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VEGF) Inhibitors Understanding and managing toxicities of vascular endothelial growth factor (VEGF) inhibitors Manuela Schmidinger * Medical University of Vienna, Vienna, Austria 1. Introduction than bevacizumab. Interestingly, the newest VEGFR–tyrosine kinase inhibitor (TKI) tivozanib appears to have little effect Vascular-endothelial growth-factor (receptor) (VEGF)(R)-inhib- on fatigue levels (all grades: up to 18%, grade P3: 5%). iting agents – sunitinib [1–3], sorafenib [4,5], pazopanib [2,6], Gastrointestinal side-effects are extremely common in pa- bevacizumab [7,8], axitinib [5] and tivozanib [9,10] –have tients on VEGFR–TKI treatment. In particular, sunitinib and changed the therapeutic landscape in metastatic renal-cell axitinib were shown to cause reduced appetite and/or anorex- carcinoma (mRCC). Five out of six agents have been approved ia in up to 34% of the patients. In the case of sunitinib, this for either first-line (sunitinib, pazopanib and bev- may be caused partly by the high incidence of stomatitis acizumab + interferon-alpha) or second-line (sorafenib, axiti- and/or dysgeusia (30% and 46%, respectively). Diarrhoea is an- nib) treatment of metastatic or advanced RCC. With these other frequent gastrointestinal toxicity: high incidences of all novel strategies, the median overall survival of patients has grades of diarrhoea were reported from patients on sunitinib increased considerably, often, however, at the expense of (61%), sorafenib (53%), pazopanib (63%) and axitinib 55%, chronic side-effects. Common treatment-related side-effects again with quite a favourable profile for tivozanib (22%). include: (1) general symptoms such as fatigue and asthenia, The most common skin toxicities caused by VEGFR inhib- (2) gastrointestinal symptoms such as diarrhoea and stomati- itors are hand–foot syndrome (HFS), skin- and/or hair-depig- tis, (3) skin toxicities, (4) cardiovascular toxicities and (5) a mentation and rash. The highest incidence of all grades of variety of laboratory abnormalities. Some of these side-effects HFS has been reported from sorafenib (51%) and sunitinib pa- are clinically highly relevant because they may jeopardise the tients (50%), with a higher grade 3 + 4 HFS incidence in sorafe- patient’s safety or quality of life, while others may have little nib patients (16%). Similarly, sorafenib was shown to cause clinical relevance. Treating physicians need to be aware of po- rash in up to 32% of patients (all grades). Hair and/or skin tential side-effects that may occur, how to prevent and/or depigmentation is commonly observed in patients on pazop- manage them, and the clinical implications for the ongoing anib (up to 38%) and sunitinib (up to 27%). treatment. This is of paramount importance since dose Among the group of cardiovascular, lung and laryngeal reductions and treatment discontinuations may significantly side-effects, hypertension is the most common (up to 46%). affect the outcome [11]. Hypertension has been observed with all of these agents and has been considered a fairly reliable biomarker for re- 2. Incidence of toxicities associated with VEGF sponse, progression-free survival (PFS) and overall survival inhibitors (OS) [14]. The highest incidence of grades 3 + 4 hypertension has been observed with tivozanib (26%). Cardiac side-effects Toxicities reported from VEGFR inhibitors in mRCC are out- include congestive heart failure (sunitinib: 13%) and ischae- lined in Table 1. Among general symptoms, fatigue (and/or mia or myocardial infarction (sorafenib: 3%; bev- asthenia) has been most commonly reported for sunitinib acizumab + interferon-alpha 1%). Bleeding events, most (up to 63% all grades; grade P3: 17%), followed by axitinib commonly epistaxis, have been observed in patients treated (all grades 39%, grade P3: 11%) and sorafenib (all grades with bevacizumab + IFN, sunitinib and sorafenib (33%, 18% 37%; grade P3: 5%). A high incidence of fatigue has also been and 15%, respectively). While dyspnoea is a common side-ef- reported from the combination of bevacizumab + interferon- fect of mTOR-inhibitors, the incidence is low in patients with alpha (IFNa). However, the incidence of fatigue appears to VEGFR inhibitors. No direct effect of these agents on lung be low in patients being treated with bevacizumab alone tissue has been reported so far; thus, the occurrence of dysp- [12,13]; thus, this side-effect may be attributed to IFNa rather noea might be a secondary event due to lung metastases or * Address: Manuela Schmidinger, Medical University of Vienna, Vienna, Austria. E-mail address: [email protected]. 1359-6349/$ - see front matter Copyright Ó 2013 ECCO - the European CanCer Organisation. All rights reserved. http://dx.doi.org/10.1016/j.ejcsup.2013.07.016 EJC SUPPLEMENTS 11 (2013) 172– 191 173 Table 1 – Toxicities reported from phase III trials (%). (Continued on next page) oedema as a result of high-grade hypertension or congestive particularly sunitinib, may induce grade 3 + 4 anaemia (8%), heart failure. In contrast, dysphonia is a common side-effect neutropenia (18%), thrombocytopenia (9%) and lymphopaenia of new-generation TKIs such as axitinib (31%) and tivozanib (18%). Infections, however, have not been reported yet. (22%). Various metabolic and laboratory abnormalities have been The incidence of grade 3 + 4 myelotoxicity is low with VEG- shown to occur in patients treated with VEGFR inhibitors. FR inhibitors when compared to classical cancer treatment These include renal and electrolyte abnormalities such as cre- such as chemotherapy. Nevertheless, multikinase inhibitors, atinine increase (up to 70%), proteinuria (71%), abnormalities 174 EJC SUPPLEMENTS 11 (2013) 172– 191 Table 1 (continued) in sodium, potassium, magnesium and calcium levels in up to to death. Dose reductions occurred in up to 51% of sunitinib 37%, 50%, 31% and 59%, respectively. In addition, pazopanib, patients, 52% of sorafenib patients, 44% of pazopanib pa- sunitinib and tivozanib in particular were shown to cause in- tients, 31% of axitinib patients and 14% of tivozanib patients, creased levels of bilirubin, alanine aminotransferase (ALT) while no dose reductions of bevacizumab were permitted in and aspartate aminotransferase (AST) in up to 36%, 60% and the Bevacizumab plus interferon alfa-2a for treatment of met- 61% of the patients, respectively. In the case of tivozanib, astatic renal cell carcinoma: a randomised, double-blind international normalised ratio (INR) and partial thrombo- phase III trial (AVOREN) and CALGB bevacizumab trials. Sim- plastin time (PTT) abnormalities were also reported (82% ilarly, dose interruptions and treatment delays were required and 53%, respectively). Sunitinib, sorafenib and tivozanib in 38% of sunitinib patients, 80% sorafenib patients, 62% bev- were shown to increase amylase and lipase levels in approx- acizumab + IFN patients and 77% of axitinib patients. In con- imately 50% of patients. Finally, the induction of hypothyroid- trast, the number of patients with dose interruptions was ism is an observation that may have been underreported in considerably lower in tivozanib patients (18%). Both dose the pivotal trials; in later analyses, up to 36% of patients reductions and treatment interruption may help to prevent was shown to develop hypothyroidism [15]. As with hyperten- or manage treatment-associated side-effects. However, sev- sion, the occurrence of hypothyroidism has been linked to a eral authors have shown that higher relative dose intensities better outcome [15,17]. were associated with better outcome. A pharmacodynamic/ pharmakokinetic analysis including six sunitinib trials re- 3. The severity of side-effects and their impact vealed that response rates, time to progression and overall on outcome survival increased with the mean daily exposure to sunitinib [11]. Similarly, intra-patient dose-escalated sorafenib was The occurrence of grade 3 + 4 toxicities, and to some extent shown to exert promising antitumour activity and led to a also toxicities of lower grades, may tempt clinicians to reduce complete/partial response (CR–PR) rate of 48%, with eight the dose, or to interrupt or discontinue treatment. Table 2 out- out of 44 patients achieving complete remission [18]. Finally, lines the incidence of dose reductions and interruptions, the Rini et al. could demonstrate in a randomised phase II study rate and most common reasons for treatment discontinua- that axitinib dose titration significantly improved overall re- tions, as well as the most common toxicities that have led sponse rates when compared to placebo in patients eligible Table 2 – Dose reductions and treatment discontinuation due to adverse events. Sunitinib [1–3] Sorafenib [4,5] Pazopanib [2,6] Bevacizumab [7,8] Axitinib [5] Tivozanib [9,10] Dose reduction 32 [1] 13 [4] 44 [2] Not permitted for 31 8 [9] due to AEs (%) 51 [2] 52 [5] bevacizumab 13.9 [10] 50 [3] Dose 38 [1] 21 [4] for nr nr [7] 77 4 [9] interruptions dermatological 61.7 [8] 18 [10] (treatment delays) events, 80 for GI events [5] Discontinuation 8 [1] 10 [4] 12 [6] 28 [7] any 49[9] EJC SUPPLEMENTS due to AEs 19 [2] 8 [5] 24 [2] 19 [7] 4 [10] bevacizumab 23 [8] Most common Cytopaenia [2] Constitutional [4], Liver events [2] nr Fatigue, and nr [9,10] reason gastrointestinal transient for [4], dermatologic ischaemic attack discontinuation [4], respiratory 11 (2013) 172 tract symptoms [4] HFS [5], diarrhoea [5], asthenia [5] AEs leading to 34 [4] Nr nr nr nr [9,10] hospitalisation – TX-related death Renal failure [1] 2 death from 4 [6] 2 [7] bleeding 0 n [9]=8/272 191 or non-PD related n =1 cardiac ischaemic stroke, events n =2,GI ischaemic stroke deaths Gastric ischaemia/ hepatic failure, perforation n =1, n = 2, acute haemorrhage [1] infarction [4] rectal myocardial coronary n =1 2 death [5] from haemorrhage, infarction n =1 syndrome, acute Respiratory tumour necrosis peritonitis and atrial fibrillation respiratory failure [1] n =1 causing bowel perforation n =1 failure, cerebral Sudden death [1] retroperitoneal pneumonia n =1 vascular accident, n =1 bleeding and n =1 hepatic failure hypotension and GI bleeding (history of active pulmonary hepatitis B) embolism all n =1 n =3[8] nr [10] nr, not reported.
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