Clinical Management of Patients Receiving Tyrosine Kinase Inhibitors for Advanced Renal Cell Carcinoma

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1 european urology supplements 7 (2008) available at journal homepage: Clinical Management of Patients Receiving Tyrosine Kinase Inhibitors for Advanced Renal Cell Carcinoma Jan Roigas * Department of Urology, Vivantes Klinikum Am Urban, Dieffenbachstrasse 1, D Berlin, Berlin, Germany Article info Keywords: Adverse event Renal cell carcinoma Sunitinib Therapy management Tyrosine kinase inhibitor This paper summarizes a presentation at a Pfizersponsored satellite symposium at the European Association of Urology Congress, March 27, Abstract Context: Targeted agents, including the multitargeted receptor tyrosine kinase inhibitor sunitinib, have demonstrated clinical efficacy in the first- and second-line treatment of patients with metastatic renal cell carcinoma (mrcc). These agents have dramatically improved the outlook for such patients. However, treatment with targeted agents is associated with a distinct pattern of adverse events (AE) that must be effectively managed for patients to derive maximum possible benefit. Objective: To review the AEs observed in sunitinib studies as well as practical therapy-management strategies to maximize clinical benefit with targeted agents in mrcc. Evidence acquisition: Sunitinib tolerability data from phase 2 and phase 3 trials and the expanded-access study and therapy-management strategies were analyzed. Evidence synthesis: Sunitinib treatment is generally well tolerated, and the majority of AEs are grade 1 or 2 in intensity. The tolerability profile of sunitinib is consistent across clinical trials and a large expanded-access study in a heterogeneous population. As such, sunitinib has a clear, predictable tolerability profile, which enables development of optimal therapy-management strategies that can be proactively adopted to prevent treatment interruptions or discontinuations. With frequent use in the clinic, knowledge of practical strategies for managing AEs and therefore optimizing clinical benefit is increasingly important. In addition, educating patients and clinicians regarding the pretreatment assessments and the possible AEs that may occur during treatment is an important aspect of managing both patients and clinicians expectations. Interdisciplinary collaboration among clinicians is a useful strategy in therapy management. Conclusions: The most common AEs observed with sunitinib treatment are described and practical strategies for minimizing the impact of AEs on patient quality of life are discussed in this article. # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Tel ; Fax: address: jan.roigas@vivantes.de /$ see front matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 594 european urology supplements 7 (2008) Introduction The management of metastatic renal cell carcinoma (mrcc) has evolved and is now largely based on the use of targeted agents, such as the multitargeted receptor tyrosine kinase (RTK) inhibitors sunitinib malate (Sutent; Pfizer Oncology, New York, NY, USA) and sorafenib tosylate (Nexavar; Bayer HealthCare Pharmaceuticals, Leverkusen, Germany), the mammalian target of rapamycin (mtor) kinase inhibitor temsirolimus (Torisel; Wyeth, Collegeville, PA, USA), and the monoclonal antibody bevacizumab (Avastin; Genentech, San Francisco, CA, USA), given in combination with interferon-a (IFN-a). These agents have all demonstrated clinical efficacy for the treatment of mrcc in the firstand/or second-line setting. The use of the targeted agents is associated with a distinct pattern of adverse events (AE) differing from that observed with chemotherapy and immunotherapy, which can significantly affect clinical outcome and patient quality of life (QoL). Practical strategies to manage AEs, together with careful management of patient expectations, can allow treatment to continue, uninterrupted by dose delay, reduction, or discontinuation. The increasingly widespread use of the targeted agents in clinical practice has led to a clearer picture of their safety profiles. As a result, it is now possible for clinicians to refine the use of targeted therapies through improved approaches to managing and minimizing the impact of AEs. Focusing on the safety profile of the oral, multitargeted RTK inhibitor sunitinib for the treatment of mrcc, this article discusses practical strategies for therapy management to support maximum patient benefit from sunitinib. In a meta-analysis of several sunitinib clinical trials in mrcc (n = 237), there was a significant association between sunitinib exposure and the probability of achieving an objective tumor response, longer time to progression, and improved overall survival (OS) [1] Therefore, strategies to support achieving maximum possible sunitinib exposure (eg, by managing AEs) may enable patients with mrcc to achieve the best possible outcome with sunitinib. 2. Sunitinib safety profile in patients with metastatic renal cell carcinoma The licensed dose of sunitinib for mrcc is 50 mg per day given for 4 wk on treatment, followed by 2 wk off treatment (schedule 4/2), in repeated 6-wk cycles. Dose modifications, including reductions made in 12.5-mg increments, are permissible based on tolerability [2]. The safety profile of sunitinib in mrcc has been assessed in two phase 2 trials in cytokine-refractory patients [3 5], in the randomized phase 3 trial comparing sunitinib to IFN-a in previously untreated patients [6], and in approximately 4000 patients treated in the international expandedaccess study [7,8]. In general, the safety profile of sunitinib has been consistent across the studies, with most AEs grade 1 and 2 in intensity. The most recent safety data from the phase 3 trial and expanded-access study are summarized below. The phase 3 trial was conducted in patients with previously untreated mrcc randomized to receive either sunitinib or IFN-a [6]. The expanded-access study included a broad range of patients, representative of a real-world population, including those with Eastern Cooperative Oncology Group performance status (ECOG PS 2; 13%) with non clear-cell renal cell carcinoma (RCC) histology (13.6%), with brain metastases (7.5%), and with prior cytokine treatment (71.4%) [7]. Across these two studies, the most commonly reported treatment-related, all-grade, nonhematologic AEs included diarrhea, fatigue, nausea, stomatitis/mucosal inflammation, and vomiting (Table 1). Other commonly reported AEs were hypertension and hand foot syndrome [6,7]. The most commonly reported grade 3 or 4 nonhematologic AEs with sunitinib in the phase 3 trial, occurring significantly more frequently than in the IFN-a arm ( p < 0.05 for all comparisons), were hypertension (8%), diarrhea (5%), hand foot syndrome (5%), and vomiting (4%) [6]. Grade 3 or 4 fatigue was, however, significantly more common in the IFN-a group than in the sunitinib group (12% vs 7%; p < 0.05) [6]. In the expanded-access study, the most frequently reported grade 3 or 4 nonhematologic AEs included fatigue (5.8%), asthenia (4.2%), hand foot syndrome (4.0%), hypertension (3.7%), and diarrhea (3.2%) [7]. Sunitinib treatment can also be associated with hematologic AEs. The overall incidence of neutropenia, anemia, and thrombocytopenia of any grade was higher in the sunitinib phase 3 trial than in the expanded-access study (Table 1), although the incidence of grade 3 and 4 events was similar. This difference between studies is most likely the result of different schedules for monitoring these events. The incidence of grade 3 or 4 leukopoenia (5% vs 2%), neutropenia (12% vs 7%), and thrombocytopenia (8% vs 0%) was significantly higher in the sunitinib group than in the IFN-a group ( p < 0.05 for all comparisons) in the phase 3 trial. In the expanded-access

3 european urology supplements 7 (2008) Table 1 Proportion of patients with treatment-related adverse events in the sunitinib arm of the phase 3 trial and in the expanded-access study Adverse event a Phase 3 trial (n = 375) Expanded-access study (n = 3997) All grades (%) Grade 3/4 (%) All grades (%) Grade 3/4 (%) Nonhematologic Diarrhea Fatigue Nausea Stomatitis Vomiting Hypertension Hand foot syndrome Mucosal inflammation Rash Asthenia Headache Dysgeusia Anorexia Dyspepsia Hematologic Neutropenia 72 11/ Anemia 71 3/ Thrombocytopenia 65 8/ a Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. study, grade 3 or 4 neutropenia and thrombocytopenia were reported in 3.7% and 5.3% of patients, respectively. The most recent analysis of the ongoing expanded-access study showed that the tolerability of sunitinib does not differ according to patients characteristics. The frequency of the four most commonly reported AEs in this study (fatigue, diarrhea, mucosal inflammation, and nausea) was similar across different patients subgroups, including elderly patients, those of poor performance status (PS), and those with brain metastases [7] (Fig. 1). Sunitinib treatment has been associated with the development of hypothyroidism. In the phase 3 trial, hypothyroidism was reported as an AE in 11 patients (3%) treated with sunitinib, and an additional 7 patients (2%) with no prior history of hypothyroidism started thyroid-replacement therapy while on the study [2]. Hypothyroidism was reported in approximately 2% of patients in the expandedaccess study [7]. Fig. 1 Sunitinib expanded-access study: selected grade 3/4 treatment-related adverse events. PS, performance status.

4 596 european urology supplements 7 (2008) Withdrawals resulting from AEs occurred in a higher proportion of patients receiving IFN-a (23%) compared to sunitinib (16%) in the phase 3 trial [6].In the expanded-access study, 5.6% of patients withdrew because of AEs [7]. A similar tolerability profile was reported in the phase 2 sunitinib trials in cytokine-refractory patients [3,4]. As such, it seems probable that the AE profile observed in these studies provides a good indication of the events most likely to be encountered in clinical practice. Although the safety profile of sunitinib can vary with treatment cycle and individual patient characteristics, AEs are usually manageable in all patient groups. 3. Sunitinib therapy management 3.1. Actions before starting treatment Before starting sunitinib treatment, clinicians should thoroughly assess the patient s risk profile, including any medical history of hypertension, cardiac problems or congestive heart failure (CHF), vascular pathology, hypothyroidism, and the presence of any calluses or corns on the hands or feet [9]. Comorbidities should be stabilized and risk factors addressed where possible, particularly unstable hypertension or arterial tension at a spontaneous value 140/80 mmhg in patients with a history of cardiovascular events [9]. Complete blood counts (CBC) should be performed at the beginning of each treatment cycle, and thyroid function should be monitored in patients with symptoms suggestive of hypothyroidism. Clinicians must also ask if the patient is taking any other medications, including over-the-counter medications and dietary supplements. Concomitant CYP3A4 inhibitors such as ketoconazole may increase the plasma concentration of sunitinib and should be avoided; if this is impossible, the dose of sunitinib may need to be reduced to 37.5 mg daily, based on careful monitoring of tolerability [2]. Conversely, CYP3A4 inducers such as rifampicin can reduce the plasma concentration of sunitinib, and concomitant medication with minimal or no enzyme induction is recommended. If this is not possible, the dose of sunitinib may need to be increased in 12.5-mg increments (up to a maximum of 87.5 mg per day), based on careful monitoring of tolerability [2]. In addition to clinical assessments, physicians should check that patients have a clear understanding of the disease itself and the course of treatment and that they are aware of any necessary tests and procedures. Educating patients about possible AEs to be anticipated is critical in aiding in their early detection, managing patient expectations, and facilitating AE management. Counselling may also be useful. Given the diverse nature of AEs that may be encountered during sunitinib treatment, a multidisciplinary approach to patient care that incorporates expertise from different disciplines is essential. In addition, patients should receive intensive support for the first two treatment cycles to minimize the impact of early onset AEs that may require dose reduction or interruption Practical strategies for therapy management In general, dose delays can allow resolution or decrease the incidence and severity of AEs in some patients [9] The administration of sunitinib in the evening versus during the day may also minimize the effect of AEs on patients QoL. The recommendations and strategies described in this paper for specific AEs (Table 2) are based on clinical experience and may be used to manage treatment-related AEs to maximize clinical outcomes Strategies for specific adverse events Fatigue Fatigue has been commonly reported in patients treated with sunitinib and other targeted agents. The severity of fatigue appears to vary from cycle to cycle; symptoms may improve during the 2-wk offtreatment period. Contributing factors include pain, emotional distress, depression, sleep disturbance, comorbidities, anemia, and hypothyroidism, some of which may be related to the underlying disease as well as to sunitinib treatment. Advising patients prior to initiation of treatment on what to expect from treatment and managing expectations in conjunction with the provision of counselling to motivate the patient to remain on therapy is useful in the management of fatigue. Patients can be encouraged to modify behavior and daily activities to conserve energy. In addition, patients should be monitored for comorbidities such as anemia, depression, and hypothyroidism, which may contribute to fatigue. Medical intervention to alleviate such contributing factors, where possible, may also allow fatigue to be managed adequately and prevent treatment interruption, delay, or discontinuation Gastrointestinal events Gastrointestinal events observed during treatment with sunitinib include diarrhea and stomatitis.

5 european urology supplements 7 (2008) Table 2 Recommended strategies for management of adverse events in patients with metastatic renal cell carcinoma treated with sunitinib a Adverse event Pretreatment management Management during treatment Fatigue Gastrointestinal events Skin disorders Advise on possible occurrence Encourage modification of daily activities or behaviours to conserve energy Educate patients about possible symptoms Consult dietician to modify diet Switch to pediatric toothpaste Advise patients to avoid spirits Educate patients regarding adverse events using visual illustrations and leaflets or brochures Advise patients on possible depigmentation of skin and hair Conduct full foot exam and consult with podiatrist Advise patients to reduce pressure on affected areas Evaluate for underlying factors: depression, emotional distress, sleep disturbance, hypothyroidism, anemia Treat underlying factors according to standard treatment Provide supportive counselling as needed Dose modifications infrequently or rarely Treat with antiemetic medication, bulking agents, and antidiarrheal medication (eg, loperamide) and dietary modification Advise on use of bicarbonate mouthwashes that have paracetamol with morphine or codeine sulfate Dose delay or reduction for grade 3 or 4 adverse events Advise patients to wear thick-soled shoes Use local corticoid, vitamin A, and urea creams Removal of grade 2 or 3 blisters by dermatologist Advise patients to wear hydrocolloidal bandages Interrupt treatment if lesions grade 2 or more (very painful) appear until resolution to grade 0 or 1 Cardiovascular events Conduct a full cardiovascular assessment Monitor for cardiac risk factors such as CHF and LVEF Monitor for hypertension and control according to standard medical practice Dose reduction or discontinuation to reverse change in LVEF of <50% and >20% below baseline Frequently monitor for BP and treat with standard antihypertensive therapy Temporarily suspend treatment until hypertension is controlled Hypothyroidism Monitor for thyroid function and treat according to standard practice Monitor for thyroid hormone levels Use preventative measures such as vitamin B 12 and iron supplements Treat with thyroid-replacement therapy Hematologic toxicity Advise patient on good hygiene and diet CBC Eliminate hypothyroidism as the cause Manage according to local guidelines Treat according to local guidelines Advise patient to avoid forceful coughing and straining bowel movements In the event of myelosuppression, delay dose; restart treatment when neutrophil and granulocyte counts are restored BP, blood pressure; CBC, complete blood count; CHF, congestive heart failure; LVEF, "." ventricular ejection fraction; mrcc, metastatic renal cell carcinoma. a Based on Sutent product information [2] and expert opinion. Patients who are educated on the symptoms may cope better with the onset of gastrointestinal AEs, and several strategies can be used to address and deal with these symptoms. Consultation with a dietician, ideally before starting treatment, may help prevent or reduce the intensity and impact of gastrointestinal AEs. Modification of the diet, following consultation with the dietician, can be useful in managing gastrointestinal AEs. Sunitinib-associated diarrhea can occur at any time during the course of treatment. It is usually mild (grade 1 or 2) and differs from that in patients receiving cytotoxic chemotherapy; it presents as loose and more frequent stools (with a strong urgency to void the bowels) rather than as watery diarrhea. Supportive measures include the use of oral hydration, bulking agents, and antidiarrheal agents, such as loperamide. Oral changes include dysgeusia, dysphasia, sensitivity, and sores, but changes do not have the appearance or severity of chemotherapy-induced mucositis. Clinical experience suggests that stomatitis often occurs during the second week of treatment and may resolve during the 2-wk offtreatment period. Stomatitis may be reduced or prevented by switching to pediatric toothpaste before starting treatment and by avoiding spirits. In addition, a bicarbonate mouthwash containing

6 598 european urology supplements 7 (2008) paracetamol with morphine or codeine sulfate may alleviate symptoms Skin disorders: hand foot syndrome Sunitinib and other targeted agents may cause hand foot syndrome (or palmar-plantar erythrodysesthia), with symptoms predominantly on the pressure points of hands and feet. This may result from the expression of tyrosine kinase receptors in the skin and associated structures [10]. These symptoms include dysaesthesia and/or paraesthesia, erythema, edema, hyperkeratosis, dry or cracked skin, callus-like blisters, and desquamation. The onset of symptoms is variable, but severity generally increases as treatment progresses. Calluses and blisters usually improve during offtreatment periods but may also resolve during treatment. Prior to initiation of treatment, a full foot examination alongside a consultation with a podiatrist may be warranted. Patient education is helpful in preventing and managing skin toxicity. Strategies to do so include providing visual illustrations as well as leaflets and brochures to educate patients and manage their expectations. Advising patients to reduce pressure on affected areas, staying off their feet where possible, and avoiding friction or pressure to the hands all serve to alleviate symptoms associated with hand foot syndrome. Preventative and treatment recommendations for grade 1 toxicity include use of local corticoid, vitamin A, and urea creams and wearing thick-soled shoes. For grade 2 and 3 toxicity, removal of blisters by a dermatologist and wearing a hydrocolloidal bandage may be helpful. Treatment may be interrupted when grade 2 or higher hand foot syndrome occurs until resolution of symptoms severity to grade 0 or 1. Resumption of treatment, at the same or a reduced dose, is an option at this stage Cardiovascular events The onset of hypertension during sunitinib treatment is highly variable. Symptoms may resolve during treatment but may recur in later treatment cycles. In the phase 2 trials in patients with cytokine-refractory mrcc, hypertension was reported in 17% of patients receiving sunitinib [2]. Hypertension of all grades has been reported in 24% of patients treated with sunitinib in the phase 3 trial comparing sunitinib to IFN-a treatment in previously untreated patients [6]. The incidence of all-grade hypertension in the expanded-access study was 13.9%. Patients should be monitored for hypertension prior to initiating treatment and blood pressure (BP) controlled according to standard medical practice. During treatment, frequent monitoring of BP and treatment with standard antihypertensive therapy can be used as needed to manage hypertension. Temporary suspension is recommended in patients with severe hypertension that is not controlled with medical management. Treatment may be resumed when hypertension is appropriately controlled [2]. Communication between practitioners with regard to individual patients medications also facilitates hypertension management. In addition, a full cardiovascular assessment should be carried out prior to starting treatment followed by monitoring for cardiac risk factors such as CHF and left ventricular ejection fraction (LVEF). Treatment with sunitinib in the phase 3 study comparing IFN-a treatment to sunitinib treatment in the first-line setting resulted in a decline of LVEF that was easily reversed through dose reductions or discontinuations and was not associated with clinical sequelae [6] Hypothyroidism Treatment with sunitinib has been associated with the incidence of hypothyroidism, often observed in the later treatment cycles. In the sunitinib phase 2 studies, hypothyroidism was reported in 4% of patients; 2% of patients receiving sunitinib and <1% of patients treated with IFN-a experienced hypothyroidism in the phase 3 trial. The overall incidence of treatment-emergent hypothyroidism in these clinical trials was 7% in patients receiving sunitinib [2]. In the expanded-access study, grade 1 or 2 hypothyroidism has been observed in 2% of patients, with the incidence of grade 3 or 4 in 0.2% of patients [7]. However, other studies have recorded higher incidences of hypothyroidism in sunitinibtreated patients [11,12]. In a single-center case series investigating thyroid function in sunitinib-treated patients who experienced fatigue, 56 of 66 patients (85%) had thyroid function abnormalities. Of these 56 patients, 47 (84%) presented with signs and/or symptoms related to hypothyroidism [11]. In a separate study, a prospective analysis of patients with mrcc treated with sunitinib indicated that 3 of 11 patients had elevated levels of thyroid-stimulating hormone (TSH) after 6 wk of treatment [12]. As such, baseline laboratory measurement of thyroid function is recommended, and patients with hypothyroidism should be treated as per standard medical practice before starting sunitinib [2]. All patients should be observed closely for signs and symptoms of hypothyroidism while receiving treatment [2]. Patients with symptoms suggestive of hypothyroidism should have their thyroid function

7 european urology supplements 7 (2008) checked by laboratory tests and preventative measures, such as vitamin B 12 and iron supplements, should be recommended [2]. Hypothyroidism is easily correctable, and treatment as per standard medical practice with thyroid-replacement therapy should be instituted to continue use of sunitinib to treat mrcc Hematologic toxicity Most hematologic toxicity during sunitinib treatment is grade 1 2. Neutropenia and thrombocytopenia typically occur during the first treatment cycle without progression in later cycles. Nonfebrile neutropenia and thrombocytopenia tend to resolve during off-treatment periods but may recur in some patients. Anemia reported during sunitinib treatment may, at least in some cases, be related to the cancer itself rather than to sunitinib. If anemia is suspected, hypothyroidism should be eliminated as a possible cause and preventative measures implemented, such as vitamin B 12 and iron supplementation. All patients should be monitored for myelosuppression at the beginning of each treatment cycle and as appropriate. In the event of a repeated low neutrophil or granulocyte count, treatment should be delayed for a few days and restarted when levels are restored. If grade 3 neutropenia or thrombocytopenia occurs and persists after the 2-wk offtreatment period, sunitinib treatment should be delayed or the dose reduced. In general, hematologic toxicity management should include advising patients on the importance of good hygiene and dietary guidelines as well as avoiding forceful coughing and straining bowel movements. Collection of blood samples at the start of each treatment cycle and more frequently if necessary can help to identify any toxicity early on, allowing initiation of preventative measures. Other AEs that may be of concern to urologists and other surgeons include rare incidences of bleeding or gross hematuria. Treatment has rarely been observed to affect wound healing, and few concerns exist regarding the use of targeted agents around surgery. To determine whether sunitinib could impair wound healing following cytoreductive surgery, postoperative complications related to sunitinib treatment in patients with metastatic gastrointestinal stromal tumor were analyzed [13]. In these patients, sunitinib therapy was stopped a median of 5 d (range: 0 26) prior to surgery and resumed a median of 33 d (range: ) postsurgery, which coincided with the first postoperative visit. The authors concluded that sunitinib treatment was not associated with an increase in wound-healing complications as compared to imatinib therapy [13]. Another study examining the postoperative use and surgical complications of sunitinib in patients with mrcc concluded that sunitinib toxicity is low during the perioperative period, and sunitinib treatment should be suspended for 10 d prior to and after surgery [14]. 4. Conclusions Sunitinib has demonstrated superior clinical efficacy compared to IFN-a in the treatment of patients with mrcc in the first-line setting and is now considered the reference standard of care in this setting [6]. Sunitinib has also demonstrated antitumor activity in patients with cytokine-refractory mrcc [3 5]. Treatment with targeted agents is associated with a specific profile of AEs. Increasing use of these agents in the clinic has allowed the development of practical strategies for managing treatment-related AEs to improve clinical outcome. The tolerability profile of sunitinib is well defined and broadly consistent across studies in mrcc, including patients who are elderly, of poor PS, or have brain metastases. Most AEs are grade 1 or 2, reversible, and manageable with standard medical intervention or dose modification. In addition, the AEs experienced by patients treated with sunitinib are similar to those observed with other targeted agents. It is essential that both the patients and clinicians develop an awareness of the likely AEs and the strategies that may be used to manage them. Early identification of AEs is important for minimizing their impact on patient health and QoL and may also help to reduce the need for dose interruption or reduction, enabling patients to derive maximum benefit from sunitinib treatment. Clinicians and staff can play a critical role in detecting AEs in a timely fashion by making appropriate baseline assessments to detect any risk factors before starting sunitinib treatment, by educating patients about the signs and symptoms of common sunitinib-related AEs, and by ensuring frequent contact with patients. In addition, interdisciplinary collaboration among clinicians in the treatment of patients experiencing specific AEs, such as a cardiovascular event, is essential. The strategies outlined here provide guidance on the implementation of practical strategies to manage AEs and reduce their impact, allowing patients to remain on the optimal treatment course and achieve the maximum potential clinical benefit.

8 600 european urology supplements 7 (2008) Conflicts of interest Jan Roigas is a consultant for and has received honoraria from Bayer Pharmaceuticals, Pfizer Inc., Roche, and Wyeth. Funding support Pfizer Inc. provided funding for editorial assistance. Acknowledgments The author acknowledges ACUMED (Tytherington, UK) for providing editorial assistance for this paper. References [1] Houk B, Bello CL, Michaelson MD, et al. A population pharmacokinetic/pharmacodynamic (PK/PD) analysis of exposure-response for sunitinib in metastatic renal cell carcinoma (mrcc) [abstract]. Eur J Cancer Suppl 2007;5: 299. [2] Sutent, summary of product characteristics. New York, NY: Pfizer Inc; [3] Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24: [4] Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006;295: [5] Motzer RJ, Michaelson MD, Rosenberg J, et al. Sunitinib efficacy against advanced renal cell carcinoma. J Urol 2007;178: [6] Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356: [7] Gore M, Szczylik C, Porta C, et al. Sunitinib in metastatic renal cell carcinoma (mrcc): preliminary assessment of safety and efficacy in an expanded access trial with subpopulation analysis [abstract]. Eur J Cancer Suppl 2007;5:299. [8] Bellmunt J. Sunitinib in advanced renal cell carcinoma: clinical evidence. Eur Urol Suppl 2008;7: [9] Negrier S, Ravaud A. Optimisation of sunitinib therapy in metastatic renal cell carcinoma: adverse-event management. Eur J Cancer Suppl 2007;5:12 9. [10] Robert C, Soria JC, Spatz A, et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005;6: [11] Rini BI, Tamaskar I, Shaheen P, et al. Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2007;99:81 3. [12] Schöffski P, Wolter P, Himpe DR, et al. Sunitinib-related thyroid dysfunction: a single-center retrospective and prospective evaluation. J Clin Oncol 2006;24:3092. [13] Raut C, Morgan JA, Quigley MT, et al. Postoperative experience in patients with metastatic GIST are similar in patients while on sunitinib or imatinib. Eur J Cancer Suppl 2007;5:409. [14] Thibault F, Billemont B, Rixe O. Perioperative use and surgical complications of sunitinib in metastatic renal cell carcinoma. Eur Urol Suppl 2008;7:306.