Sunitinib and sorafenib in metastatic renal cell carcinoma patients with ... [PDF]

2 downloads 118 Views 72KB Size Report
Jan 20, 2010 - 39.2 ml/min (14.9–60). Median time to increase in Cr ‡ 30% (range). 6.6 months (0.4–19.6)1. 4.6 months (0.4–19.1). Time on therapy (median, ...
original article

Annals of Oncology 21: 1618–1622, 2010 doi:10.1093/annonc/mdp603 Published online 20 January 2010

Sunitinib and sorafenib in metastatic renal cell carcinoma patients with renal insufficiency G. Khan1, A. Golshayan2, P. Elson2, L. Wood2, J. Garcia2, R. Bukowski2 & B. Rini2* 1

Department of Internal Medicine, Medicine Institute and 2Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

Received 23 June 2009; revised 2 December 2009; accepted 10 December 2010

original article

Background: Although clinical trials with sunitinib and sorafenib in metastatic renal cell carcinoma (mRCC) have included patients with moderate renal insufficiency (RI), the incidence of renal toxicity induced by their administration as well as the safety of these agents in patients with more severe renal insufficiency has not been extensively reported. Patients and methods: Patients with mRCC treated with vascular endothelial growth factor-targeted therapy with either RI at time of treatment initiation or who developed RI during therapy were identified. RI was defined as serum creatinine (Cr) ‡ 1.9 mg/dl or a creatinine clearance (CrCl) < 60 ml/min/1.73 m2 for >3 months before treatment. Objective outcomes and toxic effects of treatment were also measured. Results: A total of 39 patients were identified: 21 patients who initiated therapy with preexisting RI and 18 patients who developed RI during treatment. In patients with RI at the start of therapy, Cr increased in 57%, and 48% of patients required dose reduction. The median time to maximum RI was 6.6 months (range 0.4–19.6 months). In patients who developed RI while receiving therapy, median serum Cr and CrCl at the start of therapy were 1.5 mg/dl (range 1.1–1.8) and 61 ml/min (range 43–105), respectively. Patients experienced a median increase in serum Cr of 0.8 mg/dl (range 0.3–2.8) and a median decrease in CrCl of 25 ml/min (range 8.54–64.76). Overall, 5 patients (24%) achieved a partial response (PR), 13 (62%) had stable disease (SD) and 3 (14%) had progressive disease (PD). Estimated progression-free survival (PFS) was 8.4 months. The most common toxic effects (all grades) were fatigue (81%), hand–foot syndrome (HFS) (52%) and diarrhea (48%). Six patients experienced grade III toxicity (29%), primarily HFS. Conclusions: Sunitinib and sorafenib can be safely given to patients with renal insufficiency, provided adequate monitoring of renal function. For those patients developing an increase in Cr, dose modifications may be required to allow continuation of therapy. The clinical outcome of patients with baseline renal dysfunction and patients who develop renal dysfunction does not appear to be compromised. Key words: renal cell carcinoma, renal insufficiency, sorafenib, sunitinib, VEGF-targeted therapy

introduction The Von Hippel-Lindau is a tumor suppressor gene, the product of which regulates the production of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and a number of other hypoxia-inducible proteins [1–4]. These factors bind to their specific tyrosine kinase receptors on endothelial cells and promote tumor angiogenesis and subsequent tumor growth. Sunitinib and sorafenib are small oral tyrosine kinase inhibitors of VEGF and PDGF and related receptors [5–10]. Although clinical trials with sunitinib and sorafenib in metastatic renal cell carcinoma (mRCC) have included patients with moderate renal insufficiency (RI) [creatinine clearance (CrCl) 30–50 ml/min], the incidence of renal toxicity induced

*Correspondence to: Dr B. I. Rini, Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue Desk R35, Cleveland, OH 44195, USA. Tel: +1-216-444-9567; Fax: +1-216-636-1937; E-mail: [email protected]

by these agents in patients with more severe renal insufficiency has not been extensively reported. Four phase I clinical studies evaluated the safety of sorafenib in patients with refractory solid tumors in patients with normal renal function (n = 71), patients with mild renal impairment (CrCl 50–80 ml/min, n = 24) or moderate renal impairment (CrCl 30–50 ml/min, n = 4). Three of these studies excluded patients with creatinine (Cr) > 1.5 · upper limit of normal (ULN) [11–14] and did not specify dose adjustments for renal toxicity. A phase III trial, which examined sorafenib in patients with cytokine-refractory advanced renal cell carcinoma (RCC), did not mention renal toxicity and eligibility criteria included only patients with ‘adequate renal function’ [10]. Less data is available for sunitinib with regards to safety in patients with renal dysfunction. Three phase I clinical trials were conducted, but only one study included patients with RCC (n = 4 of 28, 14%) with serum Cr < 1.5 · ULN or CrCl > 40 ml/min and Cr trend following initiation of therapy was not elaborated upon [7, 15, 16]. Two phase II clinical trials

ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]

Downloaded from https://academic.oup.com/annonc/article-abstract/21/8/1618/153277/Sunitinib-and-sorafenib-in-metastatic-renal-cell by guest on 12 September 2017

original article

Annals of Oncology

included patients with adequate renal function without specified parameters [17, 18] and of these, one trial reported 9 of 63 patients (14%) with grade 2 Cr elevation [17]. The phase III sunitinib trial in patients with treatment-naive RCC included patients with adequate renal function [19]. In this study, 66 of 375 patients (18%) had increased Cr of all grades. The purpose of this retrospective review was to further characterize the effect of sorafenib and sunitinib on renal function in mRCC patients with baseline renal insufficiency and also to characterize RCC patients who develop renal insufficiency during treatment with these agents.

patients and methods All patients with mRCC who received at least 3 months of treatment with either sunitinib or sorafenib at the Cleveland Clinic Taussig Cancer Institute were retrospectively identified as part of an institutional review boardapproved chart review protocol. Patients with the presence of RI before therapy or development of renal insufficiency during treatment were selected from this group and included in the present analysis. Renal insufficiency was defined as serum Cr ‡ 1.9 mg/dl before therapy and/or CrCl £ 60 ml/min for ‡ 3 months before treatment. Development of renal insufficiency was defined as an increase in Cr > 20% compared with baseline. Development of proteinuria is not reported in this study due to lack of complete data. CrCl was estimated using the Cockcroft–Gault method.

statistical methods Patient data were collected retrospectively via electronic medical record chart review. Outcomes including overall response (OR), tumor shrinkage (TS) and progression-free survival (PFS) were recorded per investigator assessment using RECIST criteria [20]. Categorical data, such as gender, histology, prognostic risk factors, the number of patients requiring dose reductions, adverse events and OR, were summarized as frequency counts and percentages [21]. Quantitative data, such as age, Cr, CrCl, interval to maximum RI and TS, were summarized as medians and ranges. Median PFS was calculated using the method of Kaplan and Meier. The Wilcoxon rank sum test was used to compare patients with RI at on-study to those who developed it with respect to maximum Cr and interval to maximum RI. All analyses were conducted using SAS 8.1 (SAS Institute Inc., Cary, NC).

results A total of 39 patients were identified: 21 patients who initiated sunitinib or sorafenib therapy with preexisting RI and 18 patients who developed RI during treatment. Table 1 summarizes the patient characteristics. All but two patients had prior nephrectomy and 62% of patients had received prior systemic therapy. No patients received prior radiation therapy. Ninety percent of patients had an Eastern Cooperative Oncology Group performance status of zero or one.

patients with renal insufficiency at start of treatment Of patients with RI at start of treatment, 10 of 21 (48%) were receiving a diuretic (hydrochlorothiazide, loop diuretic), 8 of 21 (38%) were cardiovascular medications (angiotensin receptor inhibitor, angiotensin receptor blocker) and 3 of 21 (14%) were receiving a bisphosphonate. Of patients who developed RI while on therapy, 9 of 18 (50%) were receiving

Volume 21 | No. 8 | August 2010

Table 1. Patient characteristics (N = 39) Renal insufficiency at start of treatment (n = 21) Gender, n (%) Male Female Median age at the start of treatment, years (range) ECOG, n (%) 0 1 2 Median BSA, m2 (range) Prior nephrectomy, n (%) Median time from diagnosis to treatment, months (range) Prior systemic therapy, n (%) Single agent VEGF (sunitinib, sorafenib, bevacizumab) Cytokine Combination Cytokine + VEGF Cytokine + other Other Histology, n (%) Clear-cell Papillary Chromophobe Metastases, n (%) Contralateral kidney Lung Liver Bone Brain TKI risk group (21) Favorable Intermediate Unfavorable

17 (81) 4 (19) 68 (48–79)

5 12 4 1.99

(24) (57) (19) (1.51–2.22)

19 (90) 8.5 (1.3–55.8)

12 (57)

Developed renal insufficiency during treatment (n = 18) 13 (72) 5 (28) 66 (48–80)

6 (33) 12 (67) 0 2.06 (1.72–2.62) 18 (100) 10.5 (1.7–73.2)

12 (67)

3

4

3

3

1 4 1

4 1 0

19 (90) 1 (5) 1 (5)

17 (94) 1 (6) 0

2 18 9 12 1

1 15 6 7 4

(10) (86) (43) (57) (5)

9 (43) 5 (24) 7 (33)

(6) (83) (33) (39) (22)

8 (44) 5 (28) 5 (28)

‘Other’ chemotherapy: M200, suramin, 5-FU, capecitabine, gemcitaine, irinotecan, thalidomide, carboplatin, CC5013, CPG-7909, IGN-301. BSA, body surface area; ECOG, Eastern Cooperative Oncology Group; TKI, tyrosine kinase inhibitors; VEGF, vascular endothelial growth factor.

a diuretic, 10 of 18 (56%) cardiovascular medications and 2 of 18 (11%) a bisphosphonate. Four patients received reduced dose of therapy (400 mg daily of sorafenib) as the starting dose per treating physician discretion. In these patients, Cr decreased by any amount in 43% of patients and increased by any amount

doi:10.1093/annonc/mdp603 | 1619

Downloaded from https://academic.oup.com/annonc/article-abstract/21/8/1618/153277/Sunitinib-and-sorafenib-in-metastatic-renal-cell by guest on 12 September 2017

original article

Annals of Oncology

Table 2. Renal toxicity

On HD at start of treatment Median Cr at start of treatment (range) Median CrCl at start of treatment (range) Maximum Cr during treatment (range) Lowest CrCl during treatment Median time to increase in Cr ‡ 30% (range) Time on therapy (median, range) Dose reduction for RI during treatment, n (%) Dose reduction for other toxicity, n (%)

RI at start of treatment (n = 21) Treatment received Sorafenib (n = 13) Sunitinib (n = 8)

RI developed during treatment (n = 18) Sorafenib (n = 2)

Sunitinib (n = 16)

0 2 2.1 mg/dl (1.9–10.2) 38.4 ml/min (9.9–59) 2.4 mg/dl (1.9–5.1) 36.2 ml/min (9.9–58) 6.6 months (0.4–19.6)1 8.7 months (3.0–27.1) 1 (8) 3 (38) 5 (38) 2 (25)

0 1.5 mg/dl (1.1–1.8) 61.5 ml/min (42.7–105) 2.3 mg/dl (2.1–4.3) 39.2 ml/min (14.9–60) 4.6 months (0.4–19.1) 11.8 (3.0–35.1) 1 (50) 0

0

4 (25) 4 (25)

Cr, creatinine; CrCl, creatinine clearance; HD, hemodialysis; RI, renal insufficiency.

Table 3. Non-renal toxicity

Toxicity Fatigue HFS Diarrhea Nausea HTN Mucositis

RI at start of treatment Sorafenib (n = 13) All grades, Grades 3/4, n (%) n (%)

Sunitinib (n = 8) All grades, Grades 3/4, n (%) n (%)

RI developed during treatment Sorafenib (n = 2) All grades, Grades 3/4, n (%) n (%)

Sunitinib (n = 16) All grades, Grades 3/4, n (%) n (%)

10 8 6 4 4 2

7 3 4 4 2 2

1 1 1 1 1 0

14 8 9 6 8 7

(77) (62) (46) (31) (31) (15)

0 2 (15) 0 0 1 (8) 1 (8)

(88) (38) (50) (50) (25) (25)

2 (25) 1 (13) 0 0 0 0

(50) (50) (50) (50) (50)

0 0 0 0 0 0

(88) (50) (56) (38) (50) (44)

1 (6) 0 0 0 3 (19) 0

HFS, hand–foot syndrome; HTN, hypertension.

Table 4. Clinical outcome

RI at start of treatment, n (%) RI developed during treatment, n (%)

CR

PR

SD

PD

Tumor shrinkage (median, range)

Median PFS (months)

0 1 (6)

5 (24) 5 (28)

13 (62) 10 (56)

3 (14) 2 (11)

216% (244, +45) 214% (2100, +49)

10.2 10.2

CR, complete response; PD, progression disease; PFS, progression-free survival; PR, partial response; RI, renal insufficiency; SD, stable disease.

in 57%. The median time to maximum RI was 6.6 months (range 0.4–19.6 months) for the 12 patients whose renal function worsened.

patients who developed renal insufficiency with treatment In patients who developed RI while receiving therapy, median serum Cr and CrCl at the start of therapy were 1.5 mg/dl (range 1.1–1.8) and 61 ml/min (range 43–105), respectively (Table 2). Patients experienced a median increase in serum Cr of 0.8 mg/ dl (range 0.3–2.8) and a median decrease in CrCl of 25 ml/min (range 8.54–64.76). Renal function began to worsen a median of 2.1 months following the start of treatment (range 0.4–19.1) with RI reaching its maximum at a median of 4.6 months (range 0.9–24.5). For both groups, the maximum serum Cr reached during treatment was similar (2.3 and 2.4 mg/dl, P = 0.84).

1620 | Khan et al.

However, patients with RI at the start of treatment had a longer interval to maximum RI compared with patients who developed RI during treatment (6.6 versus 4.6 months); the difference, however, was not statistically significant, P = 0.70. Our study included two patients on dialysis. One patient was started on dialysis following bilateral nephrectomy before VEGF therapy. This patient was started on sunitinib 50 mg 4 weeks on/2 weeks off and completed two cycles with grade 1 nausea and diarrhea. Therapy was stopped after two cycles secondary to progression of disease. The second patient was started on dialysis due to chronic renal insufficiency in the remaining kidney. This patient was started on sorafenib and dose was reduced at the beginning of the treatment. The patient continued to receive sorafenib while on dialysis without complications, though the treatment was stopped following two cycles secondary to progression of disease.

Volume 21 | No. 8 | August 2010

Downloaded from https://academic.oup.com/annonc/article-abstract/21/8/1618/153277/Sunitinib-and-sorafenib-in-metastatic-renal-cell by guest on 12 September 2017

original article

Annals of Oncology

Of patients with RI at the start of treatment, dose reduction was needed in 52% of patients secondary to toxicity and two patients (10%) discontinued therapy due to toxicity. Of the patients who developed RI on treatment, dose reduction was carried out in 50% of patients and three patients (17%) discontinued therapy due to toxicity. Overall, dose reduction was required in 51% of patients, of which 23% was secondary to elevated serum Cr and 28% was due to other toxicity. The most commonly reported toxic effects (all grades) in both groups receiving either therapy were fatigue (85%), hand– foot syndrome (HFS, 51%) and diarrhea (51%) (Table 3). Five patients (24%) who had preexisting RI achieved PR, 13 patients (62%) had SD as their best response and PD occurred in 3 patients (14%) (Table 4). Estimated PFS was 10.2 months. Of the patients who developed RI on treatment, 1 patient (6%) achieved complete response, 5 (28%) achieved PR, 10 (56%) had SD and 2 (11%) had PD as the best response. Median PFS was 11.7 months. Overall, 21% of patients were hypertensive at baseline (systolic blood pressure > 150 mmHg and/or diastolic pressure > 90 mmHg). Between the two groups, there was no correlation between baseline blood pressure and either baseline CrCl or baseline serum Cr (P > 0.44 in all cases). There were no significant changes in blood pressure when compared with baseline in either group and no correlation between changes in blood pressure and changes in renal function.

discussion This retrospective analysis suggests that sunitinib and sorafenib can be safely administered to mRCC patients with baseline renal insufficiency. In the present study, a significant percentage of patients required dose modifications. This is comparable to other studies. Efficacy and safety of sorafenib in patients with renal impairment was recently studied by Parsa et al., who defined renal insufficiency as calculated CrCl £ 60 ml/min. They concluded that sorafenib can be safely administered to patients with renal impairment; however, dose adjustment was required or dose interrupted in 43% and 57%, respectively [22]. A recent abstract by Billemont et al. reported that of 40 patients, 15 patients developed acute severe renal toxicity and the treatment dose was either decreased or interrupted in 12 patients. This phase II study defined acute severe renal toxicity as ‘loss of 20 ml/min/1.73 m2 CrCl, grade 3 proteinuria or hypertension’ [23]. The present study also demonstrates that mRCC patients can develop renal insufficiency during treatment with sunitinib or sorafenib. Sunitinib more commonly required dose reduction in patients with RI at baseline (63% versus 38% for patients treated with sorafenib), and more cases of sunitinib-induced Cr elevation were identified. This is supported in other studies, particularly a systematic review and meta-analysis by Zhu et al., who looked at the risk associated with sunitinib. They found that sunitinib was associated with significant renal dysfunction and high-grade hypertension. They reported that the incidence of all-grade Cr increase was 65.6% among the patients with RCC receiving sunitinib when compared with controls [24]. It is well recognized that following nephrectomy in a patient with previously normal kidneys, serum Cr increases as much as 20% [25]. Yoshinori et al. specifically studied the role of nephrectomy in RCC patients and found that glomerular

Volume 21 | No. 8 | August 2010

filtration rate (GFR), which is a more accurate method of measuring renal function, increased on the average 40.5% at 1year follow-up [26]. Though GFR is not routinely monitored while a patient undergoes treatment with VEGF therapy, monitoring of renal function via serum Cr is necessary during treatment with more frequent monitoring in patients with baseline renal insufficiency. An increase in serum Cr may require dose adjustment but not necessarily discontinuation of drug. The metabolism of sunitinib and sorafenib provides further insight. Following oral administration, sorafenib and sunitinib are metabolized mostly by the liver, undergoing oxidative metabolism, mediated by CYP3A4 22. Nineteen percent and 16% of sorafenib and sunitinib, respectively, are excreted in the urine [24]. A recent phase I open-label parallel-group study which included eight patients on hemodialysis (HD) found that plasma exposure to sunitinib and its active metabolite were lower in HD patients than those patients with normal renal function [27]. Arterial and venous pharmacokinetic concentration data in this study indicated that this drug was not eliminated from the body via HD [27]. This study showed that a single dose of sunitinib was well tolerated in HD patients without serious toxic effects. Our study is limited by the retrospective nature and the small number of patients. Furthermore, there was no uniform standard for dose adjustment, drug discontinuation or frequency/intensity of renal function monitoring.

conclusions Sunitinib and sorafenib can be safely given to patients with renal insufficiency, provided adequate monitoring of renal function. For those patients developing an increase in Cr, dose modifications may be required and may allow for continuation of therapy. The clinical outcome of patients with baseline renal dysfunction and patients who develop renal dysfunction does not appear to be compromised.

references 1. O’Brien MF, Russo P, Motzer RJ. Sunitinib therapy in renal cell carcinoma. BJU Int 2008; 101(11): 1339–1342. 2. Gunaratnam L, Morley M, Franovic A et al. Hypoxia inducible factor activates the transforming growth factor-alpha/epidermal growth factor receptor growth stimulatory pathway in VHL(-/-) renal cell carcinoma cells. J Biol Chem 2003; 278(45): 44966–44974. 3. Kenck C, Wilhelm M, Bugert P et al. Mutation of the VHL gene is associated exclusively with the development of non-papillary renal cell carcinomas. J Pathol 1996; 179(2): 157–161. 4. Ronnen EA, Kondagunta GV, Ginsberg MS et al. Long-term response with sunitinib for metastatic renal cell carcinoma. Urology 2006; 68(3): 672. e19,672.e20. 5. Abrams TJ, Lee LB, Murray LJ et al. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2003; 2(5): 471–478. 6. Mendel DB, Laird AD, Xin X et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/ pharmacodynamic relationship. Clin Cancer Res 2003; 9(1): 327–337. 7. O’Farrell AM, Abrams TJ, Yuen HA et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003; 101(9): 3597–3605. 8. Murray LJ, Abrams TJ, Long KR et al. SU11248 inhibits tumor growth and CSF1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis 2003; 20(8): 757–766.

doi:10.1093/annonc/mdp603 | 1621

Downloaded from https://academic.oup.com/annonc/article-abstract/21/8/1618/153277/Sunitinib-and-sorafenib-in-metastatic-renal-cell by guest on 12 September 2017

original article 9. Kim DW, Jo YS, Jung HS et al. An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab 2006; 91(10): 4070–4076. 10. Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356(2): 125–134. 11. Strumberg D, Richly H, Hilger RA et al. Phase I clinical and pharmacokinetic study of the novel raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 2005; 23(5): 965–972. 12. Moore M, Hirte HW, Siu L et al. Phase I study to determine the safety and pharmacokinetics of the novel raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol 2005; 16(10): 1688–1694. 13. Clark JW, Eder JP, Ryan D et al. Safety and pharmacokinetics of the dual action raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res 2005; 11(15): 5472–5480. 14. Awada A, Hendlisz A, Gil T et al. Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer 2005; 92(10): 1855–1861. 15. Fiedler W, Serve H, Dohner H et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 2005; 105(3): 986–993. 16. Faivre S, Delbaldo C, Vera K et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006; 24(1): 25–35. 17. 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(1): 16–24.

1622 | Khan et al.

Annals of Oncology

18. Motzer RJ, Rini BI, Bukowski RM et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006; 295(21): 2516–2524. 19. Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356(2): 115–124. 20. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European organization for research and treatment of cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92(3): 205–216. 21. Choueiri TK, Plantade A, Elson P et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol 2008; 26(1): 127–131. 22. Parsa VK, Heilbrun L, Smith D et al. Safety and efficacy of sorafenib therapy in patients with metastatic kidney cancer with impaired renal function. In Genitourinaly Cancer Symposium, Orlando, 2008. (Abstr 365). 23. Billemont B, Thibault F, Ropert S et al. Association between acute severe renal toxicity (ASRT) and survival in patients (pts) with metastatic renal cell carcinoma (mRCC) receiving sunitinib. In Genitourinary Cancers Symposium, Orlando, 2009. (Abstr 307). 24. Zhu X, Stergiopoulos K, Wu S. Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis. Acta Oncol 2009; 48(1): 9–17. 25. Najarian JS, Chavers BM, McHugh LE, Matas AJ. 20 years or more of follow-up of living kidney donors. Lancet 1992; 340(8823): 807–810. 26. Shirasaki Y, Tsushima T, Saika T et al. Kidney function after nephrectomy for renal cell carcinoma. Urology 2004; 64(1): 43–47. 27. Bello C, Toh M, Garrett M. Pharmacokinetics of sunitinib in patients with severe renal impairment or end-stage renal disease on hemodialysis. Pfizer Global Res Develop, European Society of Medical Oncology Annual Meeting, Stockholm, Sweden, 2008 (Abstr 889).

Volume 21 | No. 8 | August 2010

Downloaded from https://academic.oup.com/annonc/article-abstract/21/8/1618/153277/Sunitinib-and-sorafenib-in-metastatic-renal-cell by guest on 12 September 2017