have been reported in up to 6.5% of RCC patients[52]. VEGF signaling inhibition-induced proteinuria is typically asymptomatic and depends on dosage and time[53]. Incidence of proteinuria is also related to tumor type, kidney-associated chronic disease, drug-induced renal toxicity, and patient characteristics.

The mechanism underlying TKI-related 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[54]. A third theory is based on VEGF signaling inhibition resulting in suppression of nephrin and leading to nephritic syndrome and glomerular thrombotic microangiopathy[5].

No guidelines exist for managing patients with sunitinib-specific proteinuria. Prior to beginning sunitinib therapy, all patients should undergo complete medical history-taking, 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[55,56] (GRADE moderate).

The Kidney Disease Outcomes Quality Initiative recommends ACEIs or ARAs as first-line therapy for VEGF-associated proteinuria[57] (GRADE moderate). Discontinuation of sunitinib is recommended for patients with urinary protein levels > 3 g in a 24-h period (GRADE high). The sunitinib treatment can be restarted when the urinary protein level falls below that threshold[52] (GRADE high). The tumor and patient conditions should also be considered, as well as results of risk-benefit trend evaluation. Finally, it is crucial to obtain the informed consent of patients for this management.


Targeted therapy-related 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 pathway, 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%[58,59]. 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[10].

TKI-induced 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 treatment[59].

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)[5] (GRADE moderate).

If oral fungal infection is suspected, nystatin is recommended (rinse 4 times a day for 10 d). If grade 3 or 4 stomatitis occurs, the frequency of rinse application should be increased to 8-12 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).


TKI-related cardiac toxicity may present as asymptomatic Q-T 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 imatinib-treated 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[60,61]. The mechanism underlying imatinib-induced cardiotoxicity may involve myocardial toxicity caused by c-Abl inhibition[62]. The rate of cardiac toxicity in sunitinib-treated GIST patients is higher than that of imatinib treatment, and the incidence of heart failure is reported to be 2.7%-15%[63-65], which needs to be paid more attention. The possible mechanisms of this sunitinib-induced cardiotoxicity include abnormality of mitochondrial energy metabolism induced by 5’ adenosine monophosphate-activated protein kinase (AMPK) inhibition in cardiac myocytes[66], and decreased myocardial 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)[10].

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 interrupted (GRADE high). Each patient needs to be assessed individually when the cardiac function has stabilized, with consideration given to available alternative treatments and the trade-off between the cardiac- and GIST-related 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 symptoms 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[5] (GRADE moderate).


The incidence of hypothyroidism caused by sunitinib is higher. Clinical or subclinical hypothyroidism reportedly occurs in 53%-85% of GIST patients taking sunitinib[67-69].

The mechanism of sunitinib-induced hypothyroidism is not yet clear. Although studies have shown that during the sunitinib treatment, the thyroid uptake rate of I123 is reduced. Most of such AE cases return to normal uptake rate after treatment completion, suggesting that the possible mechanism of this hypothyroidism involves an obstacle in the thyroid gland’s ability to uptake iodine[70]. Some researchers have theorized that destruction of the thyroid gland by sunitinib is the main pathogenic mechanism of the related hypothyroidism[71]. In addition, sunitinib has been shown to inhibit thyroid peroxidase activity and to reduce thyroid hormone synthesis[72], 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[73], 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 rearrangement/papillary adenocarcinoma kinase (RET/PTC) of the cell proliferation signaling pathway[74], which plays an important role in maintaining normal thyroid physiological function[75] and can induce hypothyroidism.

Thyroid dysfunction caused by sunitinib is more frequent in the early stage of treatment and most cases 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 sunitinib-induced 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[76-78] have found that the median progression-free survival in patients with sunitinib-induced hypothyroidism is longer than in those who retained normal thyroid function. Therefore, some scholars[79,80] 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 therapy, thyroid function should be assessed before the treatment initiation. For those with a past history of thyroid disease, the level of thyroid-stimulating hormone (TSH) should be monitored during the treatment course[42,81,82]; yet, the optimal TSH monitoring frequency and time have not been determined. Sunitinib-induced thyroid toxicity is usually not accompanied by clinical symptoms and is self-limiting (GRADE moderate). It is usually unnecessary to modify the dose or interrupt the administration of sunitinib (GRADE moderate). If severe symptoms of thyrotoxicosis 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 hormone 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[5,8]. Abnormal liver transaminase levels have been observed in about 5.4% of GIST patients receiving imatinib (2.7% representing grades 3 and 4)[2], and each case of imatinib-induced acute severe hepatotoxicity needs to be addressed seriously as it could cause hepatic failure or even death[83,84]. 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 periodically 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 reduction. For patients with persistent grade 2 toxicity [AST/ALT at 2.5- to 5-fold upper limit of normal (ULN) value], a complete work-up to determine the cause of abnormal liver function is necessary (GRADE moderate). In patients with ongoing grade 2 toxicity, detailed evaluation is needed to determine dose reduction or interruption[4] (GRADE moderate). The current management of grade 3 or higher elevations in transaminases (AST/ALT at > 5-fold ULN) is to interrupt the TKI treatment (GRADE high). When the liver functions return to grade 1 or less (AST/ALT at < 2.5-fold ULN or bilirubin at < 1.5-fold 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 sunitinib-treated patients is less than that in the imatinib-treated, and for sunitinib the dose can be decreased by 12.5 mg daily from the original dose when reinstituting the treatment[42] (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[85,86]. 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 well-recognized risk in patients with chronic HBV infection during chemotherapy and immunosuppressant therapy[87-90]. HBV reactivation can be severe and potentially fatal. There have been some reports of HBV reactivation in patients receiving imatinib[91-97]. HBV screening tests should be performed before receiving TKIs[98,99] (GRADE low). Prophylactic antiviral treatment should be offered to HBsAg-positive patients during treatment[98-100] (GRADE low). In addition, HBV virus load of anti-HBc-positive, HBsAg-negative patients could be monitored to assess the eventual reactivation of the occult disease[99] (GRADE low).

Nephrotoxicity has been observed rarely in GIST patients treated with TKIs. However, its monitoring should still be applied vigilantly during long-term treatment with TKIs, which may cause decline in kidney function. Cases of TKI-related acute kidney injury, chronic kidney disease, proteinuria, and nephrotic syndrome have been reported[101]. The monitoring of renal function should begin at treatment initiation and continue on a periodic schedule throughout the treatment course. When impaired kidney function is detected, it is necessary to consult a kidney specialist and evaluate the value of continuing 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, alopecia, and madarosis. Compared with imatinib-treated patients, sunitinib-treated patients experience hair discoloration during treatment at a much more frequent rate (15.2%)[102]. Some researchers have reported that inhibition of kit pathway may reduce hair pigmentation. The functions of tyrosinase and tyrosinase-related protein 1, which are related to melanin synthesis, have been found to be impaired in TKI-treated patients as well[9] (GRADE high).

GIST patients receiving TKI treatment should be informed of the possibility of developing an uneven hair pigmentation AE. It is also necessary for patients to know that hair disorders associated with sunitinib are mostly mild and generally self-limiting, and that the AE will attenuate after cessation of treatment[9,10] (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 TKI-induced interstitial lung disease need close medical attention and appropriate treatment. The incidence of interstitial lung disease among TKI-treated 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%[103]. The collective literature, albeit limited, suggests that interstitial lung disease may affect Asians more than other races and males more than females[104]. In addition, a history of interstitial lung disease is a risk factor for development of this AE during TKI therapy[105].

The mechanisms of TKI-induced interstitial lung disease 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 PDGFR-A[106,107]. The symptoms are usually unspecific and present a few months into the treatment; these include fever of unknown origin, cough, dyspnea, hypoxemia, and hyper-eosinophilia. Chest X-ray, computed tomography (CT), and high-resolution CT may help to diagnose the interstitial lung disease. The typical CT characteristics are ground-glass opacity, irregular lining or reticular areas of formation with bronchiectasis and bronchiolectasis.

The success of treating TKI-induced interstitial lung disease depends on rapid and correct diagnoses. When a TKI-treated 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 discontinue the TKI treatment and treat patients with timely and sufficient corticosteroids, and antibiotics when necessary[108] (GRADE moderate). Although the severity of TKI-induced interstitial lung disease varies, it usually responds well to corticosteroid therapy[108] (GRADE moderate). 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 effective, 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[108] (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 treatment, especially for imatinib and when administered at high dosage (800 mg/d). A reported 16.7% of imatinib-treated patients present with grade 3-4 anemia[109], as compared to only 6.2% of sunitinib-treated patients[11]. GIST patients may have iron-deficiency 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 deficiency, leading to megaloblastic anemia. Theoretically, TKIs may also inhibit KIT-expressing 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 hemoglobin level < 94 g/L), treatment regimens vary according 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 mortality rate from erythropoietin and darbepoetin alfa anemia therapies was found by meta-analyses[110,111]. 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 effects 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 undergoing TKI therapy. The majority of these AEs are of grades 1-2. The rate of grades 3-4 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[2,11,13].

For patients with grades 1-2 TKI-induced neutropenia, the TKI treatment can be continued at the initial dose and no specific management needs to be considered. If grades 3-4 neutropenia appear, administration of granulocyte colony-stimulating factor (G-CSF) is indicated and the TKI treatment should be suspended until the neutrophil count exceeds 1.5 × 106/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 3-4) 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 G-CSF treatment in a mouse model of neutropenia indicated that the G-CSF may decrease the effect of anti-VEGF therapy[112]. These bench laboratory experimental results suggest that clinical administration of G-CSF and other granulocyte growth factors in combination with anti-VEGF therapies, such as sunitinib and regorafenib, should be carefully evaluated (GRADE moderate).

Thrombocytopenia: Thrombocytopenia is rarely observed 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 3-4: 5.7%)[2,11,13].

For patients with mild or moderate TKI-induced thrombocytopenia (grades 1-2), 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 × 109/L, recombinant human thrombopoietin (TPO) or interleukin-11 is indicated and the TKI treatment should be interrupted until the platelet count rises above 75 × 109/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 3-4). 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).


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.


Manuscript source: Unsolicited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: China

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P- Reviewer: Can G, Tian YT, Yan SL S- Editor: Ma RY L- Editor: Wang TQ E- Editor: Yin SY

1.  Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE, Falck-Ytter Y, Meerpohl J, Norris S. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64:401-406.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3306]  [Cited by in F6Publishing: 3059]  [Article Influence: 330.6]  [Reference Citation Analysis (0)]
2.  Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472-480.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3018]  [Cited by in F6Publishing: 1022]  [Article Influence: 158.8]  [Reference Citation Analysis (0)]
3.  Sutent® Summary of Product Characteristics 2008. Sandwich, Kent, UK: Pfizer Ltd. .  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Deininger MW, O’Brien SG, Ford JM, Druker BJ. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol. 2003;21:1637-1647.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 262]  [Cited by in F6Publishing: 71]  [Article Influence: 14.6]  [Reference Citation Analysis (0)]
5.  Joensuu H, Trent JC, Reichardt P. Practical management of tyrosine kinase inhibitor-associated side effects in GIST. Cancer Treat Rev. 2011;37:75-88.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 62]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
6.  Demetri GD, Benjamin RS, Blanke CD, Blay JY, Casali P, Choi H, Corless CL, Debiec-Rychter M, DeMatteo RP, Ettinger DS. NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw. 2007;5 Suppl 2:S1-29; quiz S30.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Guilhot F. Indications for imatinib mesylate therapy and clinical management. Oncologist. 2004;9:271-281.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 115]  [Cited by in F6Publishing: 99]  [Article Influence: 6.8]  [Reference Citation Analysis (0)]
8.  Zong L, Chen P, Zhao W, Shi L. Efficacy evaluation of imatinib in the treatment of patients with gastrointestinal stromal tumors. Turk J Gastroenterol. 2011;22:479-485.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 2]  [Article Influence: 0.2]  [Reference Citation Analysis (0)]
9.  Gralla RJ. New agents, new treatment, and antiemetic therapy. Semin Oncol. 2002;29:119-124.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 13]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
10.  Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M, Joensuu H. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:295-302.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 774]  [Cited by in F6Publishing: 379]  [Article Influence: 86.0]  [Reference Citation Analysis (0)]
11.  Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368:1329-1338.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1773]  [Cited by in F6Publishing: 694]  [Article Influence: 118.2]  [Reference Citation Analysis (0)]
12.  Ben Ami E, Demetri GD. A safety evaluation of imatinib mesylate in the treatment of gastrointestinal stromal tumor. Expert Opin Drug Saf. 2016;15:571-578.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 19]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
13.  Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, Issels R, van Oosterom A, Hogendoorn PC, Van Glabbeke M. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364:1127-1134.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1194]  [Cited by in F6Publishing: 445]  [Article Influence: 70.2]  [Reference Citation Analysis (0)]
14.  Sutent® Summary of Product Characteristics 2010  Sandwich, Kent, UK: Pfizer Ltd.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Valeyrie L, Bastuji-Garin S, Revuz J, Bachot N, Wechsler J, Berthaud P, Tulliez M, Giraudier S. Adverse cutaneous reactions to imatinib (STI571) in Philadelphia chromosome-positive leukemias: a prospective study of 54 patients. J Am Acad Dermatol. 2003;48:201-206.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 157]  [Cited by in F6Publishing: 133]  [Article Influence: 8.7]  [Reference Citation Analysis (0)]
16.  Rosenbaum SE, Wu S, Newman MA, West DP, Kuzel T, Lacouture ME. Dermatological reactions to the multitargeted tyrosine kinase inhibitor sunitinib. Support Care Cancer. 2008;16:557-566.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 65]  [Article Influence: 6.1]  [Reference Citation Analysis (0)]
17.  Pietras K, Ostman A, Sjöquist M, Buchdunger E, Reed RK, Heldin CH, Rubin K. Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res. 2001;61:2929-2934.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Esmaeli B, Prieto VG, Butler CE, Kim SK, Ahmadi MA, Kantarjian HM, Talpaz M. Severe periorbital edema secondary to STI571 (Gleevec). Cancer. 2002;95:881-887.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 87]  [Cited by in F6Publishing: 59]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
19.  Fraunfelder FW, Solomon J, Druker BJ, Esmaeli B, Kuyl J. Ocular side-effects associated with imatinib mesylate (Gleevec). J Ocul Pharmacol Ther. 2003;19:371-375.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 69]  [Cited by in F6Publishing: 56]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
20.  Ho WL, Wong H, Yau T. The ophthalmological complications of targeted agents in cancer therapy: what do we need to know as ophthalmologists? Acta Ophthalmol. 2013;91:604-609.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 25]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
21.  Stahl JL, Cook EB, Graziano FM, Barney NP. Human conjunctival mast cells: expression of Fc epsilonRI, c-kit, ICAM-1, and IgE. Arch Ophthalmol. 1999;117:493-497.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 22]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
22.  Qiu HB, Zhuang W, Wu T, Xin S, Lin CZ, Ruan HL, Zhu X, Huang M, Li JL, Hou XY. Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1. Pharmacogenomics J. 2018;18:460-466.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 5]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
23.  Biswas SK, Zhao Y, Sandirasegarane L. Imatinib induces apoptosis by inhibiting PDGF- but not insulin-induced PI 3-kinase/Akt survival signaling in RGC-5 retinal ganglion cells. Mol Vis. 2009;15:1599-1610.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Kwon SI, Lee DH, Kim YJ. Optic disc edema as a possible complication of Imatinib mesylate (Gleevec). Jpn J Ophthalmol. 2008;52:331-333.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 18]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
25.  Govind Babu K, Attili VS, Bapsy PP, Anupama G. Imatinib-induced optic neuritis in a patient of chronic myeloid leukemia. Int Ophthalmol. 2007;27:43-44.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 23]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
26.  Masood I, Negi A, Dua HS. Imatinib as a cause of cystoid macular edema following uneventful phacoemulsification surgery. J Cataract Refract Surg. 2005;31:2427-2428.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 18]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
27.  Dogan SS, Esmaeli B. Ocular side effects associated with imatinib mesylate and perifosine for gastrointestinal stromal tumor. Hematol Oncol Clin North Am. 2009;23:109-114, ix.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 15]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
28.  McClelland CM, Harocopos GJ, Custer PL. Periorbital edema secondary to imatinib mesylate. Clin Ophthalmol. 2010;4:427-431.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 12]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
29.  Radaelli F, Vener C, Ripamonti F, Iurlo A, Colombi M, Artoni A, Reda G, Deliliers GL. Conjunctival hemorrhagic events associated with imatinib mesylate. Int J Hematol. 2007;86:390-393.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 4]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
30.  Dechend R, Luft FC. Angiogenesis factors and preeclampsia. Nat Med. 2008;14:1187-1188.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 25]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
31.  Eskens FA, Verweij J. The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer. 2006;42:3127-3139.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 252]  [Cited by in F6Publishing: 225]  [Article Influence: 16.8]  [Reference Citation Analysis (0)]
32.  George S, Blay JY, Casali PG, Le Cesne A, Stephenson P, Deprimo SE, Harmon CS, Law CN, Morgan JA, Ray-Coquard I. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer. 2009;45:1959-1968.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 246]  [Cited by in F6Publishing: 217]  [Article Influence: 20.5]  [Reference Citation Analysis (0)]
33.  Kollmannsberger C, Soulieres D, Wong R, Scalera A, Gaspo R, Bjarnason G. Sunitinib therapy for metastatic renal cell carcinoma: recommendations for management of side effects. Can Urol Assoc J. 2007;1:S41-S54.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 41]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
34.  Langenberg MH, van Herpen CM, De Bono J, Schellens JH, Unger C, Hoekman K, Blum HE, Fiedler W, Drevs J, Le Maulf F. Effective strategies for management of hypertension after vascular endothelial growth factor signaling inhibition therapy: results from a phase II randomized, factorial, double-blind study of Cediranib in patients with advanced solid tumors. J Clin Oncol. 2009;27:6152-6159.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 81]  [Cited by in F6Publishing: 29]  [Article Influence: 6.8]  [Reference Citation Analysis (0)]
35.  Lankhorst S, Kappers MH, van Esch JH, Smedts FM, Sleijfer S, Mathijssen RH, Baelde HJ, Danser AH, van den Meiracker AH. Treatment of hypertension and renal injury induced by the angiogenesis inhibitor sunitinib: preclinical study. Hypertension. 2014;64:1282-1289.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 54]  [Cited by in F6Publishing: 30]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
36.  Shen L, Yan Sun, Jian-Ming Xu, Carlos Linn, Qiao Wang, Li-Qiang Yang, Shu-Kui Qin. Phase IV Study of Sunitinib in Chinese Patients with Imatinib-Resistant or Imatinib-Intolerant Gastrointestinal Stromal Tumors. Oncol Ther. 2017;5 Suppl 1:1-10.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 1]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
37.  Sica DA. Angiogenesis inhibitors and hypertension: an emerging issue. J Clin Oncol. 2006;24:1329-1331.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 94]  [Cited by in F6Publishing: 32]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
38.  Zalcberg JR, Verweij J, Casali PG, Le Cesne A, Reichardt P, Blay JY, Schlemmer M, Van Glabbeke M, Brown M, Judson IR; EORTC Soft Tissue and Bone Sarcoma Group, the Italian Sarcoma Group; Australasian Gastrointestinal Trials Group. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer. 2005;41:1751-1757.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 260]  [Cited by in F6Publishing: 223]  [Article Influence: 16.3]  [Reference Citation Analysis (0)]
39.  Li J, Gao J, Hong J, Shen L. Efficacy and safety of sunitinib in Chinese patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors. Future Oncol. 2012;8:617-624.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 18]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
40.  Schmidinger M. Understanding and managing toxicities of vascular endothelial growth factor (VEGF) inhibitors. EJC Suppl. 2013;11:172-191.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 64]  [Cited by in F6Publishing: 61]  [Article Influence: 10.7]  [Reference Citation Analysis (0)]
41.  Li J, Ye Y, Wang J, Zhang B, Qin S, Shi Y, He Y, Liang X, Liu X, Zhou Y. Chinese consensus guidelines for diagnosis and management of gastrointestinal stromal tumor. Chin J Cancer Res. 2017;29:281-293.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 46]  [Article Influence: 11.8]  [Reference Citation Analysis (0)]
42.  Desai J, Pecori-Giraldi F, McArthur G. Sunitinib malate in the treatment of renal cell carcinoma and gastrointestinal stromal tumor: recommendations for patient management. Asian Pac J Clin Oncol. 2010;167-176.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Efficace F, Baccarani M, Breccia M, Cottone F, Alimena G, Deliliers GL, Baratè C, Specchia G, Di Lorenzo R, Luciano L. Chronic fatigue is the most important factor limiting health-related quality of life of chronic myeloid leukemia patients treated with imatinib. Leukemia. 2013;27:1511-1519.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 87]  [Reference Citation Analysis (0)]
44.  Kurzrock R. The role of cytokines in cancer-related fatigue. Cancer. 2001;92:1684-1688.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
45.  Seruga B, Zhang H, Bernstein LJ, Tannock IF. Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer. 2008;8:887-899.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 400]  [Cited by in F6Publishing: 377]  [Article Influence: 30.8]  [Reference Citation Analysis (0)]
46.  Cramer H, Lauche R, Klose P, Lange S, Langhorst J, Dobos GJ. Yoga for improving health-related quality of life, mental health and cancer-related symptoms in women diagnosed with breast cancer. Cochrane Database Syst Rev. 2017;1:CD010802.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 56]  [Article Influence: 10.8]  [Reference Citation Analysis (0)]
47.  Cassileth BR, Vickers AJ. Massage therapy for symptom control: outcome study at a major cancer center. J Pain Symptom Manage. 2004;28:244-249.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 212]  [Cited by in F6Publishing: 157]  [Article Influence: 12.5]  [Reference Citation Analysis (0)]
48.  Post-White J, Kinney ME, Savik K, Gau JB, Wilcox C, Lerner I. Therapeutic massage and healing touch improve symptoms in cancer. Integr Cancer Ther. 2003;2:332-344.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 177]  [Cited by in F6Publishing: 121]  [Article Influence: 10.4]  [Reference Citation Analysis (0)]
49.  Conley CC, Kamen CS, Heckler CE, Janelsins MC, Morrow GR, Peppone LJ, Scalzo AJ, Gross H, Dakhil S, Mustian KM. Modafinil Moderates the Relationship Between Cancer-Related Fatigue and Depression in 541 Patients Receiving Chemotherapy. J Clin Psychopharmacol. 2016;36:82-85.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 3]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
50.  National Cancer Institute. Common terminologycriteria for adverse events (CTCAE): version 4.0. [updated June 14, 2010 cited January 23, 2012] Available at: .  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349:427-434.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2070]  [Cited by in F6Publishing: 587]  [Article Influence: 115.0]  [Reference Citation Analysis (0)]
52.  Izzedine H, Massard C, Spano JP, Goldwasser F, Khayat D, Soria JC. VEGF signalling inhibition-induced proteinuria: Mechanisms, significance and management. Eur J Cancer. 2010;46:439-448.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 186]  [Cited by in F6Publishing: 157]  [Article Influence: 15.5]  [Reference Citation Analysis (0)]
53.  Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007;49:186-193.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 421]  [Cited by in F6Publishing: 363]  [Article Influence: 30.1]  [Reference Citation Analysis (0)]
54.  Schmidinger M, Bellmunt J. Plethora of agents, plethora of targets, plethora of side effects in metastatic renal cell carcinoma. Cancer Treat Rev. 2010;36:416-424.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 72]  [Cited by in F6Publishing: 64]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
55.  de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, Snapinn S, Cooper ME, Mitch WE, Brenner BM. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 2004;65:2309-2320.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 673]  [Cited by in F6Publishing: 571]  [Article Influence: 39.6]  [Reference Citation Analysis (0)]
56.  Atkins RC, Briganti EM, Lewis JB, Hunsicker LG, Braden G, Champion de Crespigny PJ, DeFerrari G, Drury P, Locatelli F, Wiegmann TB. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am J Kidney Dis. 2005;45:281-287.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 237]  [Cited by in F6Publishing: 203]  [Article Influence: 14.8]  [Reference Citation Analysis (0)]
57.  Kidney Disease Outcomes Quality Initiative. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43:S1-290.  [PubMed]  [DOI]  [Cited in This Article: ]
58.  Abdel-Rahman O, Fouad M. Risk of mucocutaneous toxicities in patients with solid tumors treated with sunitinib: a critical review and meta analysis. Expert Rev Anticancer Ther. 2015;15:129-141.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 14]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
59.  Yuan A, Kurtz SL, Barysauskas CM, Pilotte AP, Wagner AJ, Treister NS. Oral adverse events in cancer patients treated with VEGFR-directed multitargeted tyrosine kinase inhibitors. Oral Oncol. 2015;51:1026-1033.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 20]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
60.  Atallah E, Durand JB, Kantarjian H, Cortes J. Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood. 2007;110:1233-1237.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 174]  [Cited by in F6Publishing: 142]  [Article Influence: 12.4]  [Reference Citation Analysis (0)]
61.  Hatfield A, Owen S, Pilot PR. In reply to ‘Cardiotoxicity of the cancer therapeutic agent imatinib mesylate’. Nat Med. 2007;13:13; author reply 15-13; author reply 15-16.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 65]  [Reference Citation Analysis (0)]
62.  Kerkelä R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, Walters B, Shevtsov S, Pesant S, Clubb FJ. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908-916.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 818]  [Cited by in F6Publishing: 698]  [Article Influence: 54.5]  [Reference Citation Analysis (0)]
63.  Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, Nguyen L, Woulfe K, Pravda E, Cassiola F, Desai J. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007;370:2011-2019.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 771]  [Cited by in F6Publishing: 264]  [Article Influence: 55.1]  [Reference Citation Analysis (0)]
64.  Shaikh AY, Shih JA. Chemotherapy-induced cardiotoxicity. Curr Heart Fail Rep. 2012;9:117-127.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 39]  [Cited by in F6Publishing: 32]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
65.  Telli ML, Witteles RM, Fisher GA, Srinivas S. Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Ann Oncol. 2008;19:1613-1618.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 184]  [Cited by in F6Publishing: 170]  [Article Influence: 14.2]  [Reference Citation Analysis (0)]
66.  Kerkela R, Woulfe KC, Durand JB, Vagnozzi R, Kramer D, Chu TF, Beahm C, Chen MH, Force T. Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase. Clin Transl Sci. 2009;2:15-25.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 165]  [Cited by in F6Publishing: 151]  [Article Influence: 15.0]  [Reference Citation Analysis (0)]
67.  Baldazzi V, Tassi R, Lapini A, Lunghi A, Garofoli E, Caruso S, Carini M, Mazzanti R. Sunitinib-induced hyperparathyroidism: a possible mechanism to altered bone homeostasis. Cancer. 2012;118:3165-3172.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 10]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
68.  Sabatier R, Eymard JC, Walz J, Deville JL, Narbonne H, Boher JM, Salem N, Marcy M, Brunelle S, Viens P. Could thyroid dysfunction influence outcome in sunitinib-treated metastatic renal cell carcinoma? Ann Oncol. 2012;23:714-721.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 39]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
69.  Riesenbeck LM, Bierer S, Hoffmeister I, Köpke T, Papavassilis P, Hertle L, Thielen B, Herrmann E. Hypothyroidism correlates with a better prognosis in metastatic renal cancer patients treated with sorafenib or sunitinib. World J Urol. 2011;29:807-813.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 65]  [Reference Citation Analysis (0)]
70.  Mannavola D, Coco P, Vannucchi G, Bertuelli R, Carletto M, Casali PG, Beck-Peccoz P, Fugazzola L. A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab. 2007;92:3531-3534.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 166]  [Cited by in F6Publishing: 134]  [Article Influence: 11.9]  [Reference Citation Analysis (0)]
71.  Grossmann M, Premaratne E, Desai J, Davis ID. Thyrotoxicosis during sunitinib treatment for renal cell carcinoma. Clin Endocrinol (Oxf). 2008;69:669-672.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 62]  [Article Influence: 6.1]  [Reference Citation Analysis (0)]
72.  Wong E, Rosen LS, Mulay M, Vanvugt A, Dinolfo M, Tomoda C, Sugawara M, Hershman JM. Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid. 2007;17:351-355.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 156]  [Cited by in F6Publishing: 127]  [Article Influence: 11.1]  [Reference Citation Analysis (0)]
73.  Makita N, Miyakawa M, Fujita T, Iiri T. Sunitinib induces hypothyroidism with a markedly reduced vascularity. Thyroid. 2010;20:323-326.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 54]  [Cited by in F6Publishing: 46]  [Article Influence: 4.9]  [Reference Citation Analysis (0)]
74.  Salem AK, Fenton MS, Marion KM, Hershman JM. Effect of sunitinib on growth and function of FRTL-5 thyroid cells. Thyroid. 2008;18:631-635.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 39]  [Cited by in F6Publishing: 34]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
75.  Kim DW, Jo YS, Jung HS, Chung HK, Song JH, Park KC, Park SH, Hwang JH, Rha SY, Kweon GR. An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab. 2006;91:4070-4076.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 222]  [Cited by in F6Publishing: 210]  [Article Influence: 14.8]  [Reference Citation Analysis (0)]
76.  Clemons J, Gao D, Naam M, Breaker K, Garfield D, Flaig TW. Thyroid dysfunction in patients treated with sunitinib or sorafenib. Clin Genitourin Cancer. 2012;10:225-231.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 29]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
77.  Sella A, Hercbergs AH, Hanovich E, Kovel S. Does sunitinib-induced hypothyroidism play a role in the activity of sunitinib in metastatic renal cell carcinoma? Chemotherapy. 2012;58:200-205.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 17]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
78.  Schmidinger M, Larkin J, Ravaud A. Experience with sunitinib in the treatment of metastatic renal cell carcinoma. Ther Adv Urol. 2012;4:253-265.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 24]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
79.  Garfield D, Hercbergs A, Davis P. Unanswered questions regarding the management of sunitinib-induced hypothyroidism. Nat Clin Pract Oncol. 2007;4:674.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 17]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
80.  Castellano D, Ravaud A, Schmidinger M, De Velasco G, Vazquez F. Therapy management with sunitinib in patients with metastatic renal cell carcinoma: key concepts and the impact of clinical biomarkers. Cancer Treat Rev. 2013;39:230-240.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 17]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
81.  Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, Morgan JA, Dychter SS, Larsen PR, Demetri GD. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med. 2006;145:660-664.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 297]  [Cited by in F6Publishing: 233]  [Article Influence: 19.8]  [Reference Citation Analysis (0)]
82.  Rini BI, Tamaskar I, Shaheen P, Salas R, Garcia J, Wood L, Reddy S, Dreicer R, Bukowski RM. Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2007;99:81-83.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 285]  [Cited by in F6Publishing: 248]  [Article Influence: 20.4]  [Reference Citation Analysis (0)]
83.  Fuster F, Medina L, Vallansot R, Granell M, Bruguera M. [Imatinib-induced toxic hepatitis: description of two cases and review of the literature]. Gastroenterol Hepatol. 2007;30:525-530.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 5]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
84.  Tonyali O, Coskun U, Yildiz R, Karakan T, Demirci U, Akyurek N, Benekli M, Buyukberber S. Imatinib mesylate-induced acute liver failure in a patient with gastrointestinal stromal tumors. Med Oncol. 2010;27:768-773.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 35]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
85.  Yan YP, Su HX, Ji ZH, Shao ZJ, Pu ZS. Epidemiology of Hepatitis B Virus Infection in China: Current Status and Challenges. J Clin Transl Hepatol. 2014;2:15-22.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 22]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
86.  Liang X, Bi S, Yang W, Wang L, Cui G, Cui F, Zhang Y, Liu J, Gong X, Chen Y. Epidemiological serosurvey of hepatitis B in China--declining HBV prevalence due to hepatitis B vaccination. Vaccine. 2009;27:6550-6557.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 582]  [Cited by in F6Publishing: 565]  [Article Influence: 48.5]  [Reference Citation Analysis (0)]
87.  Yeo W, Chan HL. Hepatitis B virus reactivation associated with anti-neoplastic therapy. J Gastroenterol Hepatol. 2013;28:31-37.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 39]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
88.  Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology. 1991;100:182-188.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 616]  [Cited by in F6Publishing: 167]  [Article Influence: 20.5]  [Reference Citation Analysis (0)]
89.  Alexopoulos CG, Vaslamatzis M, Hatzidimitriou G. Prevalence of hepatitis B virus marker positivity and evolution of hepatitis B virus profile, during chemotherapy, in patients with solid tumours. Br J Cancer. 1999;81:69-74.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 71]  [Cited by in F6Publishing: 71]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
90.  Voican CS, Mir O, Loulergue P, Dhooge M, Brezault C, Dréanic J, Chaussade S, Pol S, Coriat R. Hepatitis B virus reactivation in patients with solid tumors receiving systemic anticancer treatment. Ann Oncol. 2016;27:2172-2184.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 40]  [Article Influence: 8.4]  [Reference Citation Analysis (0)]
91.  Kim SG, Chun JM, Jin R, Kim JY, Won DI, Hwang YJ. Living donor liver transplantation for acute hepatic failure caused by reactivation of hepatitis B virus infection after chemotherapy for hematologic malignancy: case reports. Transplant Proc. 2010;42:843-845.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 17]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
92.  Kang BW, Lee SJ, Moon JH, Kim SN, Chae YS, Kim JG, Hwang YJ, Sohn SK. Chronic myeloid leukemia patient manifesting fatal hepatitis B virus reactivation during treatment with imatinib rescued by liver transplantation: case report and literature review. Int J Hematol. 2009;90:383-387.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 35]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
93.  Ikeda K, Shiga Y, Takahashi A, Kai T, Kimura H, Takeyama K, Noji H, Ogawa K, Nakamura A, Ohira H. Fatal hepatitis B virus reactivation in a chronic myeloid leukemia patient during imatinib mesylate treatment. Leuk Lymphoma. 2006;47:155-157.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 62]  [Cited by in F6Publishing: 65]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
94.  Lai GM, Yan SL, Chang CS, Tsai CY. Hepatitis B reactivation in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor. World J Gastroenterol. 2013;19:1318-1321.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 49]  [Cited by in F6Publishing: 49]  [Article Influence: 6.1]  [Reference Citation Analysis (0)]
95.  Lakhani S, Davidson L, Priebat DA, Sherker AH. Reactivation of chronic hepatitis B infection related to imatinib mesylate therapy. Hepatol Int. 2008;2:498-499.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 27]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
96.  Thia TJ, Tan HH, Chuah TH, Chow WC, Lui HF. Imatinib mesylate-related fatal acute hepatic failure in a patient with chronic myeloid leukaemia and chronic hepatitis B infection. Singapore Med J. 2008;49:e86-e89.  [PubMed]  [DOI]  [Cited in This Article: ]
97.  Walker EJ, Simko JP, Ko AH. Hepatitis B viral reactivation secondary to imatinib treatment in a patient with gastrointestinal stromal tumor. Anticancer Res. 2014;34:3629-3634.  [PubMed]  [DOI]  [Cited in This Article: ]
98.  Chang CS, Tsai CY, Yan SL. Hepatitis B reactivation in patients receiving targeted therapies. Hematology. 2017;22:592-598.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 13]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
99.  Reinwald M, Silva JT, Mueller NJ, Fortún J, Garzoni C, de Fijter JW, Fernández-Ruiz M, Grossi P, Aguado JM. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Intracellular signaling pathways: tyrosine kinase and mTOR inhibitors). Clin Microbiol Infect. 2018;24 Suppl 2:S53-S70.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 66]  [Reference Citation Analysis (0)]
100.  Law MF, Ho R, Cheung CK, Tam LH, Ma K, So KC, Ip B, So J, Lai J, Ng J. Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy. World J Gastroenterol. 2016;22:6484-6500.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 44]  [Cited by in F6Publishing: 39]  [Article Influence: 8.8]  [Reference Citation Analysis (0)]
101.  Yilmaz M, Lahoti A, O’Brien S, Nogueras-González GM, Burger J, Ferrajoli A, Borthakur G, Ravandi F, Pierce S, Jabbour E. Estimated glomerular filtration rate changes in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. Cancer. 2015;121:3894-3904.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 27]  [Reference Citation Analysis (0)]
102.  Alexandrescu DT, Dasanu CA, Farzanmehr H, Kauffman L. Persistent cutaneous hyperpigmentation after tyrosine kinase inhibition with imatinib for GIST. Dermatol Online J. 2008;14:7.  [PubMed]  [DOI]  [Cited in This Article: ]
103.  Ohnishi K, Sakai F, Kudoh S, Ohno R. Twenty-seven cases of drug-induced interstitial lung disease associated with imatinib mesylate. Leukemia. 2006;20:1162-1164.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 65]  [Cited by in F6Publishing: 47]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
104.  Loong HH, Yeo W. Imatinib-induced interstitial lung disease and sunitinib-associated intra-tumour haemorrhage. Hong Kong Med J. 2008;14:495-498.  [PubMed]  [DOI]  [Cited in This Article: ]
105.  Bergeron A, Bergot E, Vilela G, Ades L, Devergie A, Espérou H, Socié G, Calvo F, Gluckman E, Ribaud P. Hypersensitivity pneumonitis related to imatinib mesylate. J Clin Oncol. 2002;20:4271-4272.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 8]  [Reference Citation Analysis (0)]
106.  Yamasawa H, Sugiyama Y, Bando M, Ohno S. Drug-induced pneumonitis associated with imatinib mesylate in a patient with idiopathic pulmonary fibrosis. Respiration. 2008;75:350-354.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 11]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
107.  Min JH, Lee HY, Lim H, Ahn MJ, Park K, Chung MP, Lee KS. Drug-induced interstitial lung disease in tyrosine kinase inhibitor therapy for non-small cell lung cancer: a review on current insight. Cancer Chemother Pharmacol. 2011;68:1099-1109.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 50]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
108.  Shah RR. Tyrosine Kinase Inhibitor-Induced Interstitial Lung Disease: Clinical Features, Diagnostic Challenges, and Therapeutic Dilemmas. Drug Saf. 2016;39:1073-1091.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 31]  [Article Influence: 9.3]  [Reference Citation Analysis (0)]
109.  Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, Raymond AK, Bramwell VH, Baker LH, Maki RG. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26:626-632.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 694]  [Cited by in F6Publishing: 312]  [Article Influence: 53.4]  [Reference Citation Analysis (0)]
110.  Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Djulbegovic B. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst. 2006;98:708-714.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 407]  [Cited by in F6Publishing: 297]  [Article Influence: 27.1]  [Reference Citation Analysis (0)]
111.  Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, Zwahlen M, Clarke M, Weingart O, Kluge S. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009;373:1532-1542.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 423]  [Cited by in F6Publishing: 117]  [Article Influence: 35.3]  [Reference Citation Analysis (0)]
112.  Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M, Meng YG, Ferrara N. G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci USA. 2009;106:6742-6747.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 334]  [Cited by in F6Publishing: 306]  [Article Influence: 27.8]  [Reference Citation Analysis (0)]