Although TKIs are generally better tolerated than cytotoxic chemotherapy, many patients develop side effects from on-target and off-target effects which require aggressive management in order to maintain patient compliance, optimize therapy, and avoid potentially life-threatening consequences. Since many patients require long-term use of TKIs for continued control of disease, it is imperative for the treating clinician to be familiar with the potential side effects of these drugs. The most frequent side effects of TKIs are hypertension, dermatologic effects, fatigue, and diarrhea. In addition, the risk of bleeding and liver toxicity may be fatal. The clinician should conduct thorough physical and laboratory examinations prior to considering therapy with these drugs to identify the most appropriate choice of treatment and must monitor and treat adverse events during therapy. Treatment of all comorbid conditions should be optimized and drug-drug interaction, antifungals, antiemetics, and class III antiarrhythmic agents avoided to prevent interactions with TKIs. In this section we will discuss the most common and potentially fatal side effects of TKIs with management recommendations.
lists adverse events of the commercially available TKIs relevant to thyroid cancer, their incidence, and grades (data extracted from phase III trials in renal cell carcinoma and package inserts) using Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0). The CTCAE is a list of descriptive terminology utilized for adverse event grading and reporting on clinical trials and is made available through the CTEP website at http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf
Major adverse events associated with commercially available TKIs which have been studied in thyroid cancer.
2.1. Drug-Drug Interactions
Cytochrome P450 enzymes, expressed primarily in the liver, play a primary role in the metabolism of many drugs. Sunitinib, sorafenib, pazopanib, and vandetanib are all metabolized by cytochrome P450 3A4 (CYP3A4). Of the four drugs, sorafenib appears to be the least susceptible to CYP3A4 inducers or inhibitors, although the package labeling warns against concomitant use of CYP3A4 inducers [8
]. Concomitant use of CYP3A4 inducers may decrease the plasma concentration of the TKI, resulting in decreased efficacy, while inhibitors may increase the plasma concentration, resulting in toxicity. Itraconazole, a potent inhibitor of CYP3A4, does not appear to affect the metabolism of vandetanib [9
]. lists the more common, clinically significant drugs metabolized via the CYP3A4 enzyme system.
Clinically significant CYP3A4 inducers, inhibitors, and substrates.
The medical history should include a thorough review of medications which may affect the metabolism of the TKI. Concomitant drugs which are metabolized via CYP3A4 should be avoided or substituted for another drug. If a CYP3A4 inhibitor drug cannot be eliminated, a dose reduction in the TKI should be considered. Patients should also be monitored for increasing side effects if a CYP3A4 inhibitor is coadministered.
Hypertension is the most common cardiovascular side effect associated with antiangiogenic drugs. The mechanism of hypertension is not well understood, but it has been suggested that it is due to increased fluid retention, endothelial dysfunction, nitrous oxide inhibition, rarefaction [10
], reduction of vascular surface area, and increase in peripheral vascular resistance caused by inhibition of angiogenesis [11
]. A recent study by Rini et al. suggests that the rise in blood pressure above 140/90 may be a biomarker for anticancer therapy and was associated with significant survival benefit even with treatment of antihypertensives. The use of antihypertensives did not reduce the efficacy of sunitinib in metastatic renal cell carcinoma [15
The onset of hypertension is variable. Blood pressure may begin to rise within days of therapy prior to steady state or the onset of the therapies' biological effects or may be more indolent. There are no clear guidelines for managing TKI-induced hypertension. It is our clinical practice to use ACE inhibitors, angiotensin receptor blockers (ARBs) or a beta blocker as first-line therapy for hypertension since these drugs are not metabolized via the CYP3A4 enzyme system. However, the choice of an antihypertensive should be individualized. The Angiogenesis Task Force of the National Cancer Institute Investigational Drug Steering Committee recently published guidelines for management of hypertension with TKIs [16
]. Hypertension should be controlled based on compelling and noncompelling indications to a goal of <140/90 prior to starting TKIs. Once a TKI is initiated, patients should have the blood pressure monitored within 1 week. Blood pressure monitoring at home may be more effective at prediction of outcomes from cardiovascular disease than clinic blood pressure monitoring [17
]. If the blood pressure is above goal, antihypertensive therapy should be initiated or adjusted. Patients should continue to check their blood pressure daily (with brachial blood pressure device) and report results on a weekly basis (until adequate blood pressure control is achieved), and antihypertensive drugs should be rapidly titrated or new drugs added to the regimen. Once control of blood pressure is obtained, the blood pressure should be monitored on a monthly basis. Interruption or dose reduction of the TKI may be necessary in order to achieve adequate blood pressure control. Some calcium-channel blockers, such as felodipine, diltiazem, nifedipine, and verapamil, are CYP3A4 substrates or inhibitors and should be avoided.
Sunitinib and pazopanib can lead to QT interval prolongation; therefore, they should be used with caution in patients with a history of QT prolongation and patients taking antiarrhythmic drugs. Torsade de pointes was seen in <0.1% of patients exposed to sunitinib and <2% of patients treated with pazopanib. Vandetanib carries a black box warning due to QT interval prolongation, Torsade de pointes, and sudden death observed in clinical trials involving patients with a broad variety of solid malignancies. Serial monitoring of electrocardiograms and electrolytes is mandated and electrolyte abnormalities should be corrected [9
]. In a phase III trial that examined the efficacy and safety of vandetanib 300
mg in the treatment of unresectable locally advanced or metastatic MTC, QT prolongation was reported in 14% of patients randomized to vandetanib and in 1% of patients randomized to placebo, with 8% (18/231) and 1% (1/99), respectively, being ≥grade 3 events. Vandetanib should not be given to patients who have a history of Torsades de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure. Vandetanib should not be started in patients whose corrected QT interval (QTcF, Fridericia formula) is greater than 450
ms. Specific guidelines for monitoring of QT abnormalities and electrolytes in patients taking vandetanib are specified in the package insert [9
]. In addition, use of concomitant drugs known to prolong the QT interval, such as amiodarone and erythromycin, should be avoided.
A less common but serious adverse event associated with TKIs is systolic and diastolic congestive heart failure. It appears to be more common with sunitinib but has been reported with sorafenib and pazopanib. Patients may present with very dramatic symptoms of heart failure, while others demonstrate mild symptoms which may be difficult to differentiate from fatigue due to the TKI or the tumor itself [20
]. Cardiac toxicity, although not always completely reversible, is often a manageable condition if patients have careful monitoring and treatment with routine heart failure therapies with beta blockers and ACE inhibitors/ARB as recommended by the guidelines of heart failure management by the American College of Cardiology. The etiology of the heart failure is thought to be due to direct reversible cardiomyocyte toxicity, possibly exacerbated by hypertension which may progress to irreversible, progressive injury if not treated with standard heart failure therapy [21
]. This toxicity is not completely understood, but platelet-derived growth factor receptor-β
) inhibition has been implicated as playing a role in the response to pressure-overload-induced stress [22
]. We recommend that all patients initiating TKIs have a baseline echocardiogram and periodic monitoring while they are on therapy. Furthermore, aggressive management of hypertension may help reduce cardiomyocyte damage.
Case Number 1
A 69-year-old woman with a history of hypertension and premature ventricular contractions was referred to our center. She had a history of T4a, N0, M0, stage IVA papillary thyroid cancer for 10 years prior. The patient's thyroid cancer was initially managed with total thyroidectomy and radioactive iodine ablation, but she developed local recurrence and pulmonary metastases several years later. She continued to have progressive disease in the lungs and neck and was referred to our center. The patient was enrolled into a phase II clinical trial with an investigational TKI targeting VEGFRs, PDGFR, and others. The patient's blood pressure was normal prior to initiation of the investigational TKI, but one week later she developed grade 2 hypertension which was difficult to control despite treatment with multiple antihypertensive agents. Her pretreatment echocardiogram demonstrated an ejection fraction of 55–60%. Nearly 4 months after starting on the investigational agent, she underwent adenosine stress test which identified a 30% ejection fraction with hypokinesia in the anterior septal segments which partially reversed with rest. Because of the presence of a left bundle branch block at baseline, definitive diagnosis of ischemia was not possible from the images. Carvedilol was initiated, and the investigational TKI was held. Echocardiogram confirmed the low ejection fraction. A cardiac catheterization with myocardial biopsy was performed. She was found to have mild ischemic heart disease (defined as less than 50% stenosis in any coronary) which was disproportionate to her degree of heart failure, and therefore the heart failure was attributed to the TKI. Direct cardiomyocyte toxicity was confirmed with the biopsy, demonstrating hypertrophy and interstitial edema, increased lipid droplets, and dilatation of sarcotubular elements (). Since the biopsy showed no myocyte death (indicating reversibility) and the echocardiogram showed a return to baseline, after 3 weeks, the investigational agent was reintroduced at a reduced dose. Two months later she was found to have progression of disease, and the investigational agent was discontinued permanently.
Figure 1 Transmission electron micrographs of endomyocardial biopsy from patient with systolic heart failure treated with a TKI. Section shows hypertrophy and interstitial edema with edematous mitochondria (open red arrow), with increased lipid droplets (solid (more ...)
Proteinuria associated with antiangiogenic therapies was first described with bevacizumab, a monoclonal antibody against VEGF [23
]. Small-molecule tyrosine kinase inhibitors, which inhibit VEGF-R, lead to proteinuria as well [24
]. Thrombotic microangiopathy and acute interstitial nephritis have been reported with sorafenib and sunitinib [25
]. The glomerular podocytes express VEGF, and glomerular endothelial cells express VEGF receptors. Thus, a proposed mechanism of proteinuria is that deletion of VEGF allele in podocytes or inhibited VEGF signaling leads to proteinuria and capillary endotheliosis [27
All patients who will receive antiangiogenic therapies should have a baseline urinalysis and protein to creatinine ratio, with routine monitoring for development of proteinuria while on treatment. A urine protein to creatinine ratio of ≥1 or 24-hour urine with ≥1
gram/dL/24 hours of protein should prompt intervention. The decision to hold drug should be considered on a case-by-case basis. Treatment with an ACE inhibitor or ARB should be initiated and consultation with nephrology may be warranted. As proteinuria is a class effect of antiangiogenic treatments, changing from one agent to another may not prevent this effect in a patient.
Dermatologic reactions observed with TKIs include hand-foot syndrome (HFS), skin induration or callous formation, rash, alopecia, hair texture and color changes, and skin discoloration. HFS, the most common and potentially most debilitating dermatologic effect, presents as desquamating lesions in a palmoplantar distribution typically at pressure points or areas of friction or trauma. The lesions can significantly affect a patient's quality of life, thus necessitating drug discontinuation or dose reduction. The pathogenesis of HFS is not entirely clear. Preventive application of hand and foot lubricants should be implemented at time of drug initiation. The package insert for sorafenib gives clear recommendations on dose modifications and holds for skin toxicity (). It has been the authors' experience with sorafenib that when patients develop grade ≥3 HFS, drug interruption until skin toxicity declines to grade ≤1 with reinitiation at 200
mg daily, and titration by 200
mg every 3–5
days can prevent further escalation of skin toxicity (unpublished data). Stevens-Johnson syndrome, characterized by a prodrome of malaise and fever, followed by rapid development of erythematous or purpuric macules, which can progress to epidermal necrosis or sloughing, has been reported with vandetanib. A patient with these signs and/or symptoms should discontinue drug therapy immediately and seek medical attention, as this could be a life-threatening adverse effect.
Table 3 Suggested dose modification for skin toxicity for sorafenib .
Skin induration and callous formation can lead to pain at pressure points and limit mobility. Referral to podiatry can be considered to reduce callous size. Skin evaluation for development of actinic keratoses or keratoacanthoma-type squamous cell carcinomas (KA-SCC) should be performed regularly while being treated with sorafenib and BRAF inhibitors, as these lesions have been described primarily with targeted therapy against Raf kinase or mutant BRAF [32
]. These lesions can develop as solitary or multiple lesions, weeks to months after starting drug therapy, and do not need to be confined to sun-exposed areas. Fortunately, KA-SCC has not been reported to metastasize, and spontaneous regression has been reported [32
]. KA-SCCs should be completely excised. It has not been uniformly recommended that drug discontinuation occur when KA-SCCs develop due to the low metastatic potential; however, patients should be made aware of this effect and maintain routine skin evaluations.
2.5. Gastrointestinal System
Diarrhea, nausea, mucositis, stomatitis, dysgeusia, anorexia, abdominal discomfort, and weight loss may develop with the use of these drugs. Reduced side effects may occur if medication is taken with a large meal and water, if appropriate for administration per package insert. Appropriate use of supportive therapies with antidiarrheal or antiemetic medications may prevent the need for dose reduction or discontinuation. In the case of severe, unresponsive gastrointestinal effects, drug discontinuation should be implemented and reinitiated at a reduced dose once symptoms resolve to baseline or grade 1 level. Gastrointestinal perforation or fistula development is a rare, but potentially life-threatening, adverse event reported with TKIs. Risk factors include underlying tumor at perforation, diverticulitis, bowel obstruction, recent sigmoidoscopy or colonoscopy, and historical abdominal/pelvic irradiation [36
]. Drug discontinuation is warranted if perforation event occurs. Consideration for a different TKI will need to be done with caution.
Hepatic toxicity or abnormalities, demonstrated by elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and bilirubin, can occur. Elevations in AST or ALT were the most common metabolic abnormality requiring treatment seen in the phase III trial of pazopanib in renal cell carcinoma [28
]. Although isolated elevations of total bilirubin were also seen at a similar frequency, concurrent elevations of ALT and total bilirubin were rare. The presence of a polymorphism in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene, which predisposes to Gilbert's syndrome, leads to reduced enzymatic activity necessary for the conjugation of bilirubin allowing it to be excreted in bile. Xu et al. reported that the presence of a polymorphism in UGT1A1 was significantly associated with pazopanib-induced hyperbilirubinemia, indicating that isolated unconjugated hyperbilirubinemia was a benign finding associated with Gilbert's syndrome, which did not require discontinuation of drug therapy [37
]. Conjugated hyperbilirubinemia would require further investgation. None of the genetic markers evaluated in this study were associated with hepatic transaminase elevation, thus leaving the etiology still to be determined.
TKIs can lead to asymptomatic increases in pancreatic enzymes or rarely acute pancreatitis, most commonly reported with sorafenib and pazopanib. Standard treatment for pancreatitis and evaluation with endoscopic ultrasonography and other diagnostic testings for underlying causes of pancreatitis should be implemented. However, radiologic evidence of pancreatic damage or pancreatitis often is not found. Thus, dose-limiting toxicity for pancreatic enzyme elevation should be applied to grade 4 levels associated with clinical findings of pancreatitis, or if considered to be life threatening [38
]. The cause of elevation in amylase and lipase is unclear, although some have attributed it to pancreatic ischemia from antiangiogenesis or to other drug-related effects.
Mucosal bleeding (e.g., epistaxis) to hemorrhage (i.e., gastrointestinal, pulmonary, cerebral, vaginal) has been reported with TKIs. Although mild mucosal bleeding could be attributed to inhibition of VEGFR-2 causing microvascular leaks from endothelial cell damage, clinically more severe hemorrhage is attributed to tumoral invasion of large vessels or other concurrent pathological conditions [36
]. Additionally, thrombosis has been identified with TKI use. Inhibition of VEGF signaling could lead to overproduction of erythropoietin in the liver, which increases hematocrit and blood viscosity [39
]. Additionally, as wound healing is dependent upon angiogenesis, VEGF-inhibitors can impair or delay wound healing after surgery or other invasive procedures. Thus, drug should be withheld before and after surgery to optimize wound healing [36
Hematologic laboratory abnormalities with neutropenia, lymphopenia, and thrombocytopenia are associated with TKIs. In contrast, anemia occurs less frequently, which may be explained by the relative increased erythrocytosis seen with this class of drugs. As patients with differentiated thyroid carcinoma may have received large cumulative doses of radioactive iodine and thyroid cancer patients may have received external beam radiation therapy, myelosuppression may be present prior to TKI initiation. Thus, routine monitoring of complete blood count and differential is required while on therapy.
Hypothyroidism or rising thyroid stimulating hormone (TSH), requiring increasing the thyroid hormone replacement doses, is seen as a class effect. Suggested etiologies have been poor absorption of levothyroxine from concomitant treatment-related diarrhea, or in patients with intact thyroid glands, regression of thyroid capillaries, or inhibition of thyroid peroxidase [36
]. Thyroid function should be monitored routinely while on TKI treatment to maintain a suppressed TSH in patients with DTC and a normal TSH in MTC patients.
Fatigue is a pervasive and often difficult-to-manage problem in cancer patients and may be related to many factors, in addition to direct toxicity of targeted drug therapy. Investigation for causes (e.g., anemia, hypothyroidism, cardiac dysfunction, renal dysfunction) should be performed. Supportive care with adequate nutrition, exercise, and stress reducing techniques is encouraged.