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Antiangiogenic therapy for advanced renal cell carcinoma: Management of treatment-related toxicities

Antiangiogenic therapy for advanced renal cell carcinoma: Management of treatment-related toxicities Invest New Drugs (2012) 30:2066–2079 DOI 10.1007/s10637-012-9796-8 REVIEW Antiangiogenic therapy for advanced renal cell carcinoma: Management of treatment-related toxicities Roger B. Cohen & Stéphane Oudard Received: 28 November 2011 /Accepted: 20 January 2012 /Published online: 12 February 2012 The Author(s) 2012. This article is published with open access at Springerlink.com Summary Treatment of metastatic renal cell carcinoma responses and superior progression-free survival in advanced (mRCC) has evolved rapidly over the last two decades as major RCC compared with sorafenib. pathways involved in pathogenesis have been elucidated. . . These include the vascular endothelial growth factor (VEGF) Keywords Axitinib Renal cell carcinoma Tyrosine kinase . . axis and mammalian target of rapamycin (mTOR). Therapies inhibitor Toxicity Adverse events targeting the VEGF pathway include bevacizumab, sorafenib, sunitinib, pazopanib, and axitinib, whereas temsirolimus and everolimus inhibit the mTOR pathway. All of these novel Introduction therapies—VEGF and mTOR inhibitors—are associated with a variety of unique toxicities, some of which may necessitate The incidence of kidney cancer has been increasing world- expert medical management, treatment interruption, or dose wide, accounting for approximately 2% of all cancers (ex- reduction. Common adverse events with newer drugs include cluding non-melanoma skin cancer) [1]. In 2010, 287,421 hypertension, skin reactions, gastrointestinal disturbances, thy- new cases and 122,302 deaths were estimated and, by 2015, roid dysfunction, and fatigue. Skilled management of these 325,433 new cases and 138,629 deaths are expected to toxicities is vital to ensure optimal therapeutic dosing and occur [2]. Incidence and mortality rates were highest for maximize patient outcomes, including improved survival and men in more developed areas, where kidney cancer com- quality of life. This review describes and compares the toxicity prised 4% of all cancers [3]. Although 5-year survival rates profiles of novel molecularly targeted agents used in the treat- approximate 85% for patients with localized renal cell car- ment of mRCC and presents guidance on how best to prevent cinoma (RCC) (the most common type of kidney cancer), and manage treatment-related toxicities. Particular attention is patients with advanced disease have a 5-year survival rate of given to axitinib, the newest agent to enter the armamentarium. only 10% [4]. Nearly half of patients with RCC eventually Axitinib is a second-generation receptor tyrosine kinase inhib- develop advanced disease including 30% of patients initially itor with potent VEGF receptor inhibition that provides durable presenting with advanced disease and another 20–30% with early-stage disease who relapse after nephrectomy [4]. Kid- ney cancer subtypes include clear cell RCC (85%) and the less common non-clear cell cancers, including papillary, R. B. Cohen (*) Division of Hematology/Oncology, University of Pennsylvania, collecting duct, and chromophobe RCC [5]. 16 Penn Tower, 3400 Spruce Street, Chemotherapy and hormonal therapy are generally ineffec- Philadelphia, PA 19104, USA tive in treating kidney cancer; immunotherapy with high-dose e-mail: roger.cohen@uphs.upenn.edu interleukin-2 or interferon-alfa (INF-α) is effective in some S. Oudard patients, particularly those with good performance status [6]. Medical Oncology Department, These agents are associated with low response rates (<15%) Georges Pompidou European Hospital, and significant toxicities, which often limit their use and affect 20 Rue Leblanc, patient quality of life (QoL) [7]. Paris, France Invest New Drugs (2012) 30:2066–2079 2067 Targeted pathways in advanced RCC Efficacy of new antiangiogenic agents in pivotal clinical trials Research on the molecular pathobiology of advanced RCC has identified the vascular endothelial growth factor Findings from key clinical trials of approved antiangiogenic (VEGF)/VEGF receptor (VEGFR) axis and the agents (sorafenib, sunitinib, bevacizumab, and pazopanib) phosphatidylinositol-3-kinase–protein kinase B/mammalian in advanced RCC have reported consistent prolongation of target of rapamycin (mTOR) pathway lying downstream (the progression-free survival (PFS) and, in some cases, overall “angiogenesis axis”) as clinically relevant targets [8–10]. Tran- survival (OS) in both treatment-naïve and previously treated scription of vasculogenic mediators including VEGF and patients (Table 1). platelet-derived growth factor (PDGF) is promoted by stressors The newer agent, axitinib, is a potent, selective, second- such as hypoxia, which is a strong signal for cancer angiogen- generation inhibitor of VEGFR-1, 2, and 3 with clinical esis. Angiogenesis in RCC is believed to be highly dependent antitumor activity in a variety of solid tumors [16–20]. In on VEGF, due mainly to the high frequency of germline a recent pivotal randomized phase III trial, axitinib demon- mutations in the von Hippel-Lindau (VHL) tumor suppressor strated statistically superior PFS compared with sorafenib, gene. VHL mutations result in constitutive stabilization of the as well as a higher response rate [21]. Although many of the transcription factors HIF-1α and HIF-2α, which activate toxicities of axitinib are shared with those of the other TKIs, VEGF genes, thereby promoting angiogenesis [11]. Approxi- there are important differences, most notably an apparent mately 40% to 60% of patients with VHL disease, an autoso- higher incidence of hypertension. Moreover, the safety mal dominant familial cancer disorder, develop clear cell RCC profile for axitinib is distinct from that of sorafenib. [11–13]. VHL mutation is also associated with approximately Common adverse events (AEs) more frequent with sora- 50% of nonhereditary (sporadic) clear cell RCC. fenib versus axitinib were hand-foot syndrome (HFS), The VEGF/VEGFR axis plays a critical role in tumor rash, alopecia, anemia, hypophosphatemia, hypocalcemia, growth and survival [9]. Inhibitors of this pathway are and elevated lipase whereas the predominant toxicities with thought to exert their effects by inducing apoptosis, axitinib were hypertension, fatigue, nausea, vomiting, and cytostasis, and restrictive effects on tumor vasculature hypothyroidism [21]. [10]. VEGF-targeted agents include the monoclonal an- Axitinib first demonstrated clinical activity in patients with tibody bevacizumab which neutralizes VEGF itself, and refractory advanced RCC in a phase II study [18], in which 52 receptor tyrosine kinase inhibitors (TKIs) such as sora- patients with cytokine-refractory mRCC and clear-cell histol- fenib, sunitinib, pazopanib, and axitinib. These agents ogy received axitinib 5 mg twice daily (BID). An overall target the VEGFRs, as do additional TKIs in ongoing response rate of 44% was reported with a median duration clinical development, with effects that extend beyond of response of 23.0 months (range, 4.2–29.8 months). Median the VEGFRs [14, 15]. time to progression was 15.7 months (range, 8.4–23.4 months) The new wave of US Food and Drug Administration– and median OS was 29.9 months (range, 2.4–35.8 months). In approved molecularly targeted antiangiogenic agents has a second phase II trial [19], patients with sorafenib-refractory largely supplanted cytokines as first- and second-line therapy mRCC received axitinib at a starting dose of 5 mg BID. for metastatic RCC (mRCC). Second-generation molecularly Axitinib produced a 23% response rate and median duration targeted therapies in development include axitinib (a selective of response of 17.5 months. Median PFS was 7.4 months and highly potent VEGFR inhibitor); tivozanib and cediranib (95% CI, 6.7–11.0) and median OS was 13.6 months (95% (also VEGFR inhibitors); brivanib (inhibitor of VEGFR and CI, 8.4–18.8). fibroblast growth factor receptor); motesanib (inhibitor of In the recent phase III trial in patients with advanced RCC VEGFR, PDGF receptor, and c-Kit); XL184 (inhibitor of [21], axitinib 5 mg BID demonstrated superior PFS compared VEGFR-2, MET, and RET); and VEGF TRAP (novel inhib- with sorafenib 400 mg BID (6.7 versus 4.7 months; itor of VEGF-A). P00.0001) with a significantly higher response rate (19.4 Timely and appropriate management of treatment- versus 9.4%; P00.0001) (Table 1). Patient-reported QoL related toxicities is vital in order to deliver therapy was comparable between the two treatment arms. safely and optimally. This review describes and com- pares the toxicity profiles of antiangiogenic agents used in mRCC. Particular attention is devoted to axitinib, an Toxicity profile of new antiangiogenic agents for mRCC antiangiogenic multi-targeted TKI in active clinical de- velopment for mRCC. Guidelines for preventing and Commonly reported toxicities for antiangiogenic agents in managing treatment-related toxicities of axitinib are pre- patients with mRCC include class effects of fatigue, asthe- sented, which also have general relevance to all of the nia, diarrhea, nausea, anorexia, rash, HFS, and hypertension small-molecule angiogenesis inhibitors. (Table 2)[21–25]. Other toxicities or combinations of side 2068 Invest New Drugs (2012) 30:2066–2079 Table 1 Overview of efficacy of targeted therapies for mRCC b a b a Bevacizumab Sorafenib Sunitinib Pazopanib Axitinib + IFN-α Treatment-naïve Study 1 vs IFN vs IFN vs IFN vs PBO N0649 [23] N0189 [79] N0750 [43] N0435 [55] PFS (mo) 11 vs 5 5.7 vs 5.6 11 vs 5 11.1 vs 2.8 HR 0 0.63; CI, 0.52–0.75; HR 0 0.42; CI, HR 0 0.46; CI, P00.0001 0.32–0.54; 0.34–0.62; P<0.0001 P<0.001 c d ORR (CR + PR) 31 vs 6% 5.2 vs 8.7% 37%* OS (mo) 23.3 vs 21.3 [78] NR 26.4 vs 21.8 [28] 32% NR HR 0 0.86; CI, 0.72–1.04; HR 0 0.821; CI, P<0.1291 0.673–1.001; P00.051 Study 2 vs IFN OL N0732 [80] N0155 [81] PFS (mo) 8.5 vs 5.2 NR ORR (CR + PR) 25.5 vs 13.1 34% OS (mo) 18.3 vs 17.4 [25] NR Cytokine failure Study 1 vs PBO vs PBO OL vs PBO OL N0116 [82] N0903 [30] N0106 [84] N0202 [55] N052 [18] PFS (mo) 4.8 vs 2.5 5.5 vs 2.8 8.3 7.4 vs 4.2 13.7 HR 0 0.44; CI, 0.35–0.55; P<0.01 C c c d c ORR (CR + PR) 10% 10% 44% 29% 44.2% 29.9 OS (mo) NR 17.8 vs 14.3 [83]NR NR HR 0 0.78; CI, 0.62–0.97; P00.0287 Study 2 OL OL OL vs SOR N0107 [85] N031 [81] N0723 [21] PFS (mo) 8.2 NR 6.7 vs 4.7 HR 0 0.665; CI, 0.522–0.812; P00.0001 ORR (CR + PR) 20% 37% 19.4 vs 9.4% P00.0001 OS (mo) 19.8 NR TKI failure Study 1 OL N062 [19] PFS (mo) 7.4 ORR (CR + PR) 22.6% OS (mo) 13.6 Approved in the United States (Note: bevacizumab monotherapy approved only in Europe) Approved in the United States and Europe Investigator assessment Independent assessment mRCC metastatic renal cell cancer, IFN-α interferon-α, PBO placebo, PFS progression-free survival, HR hazard ratio, CI 95% confidence interval, ORR overall response rate, CR complete response, PR partial response, OS overall survival, NR not reported, OL open-label, SOR sorafenib effects appear to be relatively specific to particular antian- compared across disease indications. AEs reported for these giogenic agents. agents in patients with mRCC are very similar to toxicities reported for sunitinib in gastrointestinal stromal tumors [22], Toxicities across cancer populations sorafenib in hepatocellular carcinoma [24], bevacizumab monotherapy in glioblastoma, and bevacizumab plus che- Toxicity profiles of antiangiogenic therapies lack disease motherapy for metastatic colorectal cancer, non-squamous non–small cell lung cancer, and metastatic breast cancer. specificity and thus can be usefully summarized and Invest New Drugs (2012) 30:2066–2079 2069 Table 2 Toxicity profile of targeted therapies as first- and second-line treatment of mRCC VEGF inhibitor TKIs Bevacizumab+IFN-α Sorafenib [30] Sunitinib [28] Pazopanib [55] Axitinib [21] [23] Previous treatment status Tx-naïve Cytokine failure Tx-naïve Tx-naïve+cytokine TKI + cytokine failure failure Dose modification, % patients Dose reduction 40 13 52 36 31 Dose interruption – 21 54 42 77 AE, % patients AE grade All 3/4 All 3/4 All 3, 4 All 3, 4 All ≥3 Cardiovascular Hypertension 26 3 17 4 30 12, 0 40 4, 0 40 16 Constitutional symptoms Fatigue 33 12 37 5 54 11, 0 19 2, 0 39 11 Asthenia 32 10 –– 20 7, <1 14 3, 0 21 5 Hypothyroidism –– – – 14 2, 0 <10 <1 19 <1 Cutaneous symptoms Rash –– 40 1 24 1, <1 –– 13 <1 Hand-foot syndrome –– 30 6 29 9, 0 <10 <1 27 5 Mucositis/stomatitis –– – – 30 1, 0 <10 <1 15 1 Gastrointestinal symptoms Diarrhea 20 2 43 2 61 9, 0 52 3, <1 55 11 Nausea –– 23 <1 52 5, 0 26 <1, 0 32 3 Vomiting –– 16 1 31 4, 0 21 2, <1 24 3 Dyspepsia –– – – 31 2, 0 –– – – Anorexia/decreased appetite 36 3 16 <1 34 2, 0 22 2, 0 34 5 Abdominal pain –– 11 2 11 2, 0 11 2, 0 –– Hemorrhage/bleeding All sites 33 3 15 2 –– 13 –– – Laboratory Lymphopenia –– – 13 –– 31 4, <1 33 3 Neutropenia 7 4 –– – – 34 1, <1 6 1 Thrombocytopenia 6 2 –– 68 8, 1 32 <1, <1 15 <1 Decreased phosphorus –– – 13 –– 34 4, 0 13 2 Elevated lipase –– 41 12 56 15, 3 –– 27 5 Anemia/decreased Hb 10 3 8 3 79 6, 2 –– 35 <1 Proteinuria 18 7 –– – – <10 <1 –– mRCC metastatic renal cell cancer, VEGF vascular endothelial growth factor, TKI tyrosine kinase inhibitor, IFN-α interferon-α, Tx treatment, AE adverse event, Hb hemoglobin VEGF inhibitors randomized controlled trials reported that the addition of bevacizumab to other cancer therapy increased the risk of Common AEs in patients with RCC receiving bevacizumab/ gastrointestinal perforation by 1.6- to 5.7-fold, depending INF-α include pyrexia, anorexia, fatigue, asthenia, bleeding, on tumor type and dose [26]. In addition, a recent meta- hypertension, and proteinuria [23]. Bevacizumab is also analysis [27] of >10,000 patients with cancer treated with associated with increased incidence of potentially life- bevacizumab revealed increased incidence of treatment- threatening gastrointestinal perforations and thrombovascu- related mortality, particularly in patients who were also lar events [23, 25]. A meta-analysis of 12,294 patients with receiving taxanes or platinum agents. In phase III trials of a variety of solid tumors treated with bevacizumab in 17 bevacizumab plus INF-α, congestive heart failure (CHF; 2070 Invest New Drugs (2012) 30:2066–2079 in <1% patients) and cardiac ischemia/infarction (in 1% The exact mechanisms underlying VEGF/VEGFR inhib- of patients) were reported [23, 25]. itor–associated hypertension remain unknown but increased Specific effects of TKIs commonly include hypertension, BP, a dose-dependent effect of these inhibitors, is believed HFS (palmoplantar erythrodysesthesia), rash, mucositis, hy- to be caused by increases in vascular tone and peripheral pothyroidism, and myelosuppression (Table 2). resistance. Interestingly, emergence of hypertension with Across oncology trials with sunitinib, toxicities occurring these agents, including axitinib, may serve as a biomarker in ≥20% of patients included anemia, diarrhea, fatigue, nau- for antitumor efficacy [38–40]. sea, asthenia, mucositis/stomatitis, vomiting, hypertension, In the sorafenib-refractory study of axitinib [19], peripheral HFS, and rash [28]. Sunitinib is also associated with myelo- edema and hypertension were reported by 19.4% and 45.2% suppression, elevated levels of thyroid-stimulating hormone of patients, respectively. Hypertension remains the major (TSH), hypothyroidism, and hepatotoxicity including liver cardiovascular-related toxicity of axitinib, reported in 51% failure. In addition, there is increased risk of CHF and decline of patients [18, 19]. A pooled analysis of phase II studies of in left ventricular ejection fraction (LVEF) in 10% of patients axitinib in mRCC [40] reported that patients with at least one [29]. Prolongation of QT interval may also lead to increased diastolic BP (dBP) measurement ≥90 mmHg during treatment risk of ventricular arrhythmias. AEs occurring in ≥20% of had a significantly longer median OS compared with patients sorafenib-treated patients included rash/desquamation, diar- with dBP <90 mmHg (30.1 versus 10.2 months, respectively; rhea, fatigue, HFS, alopecia, and nausea [30]. Sorafenib is P<0.001). Likewise, an analysis of sunitinib clinical trials in also associated with increased risk of life-threatening bleed- patients with mRCC [39], showed that treatment-emergent ing. A high frequency of intracerebral hemorrhage has been hypertension was an independent predictor of PFS and OS reported in sorafenib- or sunitinib-treated mRCC patients with (P<0.001). PFS was 12.5 versus 2.5 months in patients with brain metastases [31]. Pazopanib is associated with hypothy- maximal systolic BP (sBP) ≥140 mmHg versus <140 mmHg, roidism and proteinuria, as well as having variable effects on respectively (P<0.001). Similarly, significant clinical benefit glucose levels [32]. Pazopanib can also cause hepatotoxicity; was reported for dBP ≥90 mmHg compared with <90 mmHg. monitoring of liver function is required and dose reduction Effective control of BP with antihypertensive treatment did may be necessary in patients with baseline elevation in total not affect the improved clinical outcome. Currently, a ran- bilirubin and other hepatic function tests [32]. Similar associ- domized prospective phase II axitinib trial in patients with ations have been observed with sorafenib, with dose reduc- mRCC is evaluating axitinib-related dBP changes as a possi- tions suggested for patients with hepatic dysfunction [33]. ble predictive biomarker for response (ClinicalTrials.gov Hyperglycemia has been reported in 41% of pazopanib- identifier: NCT00835978). treated versus 33% of placebo-treated patients, whereas hypo- Before starting TKI therapy, BP should be controlled for glycemia was reported in 17% of pazopanib- versus 3% of approximately 1 week. Hypertension should be monitored placebo-treated patients. and controlled with appropriate antihypertensive agents, Toxicities of concern reported for some of the investigational with weekly monitoring of BP during the first cycle and 2 TKIs include cholecystitis and gall bladder enlargement with to 3 weeks thereafter until a stable BP has been reached, and motesanib, proteinuria with axitinib, and mucositis with then monitored per standard medical practice [41]. Like- XL184. There appear to be some relative safety differences wise, BP should be monitored following discontinuation of across the various VEFG-inhibitor therapies, although the data TKI therapy since BP can drop rapidly. must still be considered incomplete at this time. In particular, Patients who develop stage I hypertension (≥140/ bevacizumab is associated with a low incidence of hypothy- 90 mmHg) or have increases in dBP ≥20 mmHg from base- roidism, sorafenib has low cardiac toxicity compared to suniti- line should initiate antihypertensive therapy, modify the dose nib, and recipients of pazopanib report less fatigue. of the current agent for better control, or add a second antihypertensive agent [41]. In some instances, dose reduc- Proposed mechanisms of common toxicities tion of the TKI inhibitor can be implemented to manage TKI- induced hypertension. The major classes of antihypertensive Hypertension agents, including angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and calcium channel blockers, have Hypertension occurs in 17% to 45% of TKI-treated patients been used to treat TKI-induced hypertension. There are no with RCC, with grade 3 or 4 hypertension reported in 3% to consensus recommendations, however, for the use of specific 16% of patients. Elevated blood pressure (BP) typically antihypertensive agents in this setting [42]. Antihypertensive presents early, within 3 to 4 weeks of treatment initiation agents should be individualized to suit the patient’s clinical [34, 35]. Some studies of TKI-mediated BP effects reported status. ACE inhibitors, for example, are preferred for patients elevations as early as the first day [36] to first week [37]of with proteinuria, chronic kidney disease risks, or metabolic treatment. syndrome [42]. Invest New Drugs (2012) 30:2066–2079 2071 Cutaneous reactions by standard medical interventions such as antidiarrheal med- ications and dietary modification. Rash, HFS, and mucositis/stomatitis are common effects of antiangiogenic agents. HFS is characterized by palmoplantar Cardiovascular toxicities lesions in areas of friction or trauma, commonly in the hands and feet. HFS may significantly affect a patient’s QoL and Cardiovascular toxicities of TKIs include hypertension, pe- physical functioning and often leads to treatment modification ripheral edema, and cardiac dysfunction [28, 30, 55]. The rate or discontinuation [30, 43]. The precise mechanisms causing of TKI-associated cardiovascular toxicities is not well estab- these events are largely unknown. In a sunitinib study, skin lished. Cardiac damage is manageable, provided the patients toxicity appeared after 3 to 4 weeks of treatment and was receive appropriate cardiac monitoring and treatment at the characterized by dermal vascular modifications, scattered ker- first indication of myocardial damage [56]. Monitoring for atinocyte necrosis, and intra-epidermal cleavage, which may drug-related toxicities can be challenging, as symptoms such be mediated via direct anti-VEGFR and/or PDGF receptor as dyspnea, chest, pain, and dizziness can be ambiguous dis- effects on dermal endothelial cells [44]. ease indicators in patients with advanced cancer. The use of beta blockers such as carvedilol and drugs such as simvastatin Hypothyroidism has been suggested as a means to protect against TKI-induced cardiac toxicities [56]. Importantly, decline in LVEF has pre- Antiangiogenic agents are known to affect thyroid ho- ceded CHF in sorafenib- and sunitinib-treated patients, mainly meostasis but the precise mechanisms are not well un- in those with a history of coronary artery disease. LVEF derstood. Biochemical and clinical hypothyroidism is declines have been observed in patients with mRCC treated commonly reported in patients with RCC receiving suni- with sunitinib, but it is not known if patients with cardiac tinib and sorafenib [45–47]. An increase in TSH and conditions have a greater chance of developing sunitinib- decreases in thyroid hormone, indicative of hypothyroid- related LVEF [57]. Baseline and periodic assessment of LVEF ism, has been reported in sunitinib-treated patients with are strongly recommended for patients receiving TKI therapy. gastrointestinal tumors [48]. VEGFR inhibitors such as Special emphasis must be placed on monitoring for the clinical sunitinib may induce thyroiditis and hypothyroidism via a signs and symptoms of CHF. Patients with signs and symp- direct effect on the thyroid through inhibition of VEGFR toms of CHF should be thoroughly evaluated (including LVEF [49]. Thyroid dysfunction may also result from regression assessment) and discontinue therapy. Physicians are advised to of capillaries around thyroid follicles due to VEGFR consider carefully the cardiac risk: benefit ratio for any patient inhibition [50]. Changes in TSH appeared to correlate before initiating therapy with VEGF inhibitors. with fatigue in patients receiving axitinib [51]. Therefore, thyroid-function monitoring is recommended with man- Proteinuria agement of hypothyroidism following standard guidelines for levothyroxine replacement therapy [52]. Proteinuria is mostly observed in patients receiving bevaci- zumab (Table 2). The mechanism underlying proteinuria is Fatigue unclear but it may reflect a role for VEGF in normal glo- merular endothelial repair [58]. Patients should be moni- Fatigue is experienced by 19% to 77% of patients receiving tored for proteinuria before and after treatment. Therapy antiangiogenic agents. The most common factors contributing should be discontinued in patients with grade 4 proteinuria. to fatigue in patients with cancer independent of treatment with angiogenesis inhibitors are hypothyroidism, anemia, and Bleeding and wound healing dehydration. Hypogonadism may also contribute to the fa- tigue associated with sunitinib and sorafenib [53]. Fatigue has Bleeding, including epistaxis, hematemesis, gastric bleeding, a high impact on patient QoL and should be monitored and brain hemorrhage, is associated with VEGF inhibitors closely, following appropriate treatment guidelines to alle- and is more common with bevacizumab [59]. While bleed- viate symptoms [54]. ing is generally manageable, it can be serious and some- times fatal. Patients with serious bleeding should not receive Gastrointestinal disturbance bevacizumab. Angiogenesis is required for wound healing and, thus, anti-VEGF agents may directly affect the healing Gastrointestinal AEs in patients with RCC treated with process. Wound-healing complications, such as slow or antiangiogenic agents include diarrhea, nausea, and vomit- incomplete healing following surgery, have been reported ing (Table 3). These AEs are usually not associated with for bevacizumab and pazopanib. These events were fatal in treatment discontinuation because of successful management some cases. 2072 Invest New Drugs (2012) 30:2066–2079 Table 3 Toxicity profile of axitinib in phase II studies mRCC [19] N062 mRCC [18] N052 TC [16] N060 NSCLC [20] N032 Melanoma [63] N032 Previous treatment status Sorafenib Cytokine 131 Iodine AE, % patients AE grade All 3/4 All 3/4 All ≥3 All 3 All >3 Fatigue 77 16 52 8 50 5 50 22 63 22 Diarrhea 61 15 60 10 48 3 41 3 31 0 Anorexia 48 0 35 2 30 0 50 0 –– Hypertension 45 16 58 14 28 12 22 9 44 6 Nausea 44 7 44 0 33 0 34 0 22 0 Dyspnea 39 15 –– – – – – – – Dysphonia 37 0 19 0 –– 28 0 34 0 Hand-foot syndrome 36 16 8 – 15 0 –– – 3 Mucosal inflammation 34 2 –– – – 16 0 16 0 Vomiting 32 5 21 0 13 0 19 3 –– Weight decrease 31 5 27 0 25 3 16 0 16 0 Cough 29 0 –– – – – – – – Headache 29 2 15 0 22 3 –– – – Arthralgia 27 3 14 2 –– 22 0 19 6 Constipation 26 0 14 0 –– – – – – Dysgeusia 23 0 12 0 –– – – – – Abdominal pain 21 11 12 0 –– – – – – Pain in extremity 21 3 19 4 –– – – 16 0 Stomatitis –– 17 2 25 0 –– 16 3 Proteinuria –– 8 0 18 5 –– 38 3 Rash –– –– 15 0 16 0 –– mRCC metastatic renal cell cancer, TC thyroid cancer, NSCLC non–small cell lung cancer, AE adverse event Thromboembolic events Follow-up Angiogenesis inhibition, as well as cytotoxic chemother- Careful evaluation and follow-up of reported toxicities apy, is associated with increased risk of both arterial and their response to management often allow patients thromboembolic events (ATE) and venous thromboem- to continue treatment safely on the prescribed effective bolic events (VTE) [60]. Several factors related to doses of antiangiogenic agents. AEs leading to dose VEGF inhibition are believed to contribute to the in- interruption or reduction should be closely monitored creased risk of ATE and VTE, including the role of so therapy can be reinstituted once side effects improve VEGF in the regeneration of endothelial cells. A pooled or resolve. analysis of clinical trials, including trials in mRCC, reported that bevacizumab was significantly associated with an increased risk of developing VTE in patients Axitinib with cancer [61]. In this analysis, the incidence of all- grade and high-grade VTE was 11.9% and 6.3%, re- Axitinib-related toxicities in advanced RCC spectively. A recent meta-analysis to assess the risk of ATE reported that treatment with sunitinib and sorafenib Common toxicities is associated with a three-fold increase in the risk of ATE, with an overall incidence of 1.3% in patients with AEs associated with axitinib including a higher incidence of RCC [62]. Myocardial infarction and cardiac ischemia hypertension compared with some of the other TKIs, gener- have also been reported for sunitinib and sorafenib. ally respond to supportive measures and dose modifications. Invest New Drugs (2012) 30:2066–2079 2073 The most common axitinib-related AEs reported across Management of axitinib-related toxicities in advanced RCC phase II trials [16, 18–20, 63] were fatigue, diarrhea, hypertension, and anorexia (Table 3). The most common Assessments and monitoring of toxicities grade 3/4 AEs were hypertension, fatigue, and diarrhea. The most commonly reported hematologic AE was Pretreatment assessment should be performed with particular grade 1/2 anemia, which did not require dose reduction attention to the presence of comorbidities (e.g., preexisting or interruption [18, 20]. hypertension) that may indicate more frequent monitoring and In the phase III study of axitinib versus sorafenib [21], anticipation of possible dose reductions. Patients with preex- common AEs more frequently reported with sorafenib ver- isting cardiovascular dysfunction and cardiac risk factors sus axitinib, respectively, included anemia (52% versus should be monitored regularly with BP assessment at baseline 35%), HFS (51% versus 27%), rash (32% versus 13%), and during treatment. Thyroid profiles should be assessed at and alopecia (32% versus 4%) and AEs more frequently baseline and every 2 to 3 months after initiation of therapy occurring with axitinib versus sorafenib, respectively, in- [65]. Very rarely, high hematocrits have been seen with axiti- cluded hypertension (40% versus 29%), fatigue (39% versus nib [18, 66] and should be treated appropriately. 32%), nausea (32% versus 22%), vomiting (24% versus 17%), and hypothyroidism (19% versus 8%). The incidence Management of common axitinib toxicities of diarrhea was similar for axitinib and sorafenib (55% and 53%, respectively). Axitinib does not appear to cause neu- Prevention and management strategies for axitinib-related tropenia and thrombocytopenia, which have been reported AEs are presented in Table 4 and discussed below. with sunitinib. Axitinib toxicities are very similar and manageable in Fatigue patients with cancers other than RCC. For example, in the phase II study of axitinib in 60 patients with advanced Fatigue (all grades) with axitinib treatment occurs in 39% of thyroid cancer refractory to conventional therapy, grade ≥3 patients [21]. Treatment of fatigue is supportive in nature, treatment-related AEs were hypertension (12%), fatigue requiring a thorough assessment of other possible exacerbating (5%), proteinuria (5%), and diarrhea, headache, and weight factors (e.g., sleep disturbance, comorbid conditions, concom- decrease (3% each) [16]. itant medications, hypothyroidism, or anemia). Supportive strategies include a range of approaches, from decreasing en- Dose-limiting toxicities ergy expenditure to psychosocial interventions. Pharmacologic strategies include treating contributing factors (e.g., anemia, Dose-limiting AEs leading to axitinib dose reduction or hypothyroidism) and the judicious use of psychostimulants, interruption include hypertension, fatigue, and diarrhea. including methylphenidate and modafanil [67]. Axitinib- In a phase I study of patients receiving 5 to 30 mg induced thyroid dysfunction and hypothyroidism are easily axitinib BID [64], hypertension was the primary dose- controlled by thyroid hormone replacement therapy [68]. limiting toxicity. One patient receiving axitinib (20 mg BID reduced to 10 mg BID) died acutely with grade 4 Gastrointestinal symptoms hemoptysis. In patients receiving the recommended phase II 5-mg BID dose, dose-limiting toxicities were grade 2 Over half of patients will experience axitinib-related gastro- stomatitis and grade 3 diarrhea (n01 each). In phase II intestinal disturbances. Patients should be advised to con- studies [18, 19], common AEs leading to axitinib dose sume frequent small meals, drink clear fluids in regular interruption were dyspnea, nausea, fatigue, hypertension, small amounts, and avoid foods or drinks that may exacer- and vomiting. In the sorafenib-refractory mRCC study bate diarrhea (such as dairy products) [69–72]. Diarrhea can with axitinib [19], AEs led to study discontinuation in be controlled with the use of standard antidiarrheal medica- 19% of patients and to temporary dose interruptions or tion and proper hydration. reductions in 73% and 45% of patients, respectively. In the cytokine-refractory mRCC study of axitinib [18], 15 Hand-foot syndrome patients (28.8%) had a dose reduction due to AEs. Dose reduction was required for grade 3 diarrhea and fatigue HFS is experienced by up to 36% of axitinib-treated patients (n02 each); gastrointestinal upset, dehydration, myalgia, and can be minimized by various skincare measures prior to and gout (n01 each); and grade 2 hypertension (n07). In initiating antiangiogenic therapy [65, 73]. Although severe this latter study, some patients took axitinib continuously episodes of HFS may necessitate dose alterations, topical for up to 5 years without evidence for cumulative treatments and avoidance of friction, especially in the feet, toxicities. may provide some relief. In one study, patients treated with 2074 Invest New Drugs (2012) 30:2066–2079 Table 4 Prevention and management axitinib-related adverse events Prevention Grade ≥1 Grade 3 or 4 Skin Hand-foot syndrome Routine manicure/pedicure Delay or adjust dose [65, 73] Remove calluses with proper tools Implement topical treatment Cushion pressure points and protect areas Avoid constriction/friction in concerned areas Use moisturizer (alcohol-free) after bathing Oral mucositis/ Maintain oral hygiene Use mucosal-covering agents Dose reduction or interruption stomatitis [65] Use salt and baking soda mouthwash Use topical lidocaine solutions Consume a soft diet If oral candidiasis present: use oral fluconazole or local clotrimazole troche Rash [73] Use moisturizer twice daily (alcohol-free) Topical hydrocortisone cream 1% Oral prednisone Avoid abrasive clothing/detergents/shampoo For grade 4, provide referral Avoid direct sunlight to specialist Use SPF 30 lotion/clothing Gastrointestinal Diarrhea [69] Avoid diarrhea-enhancing foods/ Loperamide or diphenoxylate Admit patient to hospital drinks/supplements (e.g., lactose, alcohol, caffeine, fiber) Drink 8–10 glasses of clear liquids daily Nausea/Vomiting Eat small meals frequently Metoclopramide, prochlorperazine, [70–72] Sip fluids steadily or haloperidol; add ondansetron or granisetron Anorexia [86] Consider megestrol acetate Constitutional Fatigue [65, 86] Monitor fatigue levels Exclude/treat contributing conditions Dose reduction or interruption (e.g., depression, hypothyroidism, pain, anemia) Use energy-conserving strategies Provide supportive care Use distraction strategies Consider psychostimulant (e.g., methylphenidate, modafanil) SPF sun protective factor topical urea or tazarotene or a two-agent combination (e.g., longer-acting agents. This approach allows cancer therapy to urea, fluorouracil, and/or tazarotene) reported improvement begin expeditiously. BP assessment prior to initiating therapy, in HFS symptoms resulting from TKI therapy [74]. every 2 weeks during the first 3 months of therapy, and monthly thereafter is recommended. Patients should also mon- itor their BP daily at home (prior to taking axitinib). Axitinib- Hypertension treated patients with sBP >150 mmHg or dBP >100 mmHg or experiencing symptoms such as headache or visual disturbance Hypertension should be controlled before starting antiangio- indicating hypertension should promptly contact their physi- genic therapy. BP ≥140/90 mmHg should be actively treated using standard antihypertensive medications. Reaching a cian for axitinib-dose modification. target <140/90 mmHg may require different combinations of standard agents and a different BP goal may be appro- Drug-drug interactions priate for some patients. For hypertensive patients with uncontrolled BP, the dose of Axitinib is primarily metabolized in the liver by the cyto- antihypertensive medication should be increased or, if on a chrome P450 (CYP) 3A4 isozyme and to a lesser extent by maximal dose, a second agent should be added and its dose CYP2C19 and CYP1A2. Less than 1% of the administered increased as appropriate. At pretreatment assessment, hyper- dose is excreted in the urine unchanged [64]. Both inducers tensive patients can initiate therapy with short-acting agents to and inhibitors of CYP metabolism may affect axitinib plasma quickly achieve BP control before exchanging medications for exposures. Therefore, concomitant use of known potent Invest New Drugs (2012) 30:2066–2079 2075 Table 5 Axitinib modification for hypertension and proteinuria [19] Adverse event Action Hypertension sBP >150 mmHg or dBP >100 mmHg Previously normotensive: Initiate anti-HTN therapy; maintain axitinib dose (Two readings at least 1 h apart) Previously HTN: Increase dose of anti-HTN therapy; if already on maximal dose, reduce axitinib dose by one level sBP >160 mmHg or dBP >105 mmHg Interrupt axitinib treatment ; adjust dose of anti-HTN agents until BP (Two readings at least 1 h apart) <150/100 mmHg; immediately restart axitinib treatment at one lower-dose level Recurrent following dose reduction Reduce axitinib dose further by one level (Two readings at least 1 h apart) Proteinuria Proteinuria >1 g/24 h Perform 24-h urine collection; continue axitinib dose while awaiting test results Proteinuria ≥2 g/24 h Interrupt axitinib treatment; wait until daily protein excretion is <2 g; restart axitinib treatment at a same dose or reduce by one dose level Patients should be closely monitored for the development of hypotension sBP systolic blood pressure, dBP diastolic blood pressure, HTN hypertensive, BP blood pressure CYP3A4 inhibitors (i.e., grapefruit juice, verapamil, ketoco- potential for a different spectrum of toxicities clearly exists nazole, miconazole, erythromycin, telithromycin, clarithromy- with these newer agents, including those targeting angiogene- cin), as well as CYP3A4 or CYP1A2 inducers (e.g., sis. Class-effects such as hypertension, fatigue, and gastroin- carbamazepine, dexamethasone, phenobarbital, phenytoin), testinal disturbances are common with all the antiangiogenic should be avoided in patients receiving axitinib. Combination agents and should be anticipated and proactively managed. therapies with agents such as 5-fluorouracil, cisplatin, carbo- Other unique but important toxicities, including hypothyroid- platin, docetaxel, and paclitaxel did not affect the pharmacoki- ism, proteinuria, cutaneous reactions, and hemorrhage, occur netic profile of axitinib. less often. The mechanisms underlying the toxicities are begin- ning to be revealed, but considerable research in this area is Axitinib dose modification needed. This understanding could lead to new therapies with improved toxicity profiles and/or greater specificity for selected Dose modification or treatment interruption may be required subtypes of RCC. to alleviate axitinib-related toxicities. Stepwise increases Emerging evidence suggests that certain adverse effects from the starting dose (5 mg BID) to 7 mg BID and then may be biomarkers for efficacy in RCC. Despite a lack of complete understanding of the underlying biological 10 mg BID may be instituted at 2-week intervals in the absence of grade ≥3 AEs or the development of hyperten- sion. The benefit of titrating to higher doses is supported by preliminary data in RCC in which higher plasma axitinib Table 6 Axitinib dose modification by grade of adverse event exposure was associated with improved outcomes [75, 76]. Dose reductions are also implemented in a stepwise fashion. AE grade Type Modification Thus, 5 mg BID is reduced to 3 mg BID, and then to 2 mg 1 Non-hematologic Continue same dose BID, if needed. Similarly, for patients receiving 7 or 10 mg or Hematologic BID, stepwise reduction should be to the next lowest dose. 2 Non-hematologic Continue same dose Recommendations for dose modifications in patients who or Hematologic develop hypertension or proteinuria are presented in Table 5. 3 Non-hematologic Decrease dose to one lower-dose level Dose modifications for other nonhematologic and hemato- Hematologic Continue same dose logic events are presented in Table 6. 4 Non-hematologic Interrupt dosing; restart at one lower- or hematologic dose level when AE improves to CTCAE grade 2 or better Conclusions a Not including hypertension or proteinuria (see Table 3) Grade 4 lymphopenia or asymptomatic biochemistry abnormality The new generation of targeted therapies for advanced RCC may continue without interruption offers significant benefit compared with prior approaches AE adverse event, CTCAE Common Terminology Criteria for Adverse such as cytokines and chemotherapy. However, significant Events 2076 Invest New Drugs (2012) 30:2066–2079 mechanisms, selected toxicities such as hypertension References may prove to be clinically useful surrogates of response if they are reproducible and correlate well with out- 1. Mathew A, Devesa SS, Fraumeni JF Jr, Chow WH (2002) Global comes. Ongoing pharmacogenomic research is focused increases in kidney cancer incidence, 1973–1992. Eur J Cancer Prev 11:171–178 on identifying specific gene polymorphisms that may be 2. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM associated with increased toxicity or improved outcomes (2010) International Agency for Research on Cancer. The GLO- with RCC therapies. BOCON Project. http://globocan.iarc.fr. Accessed 16 January Proper management of these AEs will ensure that 3. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) patients receive optimal benefit from these newer thera- Global cancer statistics. CA Cancer J Clin 61:69–90 pies. In addition, grade 1 and 2 toxicities should not be 4. Motzer RJ, Bander NH, Nanus DM (1996) Renal-cell carcinoma. overlooked when treating patients since these can be N Engl J Med 335:865–875 challenging for patients who must take drugs on a daily 5. Karumanchi SA, Merchan J, Sukhatme VP (2002) Renal cancer: basis, can have substantial effects on QoL and overall molecular mechanisms and newer therapeutic options. Curr Opin Nephrol Hypertens 11:37–42 healthcare costs, and may lead to treatment discontinua- 6. Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber tions. The potentially significant impact of these cumu- DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, lative low-grade AEs on patients must also be weighed Liewehr DJ, Merino MJ, Rosenberg SA (2003) Randomized study of against the marginal clinical benefit observed with cer- high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 21:3127–3132 tain targeted agents in unselected patient populations. 7. Kapoor AK, Hotte SJ (2007) Current status of cytokine therapy in Fojo and Parkinson [77] have suggested that identifica- management of patients with metastatic renal cell carcinoma. Can tion of patient subsets by use of clinically validated Urol Assoc J 1:S28–S33 biomarkers, developed in parallel with new targeted 8. Rini BI (2009) Vascular endothelial growth factor-targeted therapy in metastatic renal cell carcinoma. Cancer 115:2306–2312 therapy, may inform more biologically based patient 9. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial selection. This approach offers the potential in the fu- growth factor pathway in tumor growth and angiogenesis. J Clin ture of maximizing efficacy, minimizing toxicity and Oncol 23:1011–1027 10. Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms effects on QoL, and reducing cost. of anti-tumour activity. Nat Rev Cancer 8:579–591 Proactive management of these toxicities involves 11. Harris AL (2000) von Hippel-Lindau syndrome: target for anti- routine monitoring of clinical symptoms, BP, and labo- vascular endothelial growth factor (VEGF) receptor therapy. On- ratory parameters, coupled with early intervention. Ac- cologist 5:32–36 12. Kim JJ, Rini BI, Hansel DE (2010) Von Hippel Lindau syndrome. tive and early treatment of adverse effects is vital to Adv Exp Med Biol 685:228–249 maintain treatment and limit the need for dose reduc- 13. Schrier RW (2006) Diseases of the kidney & urinary tract. Lippincott tions, interruptions, or discontinuations. Successful plan- Williams & Wilkins, New York ning to anticipate the occurrence of toxicities and 14. Cowey CL, Sonpavde G, Hutson TE (2010) New advancements effective management will help ensure that patients with and developments in treatment of renal cell carcinoma: focus on pazopanib. Onco Targets Ther 3:147–155 RCC receiving targeted therapies such as axitinib have 15. Oudard S, Ravaud A, Escudier B (2010) Sequencing of therapeutic optimal outcomes with AEs that are infrequent, low- agents in the treatment of advanced renal cell carcinoma: focus on grade, and manageable. mechanism of action. Ann Urology 1:19–27 16. Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, Kane MA, Sherman E, Kim S, Bycott P, Tortorici M, Shalinsky DR, Liau KF, Cohen RB (2008) Axitinib is an active treatment for Acknowledgments Editorial assistance was provided by Lynne Isbell, all histologic subtypes of advanced thyroid cancer: results from a PhD, and by Joseph Ramcharan, PhD, of UBC Scientific Solutions, phase II study. J Clin Oncol 26:4708–4713 which was funded by Pfizer Inc. 17. Rugo HS, Stopeck AT, Joy AA, Chan S, Verma S, Lluch A, Liau KF, Kim S, Bycott P, Rosbrook B, Bair AH, Soulieres D (2011) Randomized, placebo-controlled, double-blind, phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients Conflict of Interest Roger Cohen serves as a paid member of a data with metastatic breast cancer. J Clin Oncol 29:2459–2465 safety and monitoring committee for a non-oncology Pfizer product. In 18. Rixe O, Bukowski RM, Michaelson MD, Wilding G, Hudes GR, addition, Dr. Cohen has received past funding from Pfizer for the Bolte O, Motzer RJ, Bycott P, Liau KF, Freddo J, Trask PC, Kim S, conduct of clinical trials. These funds were paid to the Fox Chase Rini BI (2007) Axitinib treatment in patients with cytokine- Cancer Center. Stéphane Oudard has received honoraria from Pfizer, refractory metastatic renal-cell cancer: a phase II study. Lancet Novartis, Roche, and Sanofi-Aventis. Oncol 8:975–984 19. Rini BI, Wilding G, Hudes G, Stadler WM, Kim S, Tarazi J, Rosbrook B, Trask PC, Wood L, Dutcher JP (2009) Phase II study Open Access This article is distributed under the terms of the Crea- of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J tive Commons Attribution License which permits any use, distribution, Clin Oncol 27:4462–4468 and reproduction in any medium, provided the original author(s) and 20. Schiller JH, Larson T, Ou SH, Limentani S, Sandler A, Vokes E, the source are credited. Kim S, Liau K, Bycott P, Olszanski AJ, von Pawel J (2009) Invest New Drugs (2012) 30:2066–2079 2077 Efficacy and safety of axitinib in patients with advanced non- (2009) Phase I and pharmacokinetic study of sorafenib in patients small-cell lung cancer: results from a phase II study. J Clin Oncol with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol 27:3836–3841 27:1800–1805 21. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, 34. Veronese ML, Mosenkis A, Flaherty KT, Gallagher M, Stevenson Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier JP, Townsend RR, O’Dwyer PJ (2006) Mechanisms of hyperten- S, Ou Y, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, sion associated with BAY 43-9006. J Clin Oncol 24:1363–1369 Chen C, Rosbrook B, Kim S, Motzer RJ (2011) Comparative 35. Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, effectiveness of axitinib versus sorafenib in advanced renal cell Nguyen L, Woulfe K, Pravda E, Cassiola F, Desai J, George S, Morgan carcinoma (AXIS): a randomised phase 3 trial. Lancet 378:1931– JA, Harris DM, Ismail NS, Chen JH, Schoen FJ, Van den Abbeele AD, 1939 Demetri GD, Force T, Chen MH (2007) Cardiotoxicity associated with 22. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah tyrosine kinase inhibitor sunitinib. Lancet 370:2011–2019 MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, 36. Maitland ML, Kasza KE, Karrison T, Moshier K, Sit L, Black HR, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Undevia SD, Stadler WM, Elliott WJ, Ratain MJ (2009) Ambula- Casali PG (2006) Efficacy and safety of sunitinib in patients with tory monitoring detects sorafenib-induced blood pressure eleva- advanced gastrointestinal stromal tumour after failure of imatinib: tions on the first day of treatment. Clin Cancer Res 15:6250–6257 a randomised controlled trial. Lancet 368:1329–1338 37. Azizi M, Chedid A, Oudard S (2008) Home blood-pressure mon- 23. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, itoring in patients receiving sunitinib. N Engl J Med 358:95–97 Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova 38. Ravaud A, Sire M (2009) Arterial hypertension and clinical benefit V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007) Bevaci- of sunitinib, sorafenib and bevacizumab in first and second-line zumab plus interferon alfa-2a for treatment of metastatic renal cell treatment of metastatic renal cell cancer. Ann Oncol 20:966–967 carcinoma: a randomised, double-blind phase III trial. Lancet 39. Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, Figlin 370:2103–2111 RA, Baum MS, Motzer RJ (2011) Hypertension as a biomarker of 24. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de efficacy in patients with metastatic renal cell carcinoma treated Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, with sunitinib. J Natl Cancer Inst 103:763–773 Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, 40. Rini BI, Schiller JH, Fruehauf JP, Cohen EE, Tarazi JC, Rosbrook Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, B, Bair AH, Ricart AD, Olszanski AJ, Letrent KJ, Kim S, Rixe O Bruix J (2008) Sorafenib in advanced hepatocellular carcinoma. N (2011) Diastolic blood pressure as a biomarker of axitinib efficacy Engl J Med 359:378–390 in solid tumors. Clin Cancer Res 17:3841–3849 25. Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer 41. Maitland ML, Bakris GL, Black HR, Chen HX, Durand JB, Elliott L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ (2010) WJ, Ivy SP, Leier CV, Lindenfeld J, Liu G, Remick SC, Steingart Phase III trial of bevacizumab plus interferon alfa versus interferon R, Tang WH (2010) Initial assessment, surveillance, and manage- alfa monotherapy in patients with metastatic renal cell carcinoma: ment of blood pressure in patients receiving vascular endothelial final results of CALGB 90206. J Clin Oncol 28:2137–2143 growth factor signaling pathway inhibitors. J Natl Cancer Inst 26. Hapani S, Chu D, Wu S (2009) Risk of gastrointestinal perforation 102:596–604 in patients with cancer treated with bevacizumab: a meta-analysis. 42. Izzedine H, Ederhy S, Goldwasser F, Soria JC, Milano G, Cohen Lancet Oncol 10:559–568 A, Khayat D, Spano JP (2009) Management of hypertension in 27. Ranpura V, Hapani S, Wu S (2011) Treatment-related mortality angiogenesis inhibitor-treated patients. Ann Oncol 20:807–815 with bevacizumab in cancer patients: a meta-analysis. JAMA 43. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, 305:487–494 Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott 28. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, metastatic renal-cell carcinoma. N Engl J Med 356:115–124 Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson 44. Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, JA, Kim ST, Chen I, Huang X, Figlin RA (2009) Overall survival Bello C, Deprimo S, Brega N, Massimini G, Armand JP, Scigalla and updated results for sunitinib compared with interferon alfa in P, Raymond E (2006) Safety, pharmacokinetic, and antitumor patients with metastatic renal cell carcinoma. J Clin Oncol activity of SU11248, a novel oral multitarget tyrosine kinase 27:3584–3590 inhibitor, in patients with cancer. J Clin Oncol 24:25–35 29. Clark JW, Eder JP, Ryan D, Lathia C, Lenz HJ (2005) Safety and 45. Rini BI, Tamaskar I, Shaheen P, Salas R, Garcia J, Wood L, Reddy pharmacokinetics of the dual action Raf kinase and vascular endo- S, Dreicer R, Bukowski RM (2007) Hypothyroidism in patients thelial growth factor receptor inhibitor, BAY 43-9006, in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl with advanced, refractory solid tumors. Clin Cancer Res 11:5472– Cancer Inst 99:81–83 5480 46. Tamaskar I, Bukowski R, Elson P, Ioachimescu AG, Wood L, 30. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels Dreicer R, Mekhail T, Garcia J, Rini BI (2008) Thyroid function M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, test abnormalities in patients with metastatic renal cell carcinoma Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan treated with sorafenib. Ann Oncol 19:265–268 M, Simantov R, Bukowski RM (2007) Sorafenib in advanced 47. Miyake H, Kurahashi T, Yamanaka K, Kondo Y, Muramaki M, clear-cell renal-cell carcinoma. N Engl J Med 356:125–134 Takenaka A, Inoue TA, Fujisawa M (2010) Abnormalities of 31. Pouessel D, Culine S (2008) High frequency of intracerebral thyroid function in Japanese patients with metastatic renal cell hemorrhage in metastatic renal carcinoma patients with brain me- carcinoma treated with sorafenib: a prospective evaluation. Urol tastases treated with tyrosine kinase inhibitors targeting the vascu- Oncol 28:515–519 lar endothelial growth factor receptor. Eur Urol 53:376–381 48. Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, 32. Keisner SV, Shah SR (2011) Pazopanib: the newest tyrosine kinase Morgan JA, Dychter SS, Larsen PR, Demetri GD, Alexander EK inhibitor for the treatment of advanced or metastatic renal cell (2006) Hypothyroidism after sunitinib treatment for patients with carcinoma. Drugs 71:443–454 gastrointestinal stromal tumors. Ann Intern Med 145:660–664 33. Miller AA, Murry DJ, Owzar K, Hollis DR, Kennedy EB, Abou-Alfa 49. Faris JE, Moore AF, Daniels GH (2007) Sunitinib (sutent)-induced G, Desai A, Hwang J, Villalona-Calero MA, Dees EC, Lewis LD, thyrotoxicosis due to destructive thyroiditis: a case report. Thyroid Fakih MG, Edelman MJ, Millard F, Frank RC, Hohl RJ, Ratain MJ 17:1147–1149 2078 Invest New Drugs (2012) 30:2066–2079 50. Kamba T, McDonald DM (2007) Mechanisms of adverse effects of 68. Fujiwara Y, Kiyota N, Chayahara N, Suzuki A, Umeyama Y, anti-VEGF therapy for cancer. Br J Cancer 96:1788–1795 Mukohara T, Minami H (2011) Management of axitinib (AG- 51. Mukohara T, Nakajima H, Mukai H, Nagai S, Itoh K, Umeyama Y, 013736)-induced fatigue and thyroid dysfunction, and predictive Hashimoto J, Minami H (2010) Effect of axitinib (AG-013736) on biomarkers of axitinib exposure: results from phase I studies in fatigue, thyroid-stimulating hormone, and biomarkers: a phase I Japanese patients. Invest New Drugs. doi:10.1007/s10637-011- study in Japanese patients. Cancer Sci 101:963–968 9637-1 52. Hennessey JV, Scherger JE (2007) Evaluating and treating the 69. Kornblau S, Benson AB, Catalano R, Champlin RE, Engelking C, patient with hypothyroid disease. J Fam Pract 56:S31–S39 Field M, Ippoliti C, Lazarus HM, Mitchell E, Rubin J, Stiff PJ, 53. Wolter P, Wildiers H, Vanderschueren D, Dumez H, Clement P, Vokes E, Wadler S (2000) Management of cancer treatment-related Schöffski P (2009) Hypogonadism in male cancer patients treated diarrhea. Issues and therapeutic strategies. J Pain Symptom Man- with the tyrosine kinase inhibitors sunitinib (SUN) or sorafenib age 19:118–129 (SOR). J Clin Oncol 27:abstract 3565 70. National Cancer Institute (2011) Eating hints: before, during, and 54. Baskin H, Cobin R, Duick D, Gharib H, Guttler R, Kaplan M, after cancer treatment. http://www.cancer.gov/cancertopics/coping/ Segal R, American Association of Clinical Endocrinologists eatinghints/page1. Accessed 16 January 2012 (2002) American Association of Clinical Endocrinologists medical 71. National Comprehensive Cancer Network (2011) Antiemesis. guidelines for clinical practice for the evaluation and treatment of http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. hyperthyroidism and hypothyroidism. Endocr Pract 8:457–469 Accessed 16 January 2012 55. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, 72. National Comprehensive Cancer Network (2011) Palliative care. Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Accessed 4 November 2011 Hawkins RE (2010) Pazopanib in locally advanced or meta- 73. Di Lorenzo G, Porta C, Bellmunt J, Sternberg CN, Kirkali Z, static renal cell carcinoma: results of a randomized phase III Staehler M, Jomiau S, Montorsi F, Buonerba C (2011) Toxicities trial. J Clin Oncol 28:1061–1068 of targeted therapy and their management in kidney cancer. Eur 56. Schmidinger M, Zielinski CC, Vogl UM, Bojic A, Bojic M, Urol 59:526–540 Schukro C, Ruhsam M, Hejna M, Schmidinger H (2008) Cardiac 74. Lacouture ME, Reilly LM, Gerami P, Guitart J (2008) Hand toxicity of sunitinib and sorafenib in patients with metastatic renal foot skin reaction in cancer patients treated with the multi- cell carcinoma. J Clin Oncol 26:5204–5212 kinase inhibitors sorafenib and sunitinib. Ann Oncol 19:1955– 57. Pfizer, Inc (2011) Highlights of prescribing information: SUTENT® 1961 (sunitinib malate) http://labeling.pfizer.com/ShowLabeling.aspx? 75. Rixe O, Dutcher R, Motzer R, Wilding G, Stadler WM, Garrett W, id0607. Accessed 16 January 2012 Pithavala S, Kim S, Tarazi BI, Rini BI (2009) Diastolic blood 58. Ostendorf T, Kunter U, Eitner F, Loos A, Regele H, Kerjaschki D, pressure (dBP) and pharmacokinetics (PK) as predictors of axitinib Henninger DD, Janjic N, Floege J (1999) VEGF(165) mediates efficacy in metastatic renal cell cancer (mRCC). J Clin Oncol 27: glomerular endothelial repair. J Clin Invest 104:913–923 abstract 5045 59. Gressett SM, Shah SR (2009) Intricacies of bevacizumab- 76. Jonasch E, Bair A, Chen Y, Rini BI (2010) Axitinib with or induced toxicities and their management. Ann Pharmacother without dose titration as first-line therapy for metastatic renal cell 43:490–501 carcinoma (mRCC). J Clin Oncol 28:abstract TPS235 60. Elice F, Rodeghiero F, Falanga A, Rickles FR (2009) Thrombosis 77. Fojo T, Parkinson DR (2010) Biologically targeted cancer therapy associated with angiogenesis inhibitors. Best Pract Res Clin Hae- and marginal benefits: are we making too much of too little or are matol 22:115–128 we achieving too little by giving too much? Clin Cancer Res 61. Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S (2008) Risk of venous 16:5972–5980 thromboembolism with the angiogenesis inhibitor bevacizumab in 78. Escudier B, Bellmunt J, Negrier S, Bajetta E, Melichar B, Bracarda cancer patients: a meta-analysis. JAMA 300:2277–2285 S, Ravaud A, Golding S, Jethwa S, Sneller V (2010) Phase III trial 62. Choueiri TK, Schutz FA, Je Y, Rosenberg JE, Bellmunt J (2010) of bevacizumab plus interferon alfa-2a in patients with metastatic Risk of arterial thromboembolic events with sunitinib and sorafe- renal cell carcinoma (AVOREN): final analysis of overall survival. nib: a systematic review and meta-analysis of clinical trials. J Clin J Clin Oncol 28:2144–2150 Oncol 28:2280–2285 79. Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, 63. Fruehauf JP, Lutzky J, McDermott DF, Brown CK, Pithavala YK, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, Bycott PW, Shalinsky D, Liau KF, Niethammer A, Rixe O (2008) Shah S, Bukowski RM (2009) Randomized phase II trial of Axitinib (AG-013736) in patients with metastatic melanoma: a first-line treatment with sorafenib versus interferon Alfa-2a in phase II study. J Clin Oncol 26:abstract 9006 patients with metastatic renal cell carcinoma. J Clin Oncol 64. Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, 27:1280–1289 Pithavala YK, Reich SD, Freddo JL, Wilding G (2005) Phase I trial 80. Rini BI,HalabiS,Rosenberg JE,Stadler WM,Vaena DA, Ou of the oral antiangiogenesis agent AG-013736 in patients with SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, advanced solid tumors: pharmacokinetic and clinical results. J Clin Small EJ (2008) Bevacizumab plus interferon alfa compared Oncol 23:5474–5483 with interferon alfa monotherapy in patients with metastatic 65. Bhojani N, Jeldres C, Patard JJ, Perrotte P, Suardi N, Hutterer G, renal cell carcinoma: CALGB 90206. J Clin Oncol 26:5422– Patenaude F, Oudard S, Karakiewicz PI (2008) Toxicities associ- 5428 ated with the administration of sorafenib, sunitinib, and temsiroli- 81. Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, mus and their management in patients with metastatic renal cell Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA carcinoma. Eur Urol 53:917–930 (2010) Efficacy and safety of pazopanib in patients with metastatic 66. Alexandre I, Billemont B, Meric JB, Richard S, Rixe O (2009) renal cell carcinoma. J Clin Oncol 28:475–480 Axitinib induces paradoxical erythropoietin synthesis in metastatic 82. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, renal cell carcinoma. J Clin Oncol 27:472–473 Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A 67. National Comprehensive Cancer Network (2011) Cancer-related fa- randomized trial of bevacizumab, an anti-vascular endothelial tigue. http://www.nccn.org/professionals/physician_gls/f_guidelines. growth factor antibody, for metastatic renal cancer. N Engl J Med asp. Acessed 16 January 2012 349:427–434 Invest New Drugs (2012) 30:2066–2079 2079 83. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, 85. Escudier B, Roigas J, Gillessen S, Harmenberg U, Srinivas S, Negrier S, Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Mulder SF, Fountzilas G, Peschel C, Flodgren P, Maneval EC, Gore M, Anderson S, Hofilena G, Shan M, Pena C, Lathia C, Chen I, Vogelzang NJ (2009) Phase II study of sunitinib adminis- Bukowski RM (2009) Sorafenib for treatment of renal cell carcinoma: tered in a continuous once-daily dosing regimen in patients with Final efficacy and safety results of the phase III treatment approaches cytokine-refractory metastatic renal cell carcinoma. J Clin Oncol in renal cancer global evaluation trial. J Clin Oncol 27:3312–3318 27:4068–4075 84. Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, 86. Minton O, Richardson A, Sharpe M, Hotopf M, Stone P (2008) Redman BG, Margolin KA, Merchan JR, Wilding G, Ginsberg MS, A systematic review and meta-analysis of the pharmacological Bacik J, Kim ST, Baum CM, Michaelson MD (2006) Sunitinib in treatment of cancer-related fatigue. J Natl Cancer Inst 100:1155– patients with metastatic renal cell carcinoma. JAMA 295:2516–2524 1166 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Investigational New Drugs Pubmed Central

Antiangiogenic therapy for advanced renal cell carcinoma: Management of treatment-related toxicities

Investigational New Drugs , Volume 30 (5) – Feb 12, 2012

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Pubmed Central
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© The Author(s) 2012
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0167-6997
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1573-0646
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10.1007/s10637-012-9796-8
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Abstract

Invest New Drugs (2012) 30:2066–2079 DOI 10.1007/s10637-012-9796-8 REVIEW Antiangiogenic therapy for advanced renal cell carcinoma: Management of treatment-related toxicities Roger B. Cohen & Stéphane Oudard Received: 28 November 2011 /Accepted: 20 January 2012 /Published online: 12 February 2012 The Author(s) 2012. This article is published with open access at Springerlink.com Summary Treatment of metastatic renal cell carcinoma responses and superior progression-free survival in advanced (mRCC) has evolved rapidly over the last two decades as major RCC compared with sorafenib. pathways involved in pathogenesis have been elucidated. . . These include the vascular endothelial growth factor (VEGF) Keywords Axitinib Renal cell carcinoma Tyrosine kinase . . axis and mammalian target of rapamycin (mTOR). Therapies inhibitor Toxicity Adverse events targeting the VEGF pathway include bevacizumab, sorafenib, sunitinib, pazopanib, and axitinib, whereas temsirolimus and everolimus inhibit the mTOR pathway. All of these novel Introduction therapies—VEGF and mTOR inhibitors—are associated with a variety of unique toxicities, some of which may necessitate The incidence of kidney cancer has been increasing world- expert medical management, treatment interruption, or dose wide, accounting for approximately 2% of all cancers (ex- reduction. Common adverse events with newer drugs include cluding non-melanoma skin cancer) [1]. In 2010, 287,421 hypertension, skin reactions, gastrointestinal disturbances, thy- new cases and 122,302 deaths were estimated and, by 2015, roid dysfunction, and fatigue. Skilled management of these 325,433 new cases and 138,629 deaths are expected to toxicities is vital to ensure optimal therapeutic dosing and occur [2]. Incidence and mortality rates were highest for maximize patient outcomes, including improved survival and men in more developed areas, where kidney cancer com- quality of life. This review describes and compares the toxicity prised 4% of all cancers [3]. Although 5-year survival rates profiles of novel molecularly targeted agents used in the treat- approximate 85% for patients with localized renal cell car- ment of mRCC and presents guidance on how best to prevent cinoma (RCC) (the most common type of kidney cancer), and manage treatment-related toxicities. Particular attention is patients with advanced disease have a 5-year survival rate of given to axitinib, the newest agent to enter the armamentarium. only 10% [4]. Nearly half of patients with RCC eventually Axitinib is a second-generation receptor tyrosine kinase inhib- develop advanced disease including 30% of patients initially itor with potent VEGF receptor inhibition that provides durable presenting with advanced disease and another 20–30% with early-stage disease who relapse after nephrectomy [4]. Kid- ney cancer subtypes include clear cell RCC (85%) and the less common non-clear cell cancers, including papillary, R. B. Cohen (*) Division of Hematology/Oncology, University of Pennsylvania, collecting duct, and chromophobe RCC [5]. 16 Penn Tower, 3400 Spruce Street, Chemotherapy and hormonal therapy are generally ineffec- Philadelphia, PA 19104, USA tive in treating kidney cancer; immunotherapy with high-dose e-mail: roger.cohen@uphs.upenn.edu interleukin-2 or interferon-alfa (INF-α) is effective in some S. Oudard patients, particularly those with good performance status [6]. Medical Oncology Department, These agents are associated with low response rates (<15%) Georges Pompidou European Hospital, and significant toxicities, which often limit their use and affect 20 Rue Leblanc, patient quality of life (QoL) [7]. Paris, France Invest New Drugs (2012) 30:2066–2079 2067 Targeted pathways in advanced RCC Efficacy of new antiangiogenic agents in pivotal clinical trials Research on the molecular pathobiology of advanced RCC has identified the vascular endothelial growth factor Findings from key clinical trials of approved antiangiogenic (VEGF)/VEGF receptor (VEGFR) axis and the agents (sorafenib, sunitinib, bevacizumab, and pazopanib) phosphatidylinositol-3-kinase–protein kinase B/mammalian in advanced RCC have reported consistent prolongation of target of rapamycin (mTOR) pathway lying downstream (the progression-free survival (PFS) and, in some cases, overall “angiogenesis axis”) as clinically relevant targets [8–10]. Tran- survival (OS) in both treatment-naïve and previously treated scription of vasculogenic mediators including VEGF and patients (Table 1). platelet-derived growth factor (PDGF) is promoted by stressors The newer agent, axitinib, is a potent, selective, second- such as hypoxia, which is a strong signal for cancer angiogen- generation inhibitor of VEGFR-1, 2, and 3 with clinical esis. Angiogenesis in RCC is believed to be highly dependent antitumor activity in a variety of solid tumors [16–20]. In on VEGF, due mainly to the high frequency of germline a recent pivotal randomized phase III trial, axitinib demon- mutations in the von Hippel-Lindau (VHL) tumor suppressor strated statistically superior PFS compared with sorafenib, gene. VHL mutations result in constitutive stabilization of the as well as a higher response rate [21]. Although many of the transcription factors HIF-1α and HIF-2α, which activate toxicities of axitinib are shared with those of the other TKIs, VEGF genes, thereby promoting angiogenesis [11]. Approxi- there are important differences, most notably an apparent mately 40% to 60% of patients with VHL disease, an autoso- higher incidence of hypertension. Moreover, the safety mal dominant familial cancer disorder, develop clear cell RCC profile for axitinib is distinct from that of sorafenib. [11–13]. VHL mutation is also associated with approximately Common adverse events (AEs) more frequent with sora- 50% of nonhereditary (sporadic) clear cell RCC. fenib versus axitinib were hand-foot syndrome (HFS), The VEGF/VEGFR axis plays a critical role in tumor rash, alopecia, anemia, hypophosphatemia, hypocalcemia, growth and survival [9]. Inhibitors of this pathway are and elevated lipase whereas the predominant toxicities with thought to exert their effects by inducing apoptosis, axitinib were hypertension, fatigue, nausea, vomiting, and cytostasis, and restrictive effects on tumor vasculature hypothyroidism [21]. [10]. VEGF-targeted agents include the monoclonal an- Axitinib first demonstrated clinical activity in patients with tibody bevacizumab which neutralizes VEGF itself, and refractory advanced RCC in a phase II study [18], in which 52 receptor tyrosine kinase inhibitors (TKIs) such as sora- patients with cytokine-refractory mRCC and clear-cell histol- fenib, sunitinib, pazopanib, and axitinib. These agents ogy received axitinib 5 mg twice daily (BID). An overall target the VEGFRs, as do additional TKIs in ongoing response rate of 44% was reported with a median duration clinical development, with effects that extend beyond of response of 23.0 months (range, 4.2–29.8 months). Median the VEGFRs [14, 15]. time to progression was 15.7 months (range, 8.4–23.4 months) The new wave of US Food and Drug Administration– and median OS was 29.9 months (range, 2.4–35.8 months). In approved molecularly targeted antiangiogenic agents has a second phase II trial [19], patients with sorafenib-refractory largely supplanted cytokines as first- and second-line therapy mRCC received axitinib at a starting dose of 5 mg BID. for metastatic RCC (mRCC). Second-generation molecularly Axitinib produced a 23% response rate and median duration targeted therapies in development include axitinib (a selective of response of 17.5 months. Median PFS was 7.4 months and highly potent VEGFR inhibitor); tivozanib and cediranib (95% CI, 6.7–11.0) and median OS was 13.6 months (95% (also VEGFR inhibitors); brivanib (inhibitor of VEGFR and CI, 8.4–18.8). fibroblast growth factor receptor); motesanib (inhibitor of In the recent phase III trial in patients with advanced RCC VEGFR, PDGF receptor, and c-Kit); XL184 (inhibitor of [21], axitinib 5 mg BID demonstrated superior PFS compared VEGFR-2, MET, and RET); and VEGF TRAP (novel inhib- with sorafenib 400 mg BID (6.7 versus 4.7 months; itor of VEGF-A). P00.0001) with a significantly higher response rate (19.4 Timely and appropriate management of treatment- versus 9.4%; P00.0001) (Table 1). Patient-reported QoL related toxicities is vital in order to deliver therapy was comparable between the two treatment arms. safely and optimally. This review describes and com- pares the toxicity profiles of antiangiogenic agents used in mRCC. Particular attention is devoted to axitinib, an Toxicity profile of new antiangiogenic agents for mRCC antiangiogenic multi-targeted TKI in active clinical de- velopment for mRCC. Guidelines for preventing and Commonly reported toxicities for antiangiogenic agents in managing treatment-related toxicities of axitinib are pre- patients with mRCC include class effects of fatigue, asthe- sented, which also have general relevance to all of the nia, diarrhea, nausea, anorexia, rash, HFS, and hypertension small-molecule angiogenesis inhibitors. (Table 2)[21–25]. Other toxicities or combinations of side 2068 Invest New Drugs (2012) 30:2066–2079 Table 1 Overview of efficacy of targeted therapies for mRCC b a b a Bevacizumab Sorafenib Sunitinib Pazopanib Axitinib + IFN-α Treatment-naïve Study 1 vs IFN vs IFN vs IFN vs PBO N0649 [23] N0189 [79] N0750 [43] N0435 [55] PFS (mo) 11 vs 5 5.7 vs 5.6 11 vs 5 11.1 vs 2.8 HR 0 0.63; CI, 0.52–0.75; HR 0 0.42; CI, HR 0 0.46; CI, P00.0001 0.32–0.54; 0.34–0.62; P<0.0001 P<0.001 c d ORR (CR + PR) 31 vs 6% 5.2 vs 8.7% 37%* OS (mo) 23.3 vs 21.3 [78] NR 26.4 vs 21.8 [28] 32% NR HR 0 0.86; CI, 0.72–1.04; HR 0 0.821; CI, P<0.1291 0.673–1.001; P00.051 Study 2 vs IFN OL N0732 [80] N0155 [81] PFS (mo) 8.5 vs 5.2 NR ORR (CR + PR) 25.5 vs 13.1 34% OS (mo) 18.3 vs 17.4 [25] NR Cytokine failure Study 1 vs PBO vs PBO OL vs PBO OL N0116 [82] N0903 [30] N0106 [84] N0202 [55] N052 [18] PFS (mo) 4.8 vs 2.5 5.5 vs 2.8 8.3 7.4 vs 4.2 13.7 HR 0 0.44; CI, 0.35–0.55; P<0.01 C c c d c ORR (CR + PR) 10% 10% 44% 29% 44.2% 29.9 OS (mo) NR 17.8 vs 14.3 [83]NR NR HR 0 0.78; CI, 0.62–0.97; P00.0287 Study 2 OL OL OL vs SOR N0107 [85] N031 [81] N0723 [21] PFS (mo) 8.2 NR 6.7 vs 4.7 HR 0 0.665; CI, 0.522–0.812; P00.0001 ORR (CR + PR) 20% 37% 19.4 vs 9.4% P00.0001 OS (mo) 19.8 NR TKI failure Study 1 OL N062 [19] PFS (mo) 7.4 ORR (CR + PR) 22.6% OS (mo) 13.6 Approved in the United States (Note: bevacizumab monotherapy approved only in Europe) Approved in the United States and Europe Investigator assessment Independent assessment mRCC metastatic renal cell cancer, IFN-α interferon-α, PBO placebo, PFS progression-free survival, HR hazard ratio, CI 95% confidence interval, ORR overall response rate, CR complete response, PR partial response, OS overall survival, NR not reported, OL open-label, SOR sorafenib effects appear to be relatively specific to particular antian- compared across disease indications. AEs reported for these giogenic agents. agents in patients with mRCC are very similar to toxicities reported for sunitinib in gastrointestinal stromal tumors [22], Toxicities across cancer populations sorafenib in hepatocellular carcinoma [24], bevacizumab monotherapy in glioblastoma, and bevacizumab plus che- Toxicity profiles of antiangiogenic therapies lack disease motherapy for metastatic colorectal cancer, non-squamous non–small cell lung cancer, and metastatic breast cancer. specificity and thus can be usefully summarized and Invest New Drugs (2012) 30:2066–2079 2069 Table 2 Toxicity profile of targeted therapies as first- and second-line treatment of mRCC VEGF inhibitor TKIs Bevacizumab+IFN-α Sorafenib [30] Sunitinib [28] Pazopanib [55] Axitinib [21] [23] Previous treatment status Tx-naïve Cytokine failure Tx-naïve Tx-naïve+cytokine TKI + cytokine failure failure Dose modification, % patients Dose reduction 40 13 52 36 31 Dose interruption – 21 54 42 77 AE, % patients AE grade All 3/4 All 3/4 All 3, 4 All 3, 4 All ≥3 Cardiovascular Hypertension 26 3 17 4 30 12, 0 40 4, 0 40 16 Constitutional symptoms Fatigue 33 12 37 5 54 11, 0 19 2, 0 39 11 Asthenia 32 10 –– 20 7, <1 14 3, 0 21 5 Hypothyroidism –– – – 14 2, 0 <10 <1 19 <1 Cutaneous symptoms Rash –– 40 1 24 1, <1 –– 13 <1 Hand-foot syndrome –– 30 6 29 9, 0 <10 <1 27 5 Mucositis/stomatitis –– – – 30 1, 0 <10 <1 15 1 Gastrointestinal symptoms Diarrhea 20 2 43 2 61 9, 0 52 3, <1 55 11 Nausea –– 23 <1 52 5, 0 26 <1, 0 32 3 Vomiting –– 16 1 31 4, 0 21 2, <1 24 3 Dyspepsia –– – – 31 2, 0 –– – – Anorexia/decreased appetite 36 3 16 <1 34 2, 0 22 2, 0 34 5 Abdominal pain –– 11 2 11 2, 0 11 2, 0 –– Hemorrhage/bleeding All sites 33 3 15 2 –– 13 –– – Laboratory Lymphopenia –– – 13 –– 31 4, <1 33 3 Neutropenia 7 4 –– – – 34 1, <1 6 1 Thrombocytopenia 6 2 –– 68 8, 1 32 <1, <1 15 <1 Decreased phosphorus –– – 13 –– 34 4, 0 13 2 Elevated lipase –– 41 12 56 15, 3 –– 27 5 Anemia/decreased Hb 10 3 8 3 79 6, 2 –– 35 <1 Proteinuria 18 7 –– – – <10 <1 –– mRCC metastatic renal cell cancer, VEGF vascular endothelial growth factor, TKI tyrosine kinase inhibitor, IFN-α interferon-α, Tx treatment, AE adverse event, Hb hemoglobin VEGF inhibitors randomized controlled trials reported that the addition of bevacizumab to other cancer therapy increased the risk of Common AEs in patients with RCC receiving bevacizumab/ gastrointestinal perforation by 1.6- to 5.7-fold, depending INF-α include pyrexia, anorexia, fatigue, asthenia, bleeding, on tumor type and dose [26]. In addition, a recent meta- hypertension, and proteinuria [23]. Bevacizumab is also analysis [27] of >10,000 patients with cancer treated with associated with increased incidence of potentially life- bevacizumab revealed increased incidence of treatment- threatening gastrointestinal perforations and thrombovascu- related mortality, particularly in patients who were also lar events [23, 25]. A meta-analysis of 12,294 patients with receiving taxanes or platinum agents. In phase III trials of a variety of solid tumors treated with bevacizumab in 17 bevacizumab plus INF-α, congestive heart failure (CHF; 2070 Invest New Drugs (2012) 30:2066–2079 in <1% patients) and cardiac ischemia/infarction (in 1% The exact mechanisms underlying VEGF/VEGFR inhib- of patients) were reported [23, 25]. itor–associated hypertension remain unknown but increased Specific effects of TKIs commonly include hypertension, BP, a dose-dependent effect of these inhibitors, is believed HFS (palmoplantar erythrodysesthesia), rash, mucositis, hy- to be caused by increases in vascular tone and peripheral pothyroidism, and myelosuppression (Table 2). resistance. Interestingly, emergence of hypertension with Across oncology trials with sunitinib, toxicities occurring these agents, including axitinib, may serve as a biomarker in ≥20% of patients included anemia, diarrhea, fatigue, nau- for antitumor efficacy [38–40]. sea, asthenia, mucositis/stomatitis, vomiting, hypertension, In the sorafenib-refractory study of axitinib [19], peripheral HFS, and rash [28]. Sunitinib is also associated with myelo- edema and hypertension were reported by 19.4% and 45.2% suppression, elevated levels of thyroid-stimulating hormone of patients, respectively. Hypertension remains the major (TSH), hypothyroidism, and hepatotoxicity including liver cardiovascular-related toxicity of axitinib, reported in 51% failure. In addition, there is increased risk of CHF and decline of patients [18, 19]. A pooled analysis of phase II studies of in left ventricular ejection fraction (LVEF) in 10% of patients axitinib in mRCC [40] reported that patients with at least one [29]. Prolongation of QT interval may also lead to increased diastolic BP (dBP) measurement ≥90 mmHg during treatment risk of ventricular arrhythmias. AEs occurring in ≥20% of had a significantly longer median OS compared with patients sorafenib-treated patients included rash/desquamation, diar- with dBP <90 mmHg (30.1 versus 10.2 months, respectively; rhea, fatigue, HFS, alopecia, and nausea [30]. Sorafenib is P<0.001). Likewise, an analysis of sunitinib clinical trials in also associated with increased risk of life-threatening bleed- patients with mRCC [39], showed that treatment-emergent ing. A high frequency of intracerebral hemorrhage has been hypertension was an independent predictor of PFS and OS reported in sorafenib- or sunitinib-treated mRCC patients with (P<0.001). PFS was 12.5 versus 2.5 months in patients with brain metastases [31]. Pazopanib is associated with hypothy- maximal systolic BP (sBP) ≥140 mmHg versus <140 mmHg, roidism and proteinuria, as well as having variable effects on respectively (P<0.001). Similarly, significant clinical benefit glucose levels [32]. Pazopanib can also cause hepatotoxicity; was reported for dBP ≥90 mmHg compared with <90 mmHg. monitoring of liver function is required and dose reduction Effective control of BP with antihypertensive treatment did may be necessary in patients with baseline elevation in total not affect the improved clinical outcome. Currently, a ran- bilirubin and other hepatic function tests [32]. Similar associ- domized prospective phase II axitinib trial in patients with ations have been observed with sorafenib, with dose reduc- mRCC is evaluating axitinib-related dBP changes as a possi- tions suggested for patients with hepatic dysfunction [33]. ble predictive biomarker for response (ClinicalTrials.gov Hyperglycemia has been reported in 41% of pazopanib- identifier: NCT00835978). treated versus 33% of placebo-treated patients, whereas hypo- Before starting TKI therapy, BP should be controlled for glycemia was reported in 17% of pazopanib- versus 3% of approximately 1 week. Hypertension should be monitored placebo-treated patients. and controlled with appropriate antihypertensive agents, Toxicities of concern reported for some of the investigational with weekly monitoring of BP during the first cycle and 2 TKIs include cholecystitis and gall bladder enlargement with to 3 weeks thereafter until a stable BP has been reached, and motesanib, proteinuria with axitinib, and mucositis with then monitored per standard medical practice [41]. Like- XL184. There appear to be some relative safety differences wise, BP should be monitored following discontinuation of across the various VEFG-inhibitor therapies, although the data TKI therapy since BP can drop rapidly. must still be considered incomplete at this time. In particular, Patients who develop stage I hypertension (≥140/ bevacizumab is associated with a low incidence of hypothy- 90 mmHg) or have increases in dBP ≥20 mmHg from base- roidism, sorafenib has low cardiac toxicity compared to suniti- line should initiate antihypertensive therapy, modify the dose nib, and recipients of pazopanib report less fatigue. of the current agent for better control, or add a second antihypertensive agent [41]. In some instances, dose reduc- Proposed mechanisms of common toxicities tion of the TKI inhibitor can be implemented to manage TKI- induced hypertension. The major classes of antihypertensive Hypertension agents, including angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and calcium channel blockers, have Hypertension occurs in 17% to 45% of TKI-treated patients been used to treat TKI-induced hypertension. There are no with RCC, with grade 3 or 4 hypertension reported in 3% to consensus recommendations, however, for the use of specific 16% of patients. Elevated blood pressure (BP) typically antihypertensive agents in this setting [42]. Antihypertensive presents early, within 3 to 4 weeks of treatment initiation agents should be individualized to suit the patient’s clinical [34, 35]. Some studies of TKI-mediated BP effects reported status. ACE inhibitors, for example, are preferred for patients elevations as early as the first day [36] to first week [37]of with proteinuria, chronic kidney disease risks, or metabolic treatment. syndrome [42]. Invest New Drugs (2012) 30:2066–2079 2071 Cutaneous reactions by standard medical interventions such as antidiarrheal med- ications and dietary modification. Rash, HFS, and mucositis/stomatitis are common effects of antiangiogenic agents. HFS is characterized by palmoplantar Cardiovascular toxicities lesions in areas of friction or trauma, commonly in the hands and feet. HFS may significantly affect a patient’s QoL and Cardiovascular toxicities of TKIs include hypertension, pe- physical functioning and often leads to treatment modification ripheral edema, and cardiac dysfunction [28, 30, 55]. The rate or discontinuation [30, 43]. The precise mechanisms causing of TKI-associated cardiovascular toxicities is not well estab- these events are largely unknown. In a sunitinib study, skin lished. Cardiac damage is manageable, provided the patients toxicity appeared after 3 to 4 weeks of treatment and was receive appropriate cardiac monitoring and treatment at the characterized by dermal vascular modifications, scattered ker- first indication of myocardial damage [56]. Monitoring for atinocyte necrosis, and intra-epidermal cleavage, which may drug-related toxicities can be challenging, as symptoms such be mediated via direct anti-VEGFR and/or PDGF receptor as dyspnea, chest, pain, and dizziness can be ambiguous dis- effects on dermal endothelial cells [44]. ease indicators in patients with advanced cancer. The use of beta blockers such as carvedilol and drugs such as simvastatin Hypothyroidism has been suggested as a means to protect against TKI-induced cardiac toxicities [56]. Importantly, decline in LVEF has pre- Antiangiogenic agents are known to affect thyroid ho- ceded CHF in sorafenib- and sunitinib-treated patients, mainly meostasis but the precise mechanisms are not well un- in those with a history of coronary artery disease. LVEF derstood. Biochemical and clinical hypothyroidism is declines have been observed in patients with mRCC treated commonly reported in patients with RCC receiving suni- with sunitinib, but it is not known if patients with cardiac tinib and sorafenib [45–47]. An increase in TSH and conditions have a greater chance of developing sunitinib- decreases in thyroid hormone, indicative of hypothyroid- related LVEF [57]. Baseline and periodic assessment of LVEF ism, has been reported in sunitinib-treated patients with are strongly recommended for patients receiving TKI therapy. gastrointestinal tumors [48]. VEGFR inhibitors such as Special emphasis must be placed on monitoring for the clinical sunitinib may induce thyroiditis and hypothyroidism via a signs and symptoms of CHF. Patients with signs and symp- direct effect on the thyroid through inhibition of VEGFR toms of CHF should be thoroughly evaluated (including LVEF [49]. Thyroid dysfunction may also result from regression assessment) and discontinue therapy. Physicians are advised to of capillaries around thyroid follicles due to VEGFR consider carefully the cardiac risk: benefit ratio for any patient inhibition [50]. Changes in TSH appeared to correlate before initiating therapy with VEGF inhibitors. with fatigue in patients receiving axitinib [51]. Therefore, thyroid-function monitoring is recommended with man- Proteinuria agement of hypothyroidism following standard guidelines for levothyroxine replacement therapy [52]. Proteinuria is mostly observed in patients receiving bevaci- zumab (Table 2). The mechanism underlying proteinuria is Fatigue unclear but it may reflect a role for VEGF in normal glo- merular endothelial repair [58]. Patients should be moni- Fatigue is experienced by 19% to 77% of patients receiving tored for proteinuria before and after treatment. Therapy antiangiogenic agents. The most common factors contributing should be discontinued in patients with grade 4 proteinuria. to fatigue in patients with cancer independent of treatment with angiogenesis inhibitors are hypothyroidism, anemia, and Bleeding and wound healing dehydration. Hypogonadism may also contribute to the fa- tigue associated with sunitinib and sorafenib [53]. Fatigue has Bleeding, including epistaxis, hematemesis, gastric bleeding, a high impact on patient QoL and should be monitored and brain hemorrhage, is associated with VEGF inhibitors closely, following appropriate treatment guidelines to alle- and is more common with bevacizumab [59]. While bleed- viate symptoms [54]. ing is generally manageable, it can be serious and some- times fatal. Patients with serious bleeding should not receive Gastrointestinal disturbance bevacizumab. Angiogenesis is required for wound healing and, thus, anti-VEGF agents may directly affect the healing Gastrointestinal AEs in patients with RCC treated with process. Wound-healing complications, such as slow or antiangiogenic agents include diarrhea, nausea, and vomit- incomplete healing following surgery, have been reported ing (Table 3). These AEs are usually not associated with for bevacizumab and pazopanib. These events were fatal in treatment discontinuation because of successful management some cases. 2072 Invest New Drugs (2012) 30:2066–2079 Table 3 Toxicity profile of axitinib in phase II studies mRCC [19] N062 mRCC [18] N052 TC [16] N060 NSCLC [20] N032 Melanoma [63] N032 Previous treatment status Sorafenib Cytokine 131 Iodine AE, % patients AE grade All 3/4 All 3/4 All ≥3 All 3 All >3 Fatigue 77 16 52 8 50 5 50 22 63 22 Diarrhea 61 15 60 10 48 3 41 3 31 0 Anorexia 48 0 35 2 30 0 50 0 –– Hypertension 45 16 58 14 28 12 22 9 44 6 Nausea 44 7 44 0 33 0 34 0 22 0 Dyspnea 39 15 –– – – – – – – Dysphonia 37 0 19 0 –– 28 0 34 0 Hand-foot syndrome 36 16 8 – 15 0 –– – 3 Mucosal inflammation 34 2 –– – – 16 0 16 0 Vomiting 32 5 21 0 13 0 19 3 –– Weight decrease 31 5 27 0 25 3 16 0 16 0 Cough 29 0 –– – – – – – – Headache 29 2 15 0 22 3 –– – – Arthralgia 27 3 14 2 –– 22 0 19 6 Constipation 26 0 14 0 –– – – – – Dysgeusia 23 0 12 0 –– – – – – Abdominal pain 21 11 12 0 –– – – – – Pain in extremity 21 3 19 4 –– – – 16 0 Stomatitis –– 17 2 25 0 –– 16 3 Proteinuria –– 8 0 18 5 –– 38 3 Rash –– –– 15 0 16 0 –– mRCC metastatic renal cell cancer, TC thyroid cancer, NSCLC non–small cell lung cancer, AE adverse event Thromboembolic events Follow-up Angiogenesis inhibition, as well as cytotoxic chemother- Careful evaluation and follow-up of reported toxicities apy, is associated with increased risk of both arterial and their response to management often allow patients thromboembolic events (ATE) and venous thromboem- to continue treatment safely on the prescribed effective bolic events (VTE) [60]. Several factors related to doses of antiangiogenic agents. AEs leading to dose VEGF inhibition are believed to contribute to the in- interruption or reduction should be closely monitored creased risk of ATE and VTE, including the role of so therapy can be reinstituted once side effects improve VEGF in the regeneration of endothelial cells. A pooled or resolve. analysis of clinical trials, including trials in mRCC, reported that bevacizumab was significantly associated with an increased risk of developing VTE in patients Axitinib with cancer [61]. In this analysis, the incidence of all- grade and high-grade VTE was 11.9% and 6.3%, re- Axitinib-related toxicities in advanced RCC spectively. A recent meta-analysis to assess the risk of ATE reported that treatment with sunitinib and sorafenib Common toxicities is associated with a three-fold increase in the risk of ATE, with an overall incidence of 1.3% in patients with AEs associated with axitinib including a higher incidence of RCC [62]. Myocardial infarction and cardiac ischemia hypertension compared with some of the other TKIs, gener- have also been reported for sunitinib and sorafenib. ally respond to supportive measures and dose modifications. Invest New Drugs (2012) 30:2066–2079 2073 The most common axitinib-related AEs reported across Management of axitinib-related toxicities in advanced RCC phase II trials [16, 18–20, 63] were fatigue, diarrhea, hypertension, and anorexia (Table 3). The most common Assessments and monitoring of toxicities grade 3/4 AEs were hypertension, fatigue, and diarrhea. The most commonly reported hematologic AE was Pretreatment assessment should be performed with particular grade 1/2 anemia, which did not require dose reduction attention to the presence of comorbidities (e.g., preexisting or interruption [18, 20]. hypertension) that may indicate more frequent monitoring and In the phase III study of axitinib versus sorafenib [21], anticipation of possible dose reductions. Patients with preex- common AEs more frequently reported with sorafenib ver- isting cardiovascular dysfunction and cardiac risk factors sus axitinib, respectively, included anemia (52% versus should be monitored regularly with BP assessment at baseline 35%), HFS (51% versus 27%), rash (32% versus 13%), and during treatment. Thyroid profiles should be assessed at and alopecia (32% versus 4%) and AEs more frequently baseline and every 2 to 3 months after initiation of therapy occurring with axitinib versus sorafenib, respectively, in- [65]. Very rarely, high hematocrits have been seen with axiti- cluded hypertension (40% versus 29%), fatigue (39% versus nib [18, 66] and should be treated appropriately. 32%), nausea (32% versus 22%), vomiting (24% versus 17%), and hypothyroidism (19% versus 8%). The incidence Management of common axitinib toxicities of diarrhea was similar for axitinib and sorafenib (55% and 53%, respectively). Axitinib does not appear to cause neu- Prevention and management strategies for axitinib-related tropenia and thrombocytopenia, which have been reported AEs are presented in Table 4 and discussed below. with sunitinib. Axitinib toxicities are very similar and manageable in Fatigue patients with cancers other than RCC. For example, in the phase II study of axitinib in 60 patients with advanced Fatigue (all grades) with axitinib treatment occurs in 39% of thyroid cancer refractory to conventional therapy, grade ≥3 patients [21]. Treatment of fatigue is supportive in nature, treatment-related AEs were hypertension (12%), fatigue requiring a thorough assessment of other possible exacerbating (5%), proteinuria (5%), and diarrhea, headache, and weight factors (e.g., sleep disturbance, comorbid conditions, concom- decrease (3% each) [16]. itant medications, hypothyroidism, or anemia). Supportive strategies include a range of approaches, from decreasing en- Dose-limiting toxicities ergy expenditure to psychosocial interventions. Pharmacologic strategies include treating contributing factors (e.g., anemia, Dose-limiting AEs leading to axitinib dose reduction or hypothyroidism) and the judicious use of psychostimulants, interruption include hypertension, fatigue, and diarrhea. including methylphenidate and modafanil [67]. Axitinib- In a phase I study of patients receiving 5 to 30 mg induced thyroid dysfunction and hypothyroidism are easily axitinib BID [64], hypertension was the primary dose- controlled by thyroid hormone replacement therapy [68]. limiting toxicity. One patient receiving axitinib (20 mg BID reduced to 10 mg BID) died acutely with grade 4 Gastrointestinal symptoms hemoptysis. In patients receiving the recommended phase II 5-mg BID dose, dose-limiting toxicities were grade 2 Over half of patients will experience axitinib-related gastro- stomatitis and grade 3 diarrhea (n01 each). In phase II intestinal disturbances. Patients should be advised to con- studies [18, 19], common AEs leading to axitinib dose sume frequent small meals, drink clear fluids in regular interruption were dyspnea, nausea, fatigue, hypertension, small amounts, and avoid foods or drinks that may exacer- and vomiting. In the sorafenib-refractory mRCC study bate diarrhea (such as dairy products) [69–72]. Diarrhea can with axitinib [19], AEs led to study discontinuation in be controlled with the use of standard antidiarrheal medica- 19% of patients and to temporary dose interruptions or tion and proper hydration. reductions in 73% and 45% of patients, respectively. In the cytokine-refractory mRCC study of axitinib [18], 15 Hand-foot syndrome patients (28.8%) had a dose reduction due to AEs. Dose reduction was required for grade 3 diarrhea and fatigue HFS is experienced by up to 36% of axitinib-treated patients (n02 each); gastrointestinal upset, dehydration, myalgia, and can be minimized by various skincare measures prior to and gout (n01 each); and grade 2 hypertension (n07). In initiating antiangiogenic therapy [65, 73]. Although severe this latter study, some patients took axitinib continuously episodes of HFS may necessitate dose alterations, topical for up to 5 years without evidence for cumulative treatments and avoidance of friction, especially in the feet, toxicities. may provide some relief. In one study, patients treated with 2074 Invest New Drugs (2012) 30:2066–2079 Table 4 Prevention and management axitinib-related adverse events Prevention Grade ≥1 Grade 3 or 4 Skin Hand-foot syndrome Routine manicure/pedicure Delay or adjust dose [65, 73] Remove calluses with proper tools Implement topical treatment Cushion pressure points and protect areas Avoid constriction/friction in concerned areas Use moisturizer (alcohol-free) after bathing Oral mucositis/ Maintain oral hygiene Use mucosal-covering agents Dose reduction or interruption stomatitis [65] Use salt and baking soda mouthwash Use topical lidocaine solutions Consume a soft diet If oral candidiasis present: use oral fluconazole or local clotrimazole troche Rash [73] Use moisturizer twice daily (alcohol-free) Topical hydrocortisone cream 1% Oral prednisone Avoid abrasive clothing/detergents/shampoo For grade 4, provide referral Avoid direct sunlight to specialist Use SPF 30 lotion/clothing Gastrointestinal Diarrhea [69] Avoid diarrhea-enhancing foods/ Loperamide or diphenoxylate Admit patient to hospital drinks/supplements (e.g., lactose, alcohol, caffeine, fiber) Drink 8–10 glasses of clear liquids daily Nausea/Vomiting Eat small meals frequently Metoclopramide, prochlorperazine, [70–72] Sip fluids steadily or haloperidol; add ondansetron or granisetron Anorexia [86] Consider megestrol acetate Constitutional Fatigue [65, 86] Monitor fatigue levels Exclude/treat contributing conditions Dose reduction or interruption (e.g., depression, hypothyroidism, pain, anemia) Use energy-conserving strategies Provide supportive care Use distraction strategies Consider psychostimulant (e.g., methylphenidate, modafanil) SPF sun protective factor topical urea or tazarotene or a two-agent combination (e.g., longer-acting agents. This approach allows cancer therapy to urea, fluorouracil, and/or tazarotene) reported improvement begin expeditiously. BP assessment prior to initiating therapy, in HFS symptoms resulting from TKI therapy [74]. every 2 weeks during the first 3 months of therapy, and monthly thereafter is recommended. Patients should also mon- itor their BP daily at home (prior to taking axitinib). Axitinib- Hypertension treated patients with sBP >150 mmHg or dBP >100 mmHg or experiencing symptoms such as headache or visual disturbance Hypertension should be controlled before starting antiangio- indicating hypertension should promptly contact their physi- genic therapy. BP ≥140/90 mmHg should be actively treated using standard antihypertensive medications. Reaching a cian for axitinib-dose modification. target <140/90 mmHg may require different combinations of standard agents and a different BP goal may be appro- Drug-drug interactions priate for some patients. For hypertensive patients with uncontrolled BP, the dose of Axitinib is primarily metabolized in the liver by the cyto- antihypertensive medication should be increased or, if on a chrome P450 (CYP) 3A4 isozyme and to a lesser extent by maximal dose, a second agent should be added and its dose CYP2C19 and CYP1A2. Less than 1% of the administered increased as appropriate. At pretreatment assessment, hyper- dose is excreted in the urine unchanged [64]. Both inducers tensive patients can initiate therapy with short-acting agents to and inhibitors of CYP metabolism may affect axitinib plasma quickly achieve BP control before exchanging medications for exposures. Therefore, concomitant use of known potent Invest New Drugs (2012) 30:2066–2079 2075 Table 5 Axitinib modification for hypertension and proteinuria [19] Adverse event Action Hypertension sBP >150 mmHg or dBP >100 mmHg Previously normotensive: Initiate anti-HTN therapy; maintain axitinib dose (Two readings at least 1 h apart) Previously HTN: Increase dose of anti-HTN therapy; if already on maximal dose, reduce axitinib dose by one level sBP >160 mmHg or dBP >105 mmHg Interrupt axitinib treatment ; adjust dose of anti-HTN agents until BP (Two readings at least 1 h apart) <150/100 mmHg; immediately restart axitinib treatment at one lower-dose level Recurrent following dose reduction Reduce axitinib dose further by one level (Two readings at least 1 h apart) Proteinuria Proteinuria >1 g/24 h Perform 24-h urine collection; continue axitinib dose while awaiting test results Proteinuria ≥2 g/24 h Interrupt axitinib treatment; wait until daily protein excretion is <2 g; restart axitinib treatment at a same dose or reduce by one dose level Patients should be closely monitored for the development of hypotension sBP systolic blood pressure, dBP diastolic blood pressure, HTN hypertensive, BP blood pressure CYP3A4 inhibitors (i.e., grapefruit juice, verapamil, ketoco- potential for a different spectrum of toxicities clearly exists nazole, miconazole, erythromycin, telithromycin, clarithromy- with these newer agents, including those targeting angiogene- cin), as well as CYP3A4 or CYP1A2 inducers (e.g., sis. Class-effects such as hypertension, fatigue, and gastroin- carbamazepine, dexamethasone, phenobarbital, phenytoin), testinal disturbances are common with all the antiangiogenic should be avoided in patients receiving axitinib. Combination agents and should be anticipated and proactively managed. therapies with agents such as 5-fluorouracil, cisplatin, carbo- Other unique but important toxicities, including hypothyroid- platin, docetaxel, and paclitaxel did not affect the pharmacoki- ism, proteinuria, cutaneous reactions, and hemorrhage, occur netic profile of axitinib. less often. The mechanisms underlying the toxicities are begin- ning to be revealed, but considerable research in this area is Axitinib dose modification needed. This understanding could lead to new therapies with improved toxicity profiles and/or greater specificity for selected Dose modification or treatment interruption may be required subtypes of RCC. to alleviate axitinib-related toxicities. Stepwise increases Emerging evidence suggests that certain adverse effects from the starting dose (5 mg BID) to 7 mg BID and then may be biomarkers for efficacy in RCC. Despite a lack of complete understanding of the underlying biological 10 mg BID may be instituted at 2-week intervals in the absence of grade ≥3 AEs or the development of hyperten- sion. The benefit of titrating to higher doses is supported by preliminary data in RCC in which higher plasma axitinib Table 6 Axitinib dose modification by grade of adverse event exposure was associated with improved outcomes [75, 76]. Dose reductions are also implemented in a stepwise fashion. AE grade Type Modification Thus, 5 mg BID is reduced to 3 mg BID, and then to 2 mg 1 Non-hematologic Continue same dose BID, if needed. Similarly, for patients receiving 7 or 10 mg or Hematologic BID, stepwise reduction should be to the next lowest dose. 2 Non-hematologic Continue same dose Recommendations for dose modifications in patients who or Hematologic develop hypertension or proteinuria are presented in Table 5. 3 Non-hematologic Decrease dose to one lower-dose level Dose modifications for other nonhematologic and hemato- Hematologic Continue same dose logic events are presented in Table 6. 4 Non-hematologic Interrupt dosing; restart at one lower- or hematologic dose level when AE improves to CTCAE grade 2 or better Conclusions a Not including hypertension or proteinuria (see Table 3) Grade 4 lymphopenia or asymptomatic biochemistry abnormality The new generation of targeted therapies for advanced RCC may continue without interruption offers significant benefit compared with prior approaches AE adverse event, CTCAE Common Terminology Criteria for Adverse such as cytokines and chemotherapy. However, significant Events 2076 Invest New Drugs (2012) 30:2066–2079 mechanisms, selected toxicities such as hypertension References may prove to be clinically useful surrogates of response if they are reproducible and correlate well with out- 1. Mathew A, Devesa SS, Fraumeni JF Jr, Chow WH (2002) Global comes. Ongoing pharmacogenomic research is focused increases in kidney cancer incidence, 1973–1992. Eur J Cancer Prev 11:171–178 on identifying specific gene polymorphisms that may be 2. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM associated with increased toxicity or improved outcomes (2010) International Agency for Research on Cancer. The GLO- with RCC therapies. BOCON Project. http://globocan.iarc.fr. Accessed 16 January Proper management of these AEs will ensure that 3. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) patients receive optimal benefit from these newer thera- Global cancer statistics. CA Cancer J Clin 61:69–90 pies. In addition, grade 1 and 2 toxicities should not be 4. Motzer RJ, Bander NH, Nanus DM (1996) Renal-cell carcinoma. overlooked when treating patients since these can be N Engl J Med 335:865–875 challenging for patients who must take drugs on a daily 5. Karumanchi SA, Merchan J, Sukhatme VP (2002) Renal cancer: basis, can have substantial effects on QoL and overall molecular mechanisms and newer therapeutic options. Curr Opin Nephrol Hypertens 11:37–42 healthcare costs, and may lead to treatment discontinua- 6. Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber tions. The potentially significant impact of these cumu- DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, lative low-grade AEs on patients must also be weighed Liewehr DJ, Merino MJ, Rosenberg SA (2003) Randomized study of against the marginal clinical benefit observed with cer- high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 21:3127–3132 tain targeted agents in unselected patient populations. 7. Kapoor AK, Hotte SJ (2007) Current status of cytokine therapy in Fojo and Parkinson [77] have suggested that identifica- management of patients with metastatic renal cell carcinoma. Can tion of patient subsets by use of clinically validated Urol Assoc J 1:S28–S33 biomarkers, developed in parallel with new targeted 8. Rini BI (2009) Vascular endothelial growth factor-targeted therapy in metastatic renal cell carcinoma. Cancer 115:2306–2312 therapy, may inform more biologically based patient 9. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial selection. This approach offers the potential in the fu- growth factor pathway in tumor growth and angiogenesis. J Clin ture of maximizing efficacy, minimizing toxicity and Oncol 23:1011–1027 10. Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms effects on QoL, and reducing cost. of anti-tumour activity. Nat Rev Cancer 8:579–591 Proactive management of these toxicities involves 11. Harris AL (2000) von Hippel-Lindau syndrome: target for anti- routine monitoring of clinical symptoms, BP, and labo- vascular endothelial growth factor (VEGF) receptor therapy. On- ratory parameters, coupled with early intervention. Ac- cologist 5:32–36 12. Kim JJ, Rini BI, Hansel DE (2010) Von Hippel Lindau syndrome. tive and early treatment of adverse effects is vital to Adv Exp Med Biol 685:228–249 maintain treatment and limit the need for dose reduc- 13. Schrier RW (2006) Diseases of the kidney & urinary tract. Lippincott tions, interruptions, or discontinuations. Successful plan- Williams & Wilkins, New York ning to anticipate the occurrence of toxicities and 14. Cowey CL, Sonpavde G, Hutson TE (2010) New advancements effective management will help ensure that patients with and developments in treatment of renal cell carcinoma: focus on pazopanib. Onco Targets Ther 3:147–155 RCC receiving targeted therapies such as axitinib have 15. Oudard S, Ravaud A, Escudier B (2010) Sequencing of therapeutic optimal outcomes with AEs that are infrequent, low- agents in the treatment of advanced renal cell carcinoma: focus on grade, and manageable. mechanism of action. Ann Urology 1:19–27 16. Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, Kane MA, Sherman E, Kim S, Bycott P, Tortorici M, Shalinsky DR, Liau KF, Cohen RB (2008) Axitinib is an active treatment for Acknowledgments Editorial assistance was provided by Lynne Isbell, all histologic subtypes of advanced thyroid cancer: results from a PhD, and by Joseph Ramcharan, PhD, of UBC Scientific Solutions, phase II study. J Clin Oncol 26:4708–4713 which was funded by Pfizer Inc. 17. Rugo HS, Stopeck AT, Joy AA, Chan S, Verma S, Lluch A, Liau KF, Kim S, Bycott P, Rosbrook B, Bair AH, Soulieres D (2011) Randomized, placebo-controlled, double-blind, phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients Conflict of Interest Roger Cohen serves as a paid member of a data with metastatic breast cancer. J Clin Oncol 29:2459–2465 safety and monitoring committee for a non-oncology Pfizer product. In 18. Rixe O, Bukowski RM, Michaelson MD, Wilding G, Hudes GR, addition, Dr. Cohen has received past funding from Pfizer for the Bolte O, Motzer RJ, Bycott P, Liau KF, Freddo J, Trask PC, Kim S, conduct of clinical trials. These funds were paid to the Fox Chase Rini BI (2007) Axitinib treatment in patients with cytokine- Cancer Center. Stéphane Oudard has received honoraria from Pfizer, refractory metastatic renal-cell cancer: a phase II study. Lancet Novartis, Roche, and Sanofi-Aventis. Oncol 8:975–984 19. Rini BI, Wilding G, Hudes G, Stadler WM, Kim S, Tarazi J, Rosbrook B, Trask PC, Wood L, Dutcher JP (2009) Phase II study Open Access This article is distributed under the terms of the Crea- of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J tive Commons Attribution License which permits any use, distribution, Clin Oncol 27:4462–4468 and reproduction in any medium, provided the original author(s) and 20. Schiller JH, Larson T, Ou SH, Limentani S, Sandler A, Vokes E, the source are credited. Kim S, Liau K, Bycott P, Olszanski AJ, von Pawel J (2009) Invest New Drugs (2012) 30:2066–2079 2077 Efficacy and safety of axitinib in patients with advanced non- (2009) Phase I and pharmacokinetic study of sorafenib in patients small-cell lung cancer: results from a phase II study. J Clin Oncol with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol 27:3836–3841 27:1800–1805 21. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, 34. Veronese ML, Mosenkis A, Flaherty KT, Gallagher M, Stevenson Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier JP, Townsend RR, O’Dwyer PJ (2006) Mechanisms of hyperten- S, Ou Y, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, sion associated with BAY 43-9006. J Clin Oncol 24:1363–1369 Chen C, Rosbrook B, Kim S, Motzer RJ (2011) Comparative 35. Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, effectiveness of axitinib versus sorafenib in advanced renal cell Nguyen L, Woulfe K, Pravda E, Cassiola F, Desai J, George S, Morgan carcinoma (AXIS): a randomised phase 3 trial. Lancet 378:1931– JA, Harris DM, Ismail NS, Chen JH, Schoen FJ, Van den Abbeele AD, 1939 Demetri GD, Force T, Chen MH (2007) Cardiotoxicity associated with 22. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah tyrosine kinase inhibitor sunitinib. Lancet 370:2011–2019 MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, 36. Maitland ML, Kasza KE, Karrison T, Moshier K, Sit L, Black HR, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Undevia SD, Stadler WM, Elliott WJ, Ratain MJ (2009) Ambula- Casali PG (2006) Efficacy and safety of sunitinib in patients with tory monitoring detects sorafenib-induced blood pressure eleva- advanced gastrointestinal stromal tumour after failure of imatinib: tions on the first day of treatment. Clin Cancer Res 15:6250–6257 a randomised controlled trial. Lancet 368:1329–1338 37. Azizi M, Chedid A, Oudard S (2008) Home blood-pressure mon- 23. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, itoring in patients receiving sunitinib. N Engl J Med 358:95–97 Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova 38. Ravaud A, Sire M (2009) Arterial hypertension and clinical benefit V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007) Bevaci- of sunitinib, sorafenib and bevacizumab in first and second-line zumab plus interferon alfa-2a for treatment of metastatic renal cell treatment of metastatic renal cell cancer. Ann Oncol 20:966–967 carcinoma: a randomised, double-blind phase III trial. Lancet 39. Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, Figlin 370:2103–2111 RA, Baum MS, Motzer RJ (2011) Hypertension as a biomarker of 24. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de efficacy in patients with metastatic renal cell carcinoma treated Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, with sunitinib. J Natl Cancer Inst 103:763–773 Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, 40. Rini BI, Schiller JH, Fruehauf JP, Cohen EE, Tarazi JC, Rosbrook Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, B, Bair AH, Ricart AD, Olszanski AJ, Letrent KJ, Kim S, Rixe O Bruix J (2008) Sorafenib in advanced hepatocellular carcinoma. N (2011) Diastolic blood pressure as a biomarker of axitinib efficacy Engl J Med 359:378–390 in solid tumors. Clin Cancer Res 17:3841–3849 25. Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer 41. Maitland ML, Bakris GL, Black HR, Chen HX, Durand JB, Elliott L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ (2010) WJ, Ivy SP, Leier CV, Lindenfeld J, Liu G, Remick SC, Steingart Phase III trial of bevacizumab plus interferon alfa versus interferon R, Tang WH (2010) Initial assessment, surveillance, and manage- alfa monotherapy in patients with metastatic renal cell carcinoma: ment of blood pressure in patients receiving vascular endothelial final results of CALGB 90206. J Clin Oncol 28:2137–2143 growth factor signaling pathway inhibitors. J Natl Cancer Inst 26. Hapani S, Chu D, Wu S (2009) Risk of gastrointestinal perforation 102:596–604 in patients with cancer treated with bevacizumab: a meta-analysis. 42. Izzedine H, Ederhy S, Goldwasser F, Soria JC, Milano G, Cohen Lancet Oncol 10:559–568 A, Khayat D, Spano JP (2009) Management of hypertension in 27. Ranpura V, Hapani S, Wu S (2011) Treatment-related mortality angiogenesis inhibitor-treated patients. Ann Oncol 20:807–815 with bevacizumab in cancer patients: a meta-analysis. JAMA 43. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, 305:487–494 Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott 28. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, metastatic renal-cell carcinoma. N Engl J Med 356:115–124 Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson 44. Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, JA, Kim ST, Chen I, Huang X, Figlin RA (2009) Overall survival Bello C, Deprimo S, Brega N, Massimini G, Armand JP, Scigalla and updated results for sunitinib compared with interferon alfa in P, Raymond E (2006) Safety, pharmacokinetic, and antitumor patients with metastatic renal cell carcinoma. J Clin Oncol activity of SU11248, a novel oral multitarget tyrosine kinase 27:3584–3590 inhibitor, in patients with cancer. J Clin Oncol 24:25–35 29. Clark JW, Eder JP, Ryan D, Lathia C, Lenz HJ (2005) Safety and 45. Rini BI, Tamaskar I, Shaheen P, Salas R, Garcia J, Wood L, Reddy pharmacokinetics of the dual action Raf kinase and vascular endo- S, Dreicer R, Bukowski RM (2007) Hypothyroidism in patients thelial growth factor receptor inhibitor, BAY 43-9006, in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl with advanced, refractory solid tumors. Clin Cancer Res 11:5472– Cancer Inst 99:81–83 5480 46. Tamaskar I, Bukowski R, Elson P, Ioachimescu AG, Wood L, 30. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels Dreicer R, Mekhail T, Garcia J, Rini BI (2008) Thyroid function M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, test abnormalities in patients with metastatic renal cell carcinoma Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan treated with sorafenib. Ann Oncol 19:265–268 M, Simantov R, Bukowski RM (2007) Sorafenib in advanced 47. Miyake H, Kurahashi T, Yamanaka K, Kondo Y, Muramaki M, clear-cell renal-cell carcinoma. N Engl J Med 356:125–134 Takenaka A, Inoue TA, Fujisawa M (2010) Abnormalities of 31. Pouessel D, Culine S (2008) High frequency of intracerebral thyroid function in Japanese patients with metastatic renal cell hemorrhage in metastatic renal carcinoma patients with brain me- carcinoma treated with sorafenib: a prospective evaluation. Urol tastases treated with tyrosine kinase inhibitors targeting the vascu- Oncol 28:515–519 lar endothelial growth factor receptor. Eur Urol 53:376–381 48. Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, 32. Keisner SV, Shah SR (2011) Pazopanib: the newest tyrosine kinase Morgan JA, Dychter SS, Larsen PR, Demetri GD, Alexander EK inhibitor for the treatment of advanced or metastatic renal cell (2006) Hypothyroidism after sunitinib treatment for patients with carcinoma. Drugs 71:443–454 gastrointestinal stromal tumors. Ann Intern Med 145:660–664 33. Miller AA, Murry DJ, Owzar K, Hollis DR, Kennedy EB, Abou-Alfa 49. Faris JE, Moore AF, Daniels GH (2007) Sunitinib (sutent)-induced G, Desai A, Hwang J, Villalona-Calero MA, Dees EC, Lewis LD, thyrotoxicosis due to destructive thyroiditis: a case report. Thyroid Fakih MG, Edelman MJ, Millard F, Frank RC, Hohl RJ, Ratain MJ 17:1147–1149 2078 Invest New Drugs (2012) 30:2066–2079 50. Kamba T, McDonald DM (2007) Mechanisms of adverse effects of 68. Fujiwara Y, Kiyota N, Chayahara N, Suzuki A, Umeyama Y, anti-VEGF therapy for cancer. Br J Cancer 96:1788–1795 Mukohara T, Minami H (2011) Management of axitinib (AG- 51. Mukohara T, Nakajima H, Mukai H, Nagai S, Itoh K, Umeyama Y, 013736)-induced fatigue and thyroid dysfunction, and predictive Hashimoto J, Minami H (2010) Effect of axitinib (AG-013736) on biomarkers of axitinib exposure: results from phase I studies in fatigue, thyroid-stimulating hormone, and biomarkers: a phase I Japanese patients. Invest New Drugs. doi:10.1007/s10637-011- study in Japanese patients. Cancer Sci 101:963–968 9637-1 52. Hennessey JV, Scherger JE (2007) Evaluating and treating the 69. Kornblau S, Benson AB, Catalano R, Champlin RE, Engelking C, patient with hypothyroid disease. J Fam Pract 56:S31–S39 Field M, Ippoliti C, Lazarus HM, Mitchell E, Rubin J, Stiff PJ, 53. Wolter P, Wildiers H, Vanderschueren D, Dumez H, Clement P, Vokes E, Wadler S (2000) Management of cancer treatment-related Schöffski P (2009) Hypogonadism in male cancer patients treated diarrhea. Issues and therapeutic strategies. J Pain Symptom Man- with the tyrosine kinase inhibitors sunitinib (SUN) or sorafenib age 19:118–129 (SOR). J Clin Oncol 27:abstract 3565 70. National Cancer Institute (2011) Eating hints: before, during, and 54. Baskin H, Cobin R, Duick D, Gharib H, Guttler R, Kaplan M, after cancer treatment. http://www.cancer.gov/cancertopics/coping/ Segal R, American Association of Clinical Endocrinologists eatinghints/page1. Accessed 16 January 2012 (2002) American Association of Clinical Endocrinologists medical 71. National Comprehensive Cancer Network (2011) Antiemesis. guidelines for clinical practice for the evaluation and treatment of http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. hyperthyroidism and hypothyroidism. Endocr Pract 8:457–469 Accessed 16 January 2012 55. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, 72. National Comprehensive Cancer Network (2011) Palliative care. Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Accessed 4 November 2011 Hawkins RE (2010) Pazopanib in locally advanced or meta- 73. Di Lorenzo G, Porta C, Bellmunt J, Sternberg CN, Kirkali Z, static renal cell carcinoma: results of a randomized phase III Staehler M, Jomiau S, Montorsi F, Buonerba C (2011) Toxicities trial. J Clin Oncol 28:1061–1068 of targeted therapy and their management in kidney cancer. Eur 56. Schmidinger M, Zielinski CC, Vogl UM, Bojic A, Bojic M, Urol 59:526–540 Schukro C, Ruhsam M, Hejna M, Schmidinger H (2008) Cardiac 74. Lacouture ME, Reilly LM, Gerami P, Guitart J (2008) Hand toxicity of sunitinib and sorafenib in patients with metastatic renal foot skin reaction in cancer patients treated with the multi- cell carcinoma. J Clin Oncol 26:5204–5212 kinase inhibitors sorafenib and sunitinib. Ann Oncol 19:1955– 57. Pfizer, Inc (2011) Highlights of prescribing information: SUTENT® 1961 (sunitinib malate) http://labeling.pfizer.com/ShowLabeling.aspx? 75. Rixe O, Dutcher R, Motzer R, Wilding G, Stadler WM, Garrett W, id0607. Accessed 16 January 2012 Pithavala S, Kim S, Tarazi BI, Rini BI (2009) Diastolic blood 58. Ostendorf T, Kunter U, Eitner F, Loos A, Regele H, Kerjaschki D, pressure (dBP) and pharmacokinetics (PK) as predictors of axitinib Henninger DD, Janjic N, Floege J (1999) VEGF(165) mediates efficacy in metastatic renal cell cancer (mRCC). J Clin Oncol 27: glomerular endothelial repair. J Clin Invest 104:913–923 abstract 5045 59. Gressett SM, Shah SR (2009) Intricacies of bevacizumab- 76. Jonasch E, Bair A, Chen Y, Rini BI (2010) Axitinib with or induced toxicities and their management. Ann Pharmacother without dose titration as first-line therapy for metastatic renal cell 43:490–501 carcinoma (mRCC). J Clin Oncol 28:abstract TPS235 60. Elice F, Rodeghiero F, Falanga A, Rickles FR (2009) Thrombosis 77. Fojo T, Parkinson DR (2010) Biologically targeted cancer therapy associated with angiogenesis inhibitors. Best Pract Res Clin Hae- and marginal benefits: are we making too much of too little or are matol 22:115–128 we achieving too little by giving too much? Clin Cancer Res 61. Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S (2008) Risk of venous 16:5972–5980 thromboembolism with the angiogenesis inhibitor bevacizumab in 78. Escudier B, Bellmunt J, Negrier S, Bajetta E, Melichar B, Bracarda cancer patients: a meta-analysis. JAMA 300:2277–2285 S, Ravaud A, Golding S, Jethwa S, Sneller V (2010) Phase III trial 62. Choueiri TK, Schutz FA, Je Y, Rosenberg JE, Bellmunt J (2010) of bevacizumab plus interferon alfa-2a in patients with metastatic Risk of arterial thromboembolic events with sunitinib and sorafe- renal cell carcinoma (AVOREN): final analysis of overall survival. nib: a systematic review and meta-analysis of clinical trials. J Clin J Clin Oncol 28:2144–2150 Oncol 28:2280–2285 79. Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, 63. Fruehauf JP, Lutzky J, McDermott DF, Brown CK, Pithavala YK, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, Bycott PW, Shalinsky D, Liau KF, Niethammer A, Rixe O (2008) Shah S, Bukowski RM (2009) Randomized phase II trial of Axitinib (AG-013736) in patients with metastatic melanoma: a first-line treatment with sorafenib versus interferon Alfa-2a in phase II study. J Clin Oncol 26:abstract 9006 patients with metastatic renal cell carcinoma. J Clin Oncol 64. Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, 27:1280–1289 Pithavala YK, Reich SD, Freddo JL, Wilding G (2005) Phase I trial 80. Rini BI,HalabiS,Rosenberg JE,Stadler WM,Vaena DA, Ou of the oral antiangiogenesis agent AG-013736 in patients with SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, advanced solid tumors: pharmacokinetic and clinical results. J Clin Small EJ (2008) Bevacizumab plus interferon alfa compared Oncol 23:5474–5483 with interferon alfa monotherapy in patients with metastatic 65. Bhojani N, Jeldres C, Patard JJ, Perrotte P, Suardi N, Hutterer G, renal cell carcinoma: CALGB 90206. J Clin Oncol 26:5422– Patenaude F, Oudard S, Karakiewicz PI (2008) Toxicities associ- 5428 ated with the administration of sorafenib, sunitinib, and temsiroli- 81. Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, mus and their management in patients with metastatic renal cell Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA carcinoma. Eur Urol 53:917–930 (2010) Efficacy and safety of pazopanib in patients with metastatic 66. Alexandre I, Billemont B, Meric JB, Richard S, Rixe O (2009) renal cell carcinoma. J Clin Oncol 28:475–480 Axitinib induces paradoxical erythropoietin synthesis in metastatic 82. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, renal cell carcinoma. J Clin Oncol 27:472–473 Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A 67. National Comprehensive Cancer Network (2011) Cancer-related fa- randomized trial of bevacizumab, an anti-vascular endothelial tigue. http://www.nccn.org/professionals/physician_gls/f_guidelines. growth factor antibody, for metastatic renal cancer. N Engl J Med asp. Acessed 16 January 2012 349:427–434 Invest New Drugs (2012) 30:2066–2079 2079 83. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, 85. Escudier B, Roigas J, Gillessen S, Harmenberg U, Srinivas S, Negrier S, Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Mulder SF, Fountzilas G, Peschel C, Flodgren P, Maneval EC, Gore M, Anderson S, Hofilena G, Shan M, Pena C, Lathia C, Chen I, Vogelzang NJ (2009) Phase II study of sunitinib adminis- Bukowski RM (2009) Sorafenib for treatment of renal cell carcinoma: tered in a continuous once-daily dosing regimen in patients with Final efficacy and safety results of the phase III treatment approaches cytokine-refractory metastatic renal cell carcinoma. J Clin Oncol in renal cancer global evaluation trial. J Clin Oncol 27:3312–3318 27:4068–4075 84. Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, 86. Minton O, Richardson A, Sharpe M, Hotopf M, Stone P (2008) Redman BG, Margolin KA, Merchan JR, Wilding G, Ginsberg MS, A systematic review and meta-analysis of the pharmacological Bacik J, Kim ST, Baum CM, Michaelson MD (2006) Sunitinib in treatment of cancer-related fatigue. J Natl Cancer Inst 100:1155– patients with metastatic renal cell carcinoma. JAMA 295:2516–2524 1166

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Published: Feb 12, 2012

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