Sunitinib Group Research Articles

Sorafenib or sunitinib as postoperative adjuvant therapy for Chinese patients with locally advanced clear cell renal cell carcinoma at high risk for disease recurrence

ObjectiveTo evaluate the efficacy and safety of targeted agents (sorafenib and sunitinib) as postoperative adjuvant therapy in Chinese patients with clear cell renal cell carcinoma (CC-RCC) who are at high risk for disease recurrence. Materials and methodsForty-three patients treated at our center between December 2007 and December 2010 with locally advanced CC-RCC who were at a high risk for disease recurrence were enrolled into the study. The criteria for high risk of CC-RCC recurrence postoperatively were defined according to the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score for CC-RCC. After radical nephrectomy, patients received either sorafenib (group A, n = 20) or sunitinib (group B, n = 23) and were followed up for at least 1 year to determine the efficacy and safety of the test products. The duration of maintenance targeted medication treatment was approximately 1 year. Group C consisted of 388 CC-RCC patients treated at our center between 1992 and 2007, who were at high risk for disease recurrence and who received no adjuvant therapy. ResultsThe demography characteristics were similar among the 3 groups. The overall rate of recurrence in groups A and B was not different (15.0% and 17.4% (P > 0.05), respectively), which was lower than that of group C (38.7%, P < 0.05 compared with groups A and B). Disease-free survival (DFS) was longer in groups A and B (18.9 ± 5.9 months and 16.9 ± 6.1 months [P > 0.05], respectively), compared with group C (13.3 ± 7.2 months, P < 0.05 compared with groups A and B). The common adverse effects of targeted therapy included hand-foot syndrome, fatigue, diarrhea, taste disturbance, rash, hypertension, alopecia, stomatitis, neutropenia, nausea, pruritus, hypothyroidism in groups A and B. The adverse effects were mild in both groups and the incidence was not significantly different between groups A and B. ConclusionsTargeted adjuvant therapy postoperatively with sorafenib or sunitinib in patients with CC-RCC who are at a high risk for disease recurrence was well tolerated and effective in reducing the rate of CC-RCC recurrence in these patients. This study is an attempt to assess the utility of adjuvant tyrosine kinase inhibitors (TKIs) after surgery for renal carcinoma. The apparently improved outcomes, compared with a historical control population, are of sufficient interest to support the continuation of an ongoing randomized clinical trial to validate the hypothesis.

Comparative efficacy of sunitinib versus sorafenib as the first-line treatment for patients with metastatic renal cell carcinoma.

e15080 Background: Currently, sunitinib has been recommended as the primary treatment in the patients with metastatic renal cell carcinoma (mRCC) among the vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI). However, there are no published clinical data that compared directly the efficacy of targeted agents in the first line setting, and first-line treatment in mRCC patients is yet to be determined. Methods: To compare the efficacy and toxicities between sorafenib and sunitinb, clinical database was used to identify all patients with mRCC treated with VEGF TKIs in Asan Medical Center from April 2005 to March 2011. Among 304 patients, we identified 49 and 220 patients who were treated first with sorafenib and sunitinib, respectively. Results: The patients in the sorafenib group were older than those in the sunitinib group (62 vs 56.5 years, p=0.019). Disease control rate (DCR) of 82% was achieved in both groups. After a median follow-up duration of 49 months, progression free survival (PFS) and overall survival (OS) were not significantly different (sorafenib vs sunitinib, PFS; 8.6 months vs 9.9 months, p=0.948, OS; 25.7 months and 22.6 months, p=0.774). The patients treated with sorafenib have required dose reduction due to toxicities less frequently than those treated with sunitinib (37% vs 54%, p=0.034). Hematologic toxicities of grade 3 or 4 were more common in sunitinib group (4.2% vs 44.6%, p&lt;0.001), and also was grade 3 or 4 hypertension, although it was not statistically significant (4.2% vs 13.7%, p=0.06). Age (&gt; 60 years), duration from diagnosis to treatment (less than 1 year), Anemia, Neutrophilia, thorombocytosis, bone and liver metastases were independent prognostic factors affecting OS. Multivariate analysis also showed first-line VEGF TKI did not affect OS [hazard ratio (HR, sorafenib vs sunitinib) = 0.94, p=0.774]. Conclusions: Sorafenib showed comparable efficacy to sunitinb and demonstrated superiority in toxicities in the treatment of mRCC patients.

Efficacy and safety of sunitinib (SU) in patients (pts) with metastatic renal cell carcinoma (mRCC) and lung metastases (mets) only at baseline.

e15098 Background: The lungs may be the sole site of mets in RCC.In this retrospective analysis, we analyzed the efficacy and safety of SU in mRCC pts from a global phase (ph) III study and a Japanese ph II study who had lung mets only at baseline. Methods: In the ph III study, treatment (Tx)-naïve mRCC pts were randomized 1:1 to SU 50 mg/d on a 4-weeks-on-2-weeks-off schedule (n=375) or interferon-a (IFN) 9 MU subcutaneously TIW (n=360). In the single-arm ph II study, Tx-naïve (n=25) and cytokine refractory (n=26) mRCC pts received the same SU Tx. In the ph III study, progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan–Meier method, with median values compared by log-rank test. In both studies, objective response rate (ORR) was calculated with a two-sided 95% CI. PFS, OS, ORR, and safety were analyzed at final data cutoff. Results: In the ph III study, 31 (8%) and 42 (11%) pts in the SU and IFN groups, respectively, had lung mets only, compared with 12 (24%) in the ph II study. Baseline characteristics in lung mets pts were similar to all pts. In lung mets pts from the ph III study, ORR was higher with SU than with IFN (58.1% [95% CI: 39.1–75.5] vs. 19.0% [95% CI: 8.6–34.1]; P&lt;0.001); there was a trend for longer median PFS with SU (14.1 vs. 7.8 months; HR: 0.531 [95% CI: 0.278–1.015]; P=0.0513); and median OS was comparable in both Tx subgroups (HR: 0.739 [95% CI: 0.335–1.628]; P=0.4507), although, at 25% of events, median OS was 22.9 months with SU vs. 15.8 months with IFN. In lung mets pts from the ph II study, ORR was 75.0% (95% CI: 42.8–94.5); at the time of analysis, median PFS and OS had not been reached; 4 pts (33%) had died due to any cause and 8 (67%) were alive without disease progression. The most common grade ≥3 SU-related AEs were fatigue, hand-foot syndrome, and diarrhea (all 19%) in the ph III study, and decreased platelets (100%), white blood cells (92%), and neutrophils (92%) in the ph II study. Conclusions: In the ph III study, Tx-naïve mRCC pts with lung mets only had significantly higher ORR and a trend for improved PFS and OS with SU compared with IFN. In the Japanese ph II study, ORR with SU was 75% in lung mets pts. Thus, 1st-line use of SU in mRCC pts with lung mets should be encouraged.

Abstract A39: The exploration of novel strategy for treatment of pancreactic ductal adenocarcinoma targeting tumor microenvironment with multi-kinase inhibitors

Abstract Background and Aim: Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in humans. Previously, we have reported a genetically engineered mouse PDAC progression model which has pancreatic-specific transforming growth factor-beta receptor type II knockout in the context of Kras activation (Ijichi H, et al 2006). This model shows PDAC with 100% penetrance and recapitulates the signature of human PDAC well. Using this model, we explored novel treatment for PDAC. Materials and Methods: At first, to investigate whether the mice model is suitable for the drug screening, the mice were treated with gemcitabine (12.5 mg/kg) by intraperitoneal (i.p.) injection or S-1 (8.4 mg/kg) per oral, which are the standard drug for human PDAC. To the next, for single agent treatment, mice were treated orally 6 times a week with vehicle (0.5 % carboxymethyl cellulose, CMC), sunitinib (40 mg/kg), and axitinib (30mg/kg), both of which are multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) from the 3 weeks of age. For combined agent experiment, mice were treated orally with vehicle (0.5 % CMC) or axitinib from the 3 weeks of age and also treated with saline or gemcitabine, i.p. twice a week from the 4 weeks of age. Treatment continued until 8 weeks of age. Moreover, for the survival analysis, the drug treatment was continued until the mice became distressed according to the same schedule stated above. In vivo anti-tumor effect and survival time were assessed. Immunostaining of tumor tissue for caspase 3, Ki67, CD31, F4/80 and VEGF was performed. Azan staining also performed for the assessment of fibrosis in the tumor. Results: Gemcitabine and S-1 showed antiproliferative effect and prolonged overall survival of these mice compared to control, as well as human cases. Median survival time of single use of axtinib and sunitinib group was significantly longer (p &amp;lt;0.01) than that of control group. Axitinib and sunitinib group showed significantly stronger anti-tumor effect in vivo (p &amp;lt;0.01). In the combined treatment experiment, gemcitabine plus axitinib-treated group showed statistically significant longer survival and more anti-tumor effect than that of gemcitabine or axtinib alone-treated group (p &amp;lt;0.01). Axitinib and sunitinib group showed significantly higher caspase 3 stainng and lower Ki67 staining than that of control (p &amp;lt;0.01). Microvessel density (CD 31 staining) of axitinib and sunitinib group was significantly lower than that of control (p &amp;lt;0.01). F4/80 staining was significantly lower in axitinib and sunitinib-treated group than that of control (p &amp;lt;0.05). VEGF expression of axitinib and sunitinib group was significantly lower than that of control a (p &amp;lt;0.001). Azan staining showed significantly lower fibrosis in axitinib and sunitinib-treated group compared to control (p &amp;lt;0.01). Conclusion: Targeting not only cancer cells but also tumor microenvironment, such as angiogenesis, infiltration of immune cells, and fibrosis, with the use of multikinase inhibitors in addition to gemcitabine, may be a promising therapeutics for PDAC.

308 DETECTION OF FUNCTIONAL CHANGES IN RENAL CELL CARCINOMA WITH POSITRON EMISSION TOMOGRAPHY

You have accessJournal of UrologyKidney Cancer: Basic Research II1 Apr 2012308 DETECTION OF FUNCTIONAL CHANGES IN RENAL CELL CARCINOMA WITH POSITRON EMISSION TOMOGRAPHY David W. Chapman, Melinda Wuest, Leonard I. Wiebe, and Ronald B. Moore David W. ChapmanDavid W. Chapman Edmonton, Canada More articles by this author , Melinda WuestMelinda Wuest Edmonton, Canada More articles by this author , Leonard I. WiebeLeonard I. Wiebe Edmonton, Canada More articles by this author , and Ronald B. MooreRonald B. Moore Edmonton, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.367AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Broad-spectrum tyrosine kinase inhibitors (TKIs) are clinically used for the therapy of metastasizing renal cell carcinoma (RCC). It has been shown in vivo that multitargeted TKIs such as sunitinib exert antiangiogenic effects directly on endothelial cells, but also by blocking compensatory changes in the activity of hypoxia-inducible factors (HIF), mainly HIF-1α. The present study investigated whether sunitinib-induced changes in the microenvironment of a mouse RCC tumor model can be detected utilizing positron-emission tomography (PET). METHODS Caki-1 tumors were grown for 4 weeks in Balb c/nu-nu mice after implantation subcutaneously or into the renal subcapsule. Both models were analyzed first with dynamic small animal PET with [18F]FDG and [18F]FAZA up to 3h post-injection (p.i.). In a second setup, mice bearing 2 subcutaneous Caki-1 tumors were sorted into 2 groups: a) receiving 40mg/kg/d sunitinib i.p. for 5 days prior to analysis with [18F]FAZA PET, b) vehicle control injections. Tumor uptake of [18F]FAZA and immunohistochemical tissue staining with pimonidazole HCl and CD-31 were determined. RESULTS Functional analysis of subcutaneous Caki-1 tumors with PET revealed a mean standardized uptake value (SUV) after 3h p.i. of 0.60±0.02 for [18F]FDG, which is indicative of glucose metabolism within the tumor, and 0.32±0.02 (n=6/3) for [18F]FAZA determining tumor's hypoxia status. Based on the clearance patterns, orthotopically grown tumors were not detectable with PET alone. The SUV3h for [18F]FAZA was significantly lower in sunitinib group compared to controls in the subcutaneous model: 0.23±0.02 vs. 0.42±0.05 (n=4/2). The time-activity curve indicated significant [18F]FAZA washout from treated tumors as compared to the control. This observation was confirmed by the biodistribution of [18F]FAZA, resulting in SUV3h of 0.29±0.03 in treated vs. 0.45±0.06 (n=8/4) in control mice. Pimonidazole binding was reduced by 9% in the treated tumors. CD31 binding (%) was reduced in sunitinib treated groups: 1.8±0.1% vs. 0.6±0.1% (n=80/4). CONCLUSIONS Reduced trapping of [18F]FAZA in this RCC tumor model, in vivo, indicates that TKI inhibition with mutitargeting sunitinib leads to changes in tumor oxygenation, which is functionally detectable with PET. Furthermore, sunitinib led to a significant reduction in vascular density. Monitoring early response to TKI therapy in RCC tumor patients could potentially utilize [18F]FAZA. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e125 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information David W. Chapman Edmonton, Canada More articles by this author Melinda Wuest Edmonton, Canada More articles by this author Leonard I. Wiebe Edmonton, Canada More articles by this author Ronald B. Moore Edmonton, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Observation as a treatment strategy for advanced renal cell carcinoma—a call for prospective validation

OPINION article Front. Oncol., 31 October 2012 | https://doi.org/10.3389/fonc.2012.00155

Abstract 3292: The exploration of novel strategy for treatment of pancreactic cancer using genetically engineered mice

Abstract (Background and Aim) Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in human. Previously, we have reported a genetically engineered mouse PDAC progression model which has pancreatic-specific transforming growth factor-beta receptor type II knockout in the context of Kras activation (Ijichi H, et al 2006). This model shows PDAC with 100 % penetrance and recapitulates the signature of human PDAC well. Using this model, we explored novel treatment for PDAC. (Materials and Methods) For single agent treatment, mice were treated orally 6 times per week with vehicle (0.5 % carboxymethyl cellulose, CMC), sunitinib, axitinib, 5 kinds of anigiotensin II receptor blockers (ARBs), such as candesartan, telmisartan, losartan, valsartan, or olmesartan, respectively from the 3 wk of age. For combined agent experiment, mice were treated orally with vehicle (0.5 % CMC), axitinib or candesartan from the 3 wk of age and also treated with saline or gemcitabine, i.p. twice a week, from the 4 wk of age. Treatment continued until the mice became distressed, and then they were dissected. In vivo anti-tumor effect and survival time were assessed. Immunostaining of tumor tissue for caspase 3, Ki67, CD31, and VEGF was performed. (Results)Median survival time of single use of axtinib and sunitinib group was statistically longer and that of candesartan and telmisartan group was tended to be longer than that of control group. Axtinib, sunitinib, candesartan, and telmisartan group showed significant anti-tumor effect in vivo. In the combined treatment experiment, using gemcitabine showed statistically significant longer survival and more anti-tumor effect than that of single agent treatment group. Axitinib and sunitinib group showed significantly higher caspase 3 score and lower Ki67 score than that of control, however, candesartan and telimisartan group showed no change of these scores, compared to control. Microvessel density of axtinib, sunitinib, candesartan, and telmisartan group was significantly lower than that of control and other ARBs. VEGF expression of candesartan and telmisartan group was significantly lower than that of control and other ARBs. (Conclusion)Targeting angiogenesis with multikinase inhibitor or ARB in addition to gemcitabine may be a promising therapeutics for PDAC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3292. doi:10.1158/1538-7445.AM2011-3292

Phase III, randomized, placebo-controlled study of everolimus in patients with metastatic renal cell carcinoma (mRCC): Subgroup analysis of patients intolerant of prior vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy.

312 Background: In the RECORD-1 phase III study, the mammalian target of rapamycin (mTOR) inhibitor everolimus (ClinicalTrials.gov: NCT00410124 ) prolonged progression-free survival (PFS) versus placebo (median PFS 4.9 vs 1.9 months) in patients with mRCC whose disease progressed during or within 6 months of VEGFr-TKI (sunitinib and/or sorafenib) therapy. In this retrospective analysis, we evaluated the effect of everolimus on PFS in the subgroup of patients who discontinued prior VEGFr-TKI therapy because of adverse events. Methods: In the randomized, double-blind RECORD-1 trial, patients with mRCC who had prior VEGFr-TKI therapy were randomized (2:1) to receive everolimus 10 mg/day (n = 277) or placebo (n = 139) plus best supportive care. Results: Patients who were intolerant of prior VEGFr-TKI therapy included 50 patients (sunitinib = 26; sorafenib = 24) in the everolimus group and 13 patients (sunitinib = 5; sorafenib = 8) in the placebo group. The median PFS in the sunitinib group was 5.13 mo (95% confidence interval [CI]: 3.71, not available [NA]) in patients receiving everolimus vs 2.81 mo (95% CI: 1.87, 3.71) in those receiving placebo (HR: 0.28; 95% CI: 0.07, 1.18; p = 0.033). In the sorafenib subgroup, median PFS was 5.59 mo (95% CI: 3.78, NA) versus 1.91 mo (95% CI: 1.68, 3.48), respectively (HR: 0.29; 95% CI: 0.09, 0.91; p = 0.012). Conclusions: Everolimus prolonged PFS in a subgroup of patients with mRCC who were intolerant of prior VEGFr-TKI therapy. These results suggest that mTOR inhibition with everolimus was active in patients with mRCC who were intolerant of a previous VEGFr-TKI. [Table: see text]

Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors

The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials. We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety. The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue. Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.).

Role of sorafenib and sunitinib in the induction of expressions of NKG2D ligands in nasopharyngeal carcinoma with high expression of ABCG2

Sorafenib and sunitinib are novel small molecule tyrosine kinase inhibitors with multiple targets on tumor cells, which have been demonstrated to be beneficial in the treatment of several carcinomas. Combining the usage of molecular targeted agents and adoptive cellular immunotherapy (ACI) against drug-resistant relapse nasopharyngeal carcinoma which had no standard therapeutic regimen was investigated by our research in order to study whether synergistic effects exist and related mechanisms. Human multidrug-resistant nasopharyngeal carcinoma cell line CNE2/DDP with high and low expressions of ABCG(2) (abbreviated to ABCG (2) (High) CNE2/DDP and ABCG (2) (Low) CNE2/DDP) cells and NK cells were isolated by magnetic activated cell sorting, and the purity of isolated cells was detected by flow cytometry. mRNA expressions of drug-resistant gene ABCG(2), Bcl-2, MDR1, MRP and MGMT in ABCG (2) (High) CNE2/DDP and ABCG (2) (Low) CNE2/DDP cells were detected by reverse transcription polymerase chain reaction (RT-PCR). Drug sensitivity of two kinds of cells to fluorouracil, cisplatin, vincristine, carboplatin, epirubicin, daunorubicin, paclitaxel, mitomycin, sorafenib, and sunitinib were detected by MTT assay. FCM was used to evaluate the expressions of NKG2D ligands (NKG2DLs,) on target cells before and after incubated with sorafenib and sunitinib. Subsequently, the cytotoxic sensitivity of incubated and un-incubated ABCG (2) (High) CNE2/DDP and ABCG (2) (Low) CNE2/DDP cells to NK cells was measured by CytoTox 96(®) Non-Radioactive Cytotoxicity Assay. The results revealed that target cells' cytotoxic sensitivity to natural killer (NK) cells increased in association with up-regulation of NKG2DLs on tumor cells after incubation with sorafenib and sunitinib. Furthermore, up-regulation in sunitinib group was much higher than in sorafenib group when it came to the expressions of NKG2DLs on tumor cells. For another, ABCG (2) (High) CNE2/DDP was much more sensitive to the regulation than ABCG (2) (Low) CNE2/DDP. Our research revealed for the first time that sorafenib and sunitinib could up-regulate NKG2DLs on tumor cells resulting in markedly increased tumor cells cytotoxic sensitivity to NK cells, which suggested that combining usage of molecular targeted agents and ACI may result in great benefits in clinical practice for the therapy-resistant cases and drug-resistant relapse.

ADMINISTRATION OF SUNITINIB, AN ORAL ANGIOGENESIS INHIBITOR, IS ASSOCIATED WITH HYPERTENSION, BUT NOT WITH STRUCTURAL CARDIAC CHANGES OR CARDIOMYOCYTE MITOCHONDRIAL DYSFUNCTION: PP.22.363

Objectives: Inhibition of angiogenesis by blocking vascular endothelial growth factor (VEGF)-mediated signaling is an established treatment for various forms of cancer. This therapy is frequently associated with hypertension, but may also cause cardiac toxicity, mainly a decreased left ventricular ejection fraction (LVEF). Cardiomyocyte hypertrophy and changes in cardiac mitochondrial structure (swelling) have been reported in mice, suggesting that impaired adenosine triphosphate (ATP) generation secondary to mitochondrial dysfunction underlies the decrease in LVEF. We aimed to assess the effects of sunitinib on blood pressure (BP), cardiac structure and mitochondrial function in an ex-vivo rodent model. Methods: Normotensive male Wistar-Kyoto rats were administered sunitinib (n = 10) or vehicle (n = 6) by oral gavage and BP and heart rate (HR) were monitored telemetrically until a plateau in BP occurred at which time animals were euthanized. Blood and hearts were collected for determination of brain natriuretic peptide (BNP)-45 levels, heart weight, cardiomyocyte size and isolation of cardiomyocyte mitochondria for measurement of complex I- and II-dependent ATP production. Results: A plateau in BP rise was found after 6 days of treatment. At that time, mean arterial BP had increased from 98.3 ± 0.3mmHg to 126 ± 1.5mmHg and HR had decreased from 319.3 ± 1.4bpm to 271.6 ± 3.0bpm (both p < 0.001), while BP and HR did not change in the control group. Circulating BNP-45 levels were almost 2-fold (163.9 ± 33.9ng/ml vs 92.7 ± 15.0ng/ml; p = 0.03) and serum creatinine levels (28.8 ± 6.4 vs 8.0 ± 2.7 μmol/l; p = 0.03) almost threefold higher in the sunitinib compared to the control group. Heart weight-to-body weight ratio and cardiomyocyte area were not different between groups. Complex I-dependent ATP production between the sunitinib and control group (659.7 ± 88.1; vs 1028 ± 278 nmol/mg mitochondrial protein/30 min; p = 0.26) and complex II-dependent ATP-production (955.6 ± 93.3 vs 1409 ± 255 nmol/mg mitochondrial protein/30 min; p = 0.15) did not differ. Conclusions: Although circulating BNP-45 levels were increased in sunitinib-administered rats, no evidence for structural cardiac abnormalities or impaired cardiomyocyte mitochondrial ATP production was found. The rise in BNP-45 might be a consequence of the BP-rise and the decrease in renal function.

Dose reductions and delays in patients (pts) with renal cell carcinoma (RCC) treated with sorafenib (SR) or sunitinib (SU): Retrospective analysis of two large U.S. health care claims databases.

6090 Background: A previously conducted retrospective analysis demonstrated that RCC pts treated with first-line SU have a higher incidence of dose reduction than pts treated with SR. The primary objective of this study was to validate these findings through the addition of a second claims database and introduction of a comparison of treatment delays. Methods: Authors pooled data from two U.S. health care claims databases to create the primary dataset used to support this retrospective cohort study. Claims originated from the care of 35 million pts per year on average from 2002 to 2009 and represented all U.S. census regions. The analysis cohort included pts with ≥ 2 RCC claims (ICD9 189.0 or 198.0) who had continuous coverage during illness, ≥ 180 days' coverage preceding diagnosis (first RCC claim) with no prior SR/SU treatment. Only pts with ≥ 2 dispensings of standard doses of SR or SU as first-line treatment were compared. Reductions in dose and treatment delays (interruption of treatment for > 30 d for SR, > 42 d for SU) were tracked across first-line therapy. Results: Most first-line pts were treated initially with standard full doses (SR 89.5%, SU 88.2%; p = 0.449). Baseline characteristics were similar between 320 SR-treated and 684 SU-treated pts, except that SR- treated pts were older (mean age 62.7 vs. 60.2; p < 0.001) and had a higher prevalence of renal disease (24.1% vs. 16.8%; p = 0.007). First-line SU- treated pts were 1.95 times more likely and had a significantly higher incidence of ≥1 dose reduction (17.5% vs. 34.1%; p < 0.001). There was no difference in treatment delays between SR (19.7%) and SU (16.0%) groups (p = 0.142). Conclusions: This study, the largest comparative retrospective US claims database analysis of its kind to date, validates prior work presented by the authors. The incidences of dose reductions in this real- world cohort are comparable to those observed in phase 3 clinical trials of these agents. There was no difference in treatment delays between groups. Differences observed between SR- and SU-treated pts suggest that SR may be chosen in practice more often for older and sicker pts. Further analyses assessing outcomes are warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Bayer Bayer Bayer

Comparative Analysis between Immunochemotherapy and Target Therapy for Metastatic Renal Cell Carcinoma: Overview of Treatment-Related Adverse Events and the Dropout Rate in Korea

PurposeTo comparatively analyze treatment-related adverse events and the treatment dropout rate between immunochemotherapy and target therapy in Korea.Materials and MethodsForty-nine subjects with metastatic renal cell carcinoma (21 target therapy recipients and 28 immunochemotherapy recipients) who underwent either 6-week cycles of sunitinib treatment (50 mg once daily for 4 weeks on and 2 weeks off) or 8-week cycles of immunochemotherapy (combination of interleukin [IL]-2, interferon [IFN]-alpha, and 5-fluorouracil [FU]) were enrolled. Treatment-related toxicity was objectively graded and quantitative analysis was performed with a scoring system. Patient compliance was categorized into three classes (1: administration as scheduled, 2: dose modification required, 3: discontinuation required).ResultsCompared with those of the immunochemotherapy group, subjects of the sunitinib-treatment group had higher occurrence rates of mucositis-stomatitis (43% vs. 10%), hand-foot syndrome (38% vs. 0%), diarrhea (33% vs. 14%), and hypertension (33% vs. 14%). According to the toxicity-grade-based scoring system, the total incidence and severity of toxicities were not significantly different between the two groups (p>0.05), whereas high-grade hematologic toxicities were more frequent in the immunochemotherapy group. The dropout rate of the immunochemotherapy group was significantly higher than that of the sunitinib group (administration as scheduled: 52% vs. 21%, p=0.026; discontinuation required: 19% vs. 50%, p=0.037).ConclusionsThe results of this study are indicative of a comparable treatment-related toxicity profile of sunitinib and greater adherence to the treatment protocol in comparison with immunochemotherapy in patients with metastatic renal cell carcinoma (mRCC).

Patient-reported outcomes in a phase III, randomized study of sunitinib versus interferon-α as first-line systemic therapy for patients with metastatic renal cell carcinoma in a European population

BackgroundThe purpose of this study is to evaluate the impact on the health-related quality of life (HRQoL) of sunitinib versus interferon-alpha (IFN-α) treatment in patients with metastatic renal cell carcinoma (mRCC). Patients and methodsIn all, 304 mRCC patients (European cohort) were randomized 1:1 to receive sunitinib (50 mg/day for 4 weeks, followed by 2 weeks off) or IFN-α (9 million units s.c. injection three times/week). The following questionnaires were completed (days 1 and 28 per cycle): Functional Assessment of Cancer Therapy-General (FACT-G), the FACT-Kidney Symptom Index and the EuroQol Group's EQ-5D self-report questionnaire (EQ-5D). Results correspond to an ongoing trial with progression-free survival time as primary end point, and patients were still being followed up. Data were analyzed using repeated measures mixed effects models (MEMs) that allow the inclusion of initial differences and uncompleted repeated measures, with the assumption of data missing at random. Six-cycle results were included. ResultsResults consistently showed that patients in sunitinib group experienced statistically significantly milder kidney-related symptoms, better cancer-specific HRQoL and general health status (in social utility scores) during the study period as measured by these patient-reported outcome end points. No statistical differences between groups were found on the FACT-G physical well-being subscale or the EQ-5D VAS values. ConclusionsResults from MEM showed the sunitinib's benefit on HRQoL compared with IFN-α.

Commentary on Sequential therapy with sorafenib and sunitinib in renal cell carcinoma: Dudek AZ, Zolnierek J, Dham A, Lindgren BR, Szczylik C, Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN

Sunitinib and sorafenib are small-molecule tyrosine kinase inhibitors (TKI) with antitumor activity in advanced renal cell carcinoma. A retrospective study was conducted to assess the response of renal cell carcinoma to sequential treatment with these 2 agents. Tumor response was evaluated by using Response Evaluation Criteria in Solid Tumors (RECIST) in patients failing first-line therapy with either sunitinib or sorafenib and subsequently receiving second-line therapy with the other TKI agent. Twenty-nine patients received sorafenib followed by sunitinib (group A), and 20 patients received sunitinib followed by sorafenib (group B). TKI drugs were terminated in 6 (12%) patients in group A and 4 (8%) in group B because of toxicity. Median duration of stable disease for groups A and B was 20 and 9.5 weeks, respectively. Median time from starting first TKI to disease progression after second TKI (time to progression) in groups A and B was 78 and 37 weeks, respectively. Multivariate analysis revealed that group B had a shorter time to progression than group A (risk ratio [RR] 3.0; P = 0.016). Median overall survival was 102 and 45 weeks in groups A and B, respectively ( P = 0.061). The longer duration of disease control in patients who received sorafenib followed by sunitinib warrants further investigation.

Efficacy of Sunitinib and Radiotherapy in Genetically Engineered Mouse Model of Soft-Tissue Sarcoma

Sunitinib (SU) is a multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors. The present study examined SU and radiotherapy (RT) in a genetically engineered mouse model of soft tissue sarcoma (STS). Primary extremity STSs were generated in genetically engineered mice. The mice were randomized to treatment with SU, RT (10 Gy x 2), or both (SU+RT). Changes in the tumor vasculature before and after treatment were assessed in vivo using fluorescence-mediated tomography. The control and treated tumors were harvested and extensively analyzed. The mean fluorescence in the tumors was not decreased by RT but decreased 38-44% in tumors treated with SU or SU+RT. The control tumors grew to a mean of 1378 mm(3) after 12 days. SU alone or RT alone delayed tumor growth by 56% and 41%, respectively, but maximal growth inhibition (71%) was observed with the combination therapy. SU target effects were confirmed by loss of target receptor phosphorylation and alterations in SU-related gene expression. Cancer cell proliferation was decreased and apoptosis increased in the SU and RT groups, with a synergistic effect on apoptosis observed in the SU+RT group. RT had a minimal effect on the tumor microvessel density and endothelial cell-specific apoptosis, but SU alone or SU+RT decreased the microvessel density by >66% and induced significant endothelial cell apoptosis. SU inhibited STS growth by effects on both cancer cells and tumor vasculature. SU also augmented the efficacy of RT, suggesting that this combination strategy could improve local control of STS.

Differential effect of sunitinib on the distribution of temozolomide in an orthotopic glioma model

Normalization of tumor vasculature by antiangiogenic agents may improve the delivery of cytotoxic drugs to the tumor, leading to more effective therapy. In this study, we used pharmacokinetic and pharmacodynamic approaches to investigate how sunitinib at different dose levels affects brain distribution of temozolomide (TMZ), and to ascertain the relationship between intratumoral TMZ concentrations and tumor vascularity in an orthotopic human glioma model. Three groups of intracerebral U87MG tumor-bearing mice were given either vehicle or sunitinib at 20 mg/kg or 60 mg/kg per day for 7 days before receiving a steady-state regimen of TMZ that consisted of an intravenous bolus and a 3-h intraarterial infusion. TMZ concentrations in plasma, normal brain, and brain tumor were determined, and several biomarkers related to the antiangiogenic activity of sunitinib were examined. TMZ distribution in the normal brain as indicated by the brain-to-plasma steady-state TMZ concentration ratios was analogous across the three treatment groups. The brain tumor-to-plasma steady-state TMZ concentration (ss C(t)/C(p)) ratio was significantly increased in the 20 mg/kg sunitinib group (0.98 +/- 0.17) compared with the control (0.76 +/- 0.17) and 60 mg/kg sunitinib (0.68 +/- 0.09) groups. The ss C(t)/C(p) ratios were significantly correlated with the vascular normalization index (VNI), derived from the expression of CD31, collagen IV, and alpha-smooth muscle actin, which represents the fraction of functioning vessels out of the total tumor vessels. In conclusion, the effect of sunitinib on the brain tumor distribution of TMZ was dose dependent and indicated that optimal tumor exposure was achieved at a lower dose and was associated with the VNI.

Effective Therapy for Metastatic Renal Cancer, Whither to Now

Effective Therapy for Metastatic Renal Cancer, Whither to Now

A population‐based study evaluating the impact of sunitinib on overall survival in the treatment of patients with metastatic renal cell cancer

Sunitinib has replaced interferon (IFN) as a first-line standard of care in the treatment of metastatic renal cell carcinoma (RCC). This study aimed to determine overall survival and to confirm effectiveness in a population that includes poor prognosis patients. Data were collected on all patients identified by the BC Cancer Registry with metastatic RCC who were treated with IFN or sunitinib. The IFN group consisted of patients who received IFN between January 2000 and October 2005, and the sunitinib group included patients treated with first-line sunitinib from October 2005 to September 2007. There were 131 and 69 patients in the IFN and sunitinib groups, respectively. The median follow-up of those still alive was 12.6 months. The median age (62 vs 63 years; P = .41), Memorial Sloan Kettering Cancer Center (MSKCC) prognostic criteria (poor in 19% vs 30%; P = .41), and proportion with >1 metastasis (53% vs 62%; P = .21) were similar between the IFN and sunitinib groups, respectively. The median survival of the IFN and sunitinib groups was 8.7 and 17.3 months, respectively (log-rank P = .004). The median survival of patients with favorable, intermediate, and poor MSKCC prognostic profiles in the IFN group was 22.9, 8.7, and 4.1 months, respectively (P < .001), whereas in the sunitinib group it was not reached, 16.8, and 10.7 months, respectively (P = .006). The hazard ratio of death after adjusting for MSKCC criteria was 0.49 (95% confidence interval, 0.31-0.76; P = .001). The introduction of first-line sunitinib was associated with a doubling of overall survival compared with patients treated with IFN alone. This benefit extended to patients with poor MSKCC prognostic profiles.

Sequential therapy with sorafenib and sunitinib in renal cell carcinoma

Sunitinib and sorafenib are small-molecule tyrosine kinase inhibitors (TKI) with antitumor activity in advanced renal cell carcinoma. A retrospective study was conducted to assess the response of renal cell carcinoma to sequential treatment with these two agents. Tumor response was evaluated by using Response Evaluation Criteria In Solid Tumors (RECIST) criteria in patients failing first-line therapy with either sunitinib or sorafenib and subsequently receiving second-line therapy with the other TKI agent. Twenty-nine patients received sorafenib followed by sunitinib (Group A), and 20 patients received sunitinib followed by sorafenib (Group B). TKI drugs were terminated in 6 (12%) patients in Group A and 4 (8%) in Group B because of toxicity. Median duration of stable disease for Groups A and B was 20 and 9.5 weeks, respectively. Median time from starting first TKI to disease progression after second TKI (time to progression) in Groups A and B was 78 and 37 weeks, respectively. Multivariate analysis revealed that Group B had a shorter time to progression than Group A (risk ratio [RR] 3.0; P=.016). Median overall survival was 102 and 45 weeks in Groups A and B, respectively (P=.061). The longer duration of disease control in patients who received sorafenib followed by sunitinib warrants further investigation.