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SAFETY AND EFFICACY OF AVANAFIL, A NEW PDE5 INHIBITOR FOR TREATING ERECTILE DYSFUNCTION
461
462
GENE-EXPRESSION PROFILES PREDICT NODAL METASTASIS AND SURVIVAL IN PATIENTS UNDERGOING RADICAL CYSTECTOMY
COMPARISON OF URINARY CYTOLOGY AND FLUORESCENCEIN-SITU HYBRIDISATION ASSAY (FISH) FOR THE DETECTION OF UROTHELIAL BLADDER CARCINOMA
Liedberg F.1, Gudjonsson S.1, Höglund M.2, Lindgren D.2, Månsson W.1 1
Lund University Hospital, Department of Urology, Lund, Sweden, 2Lund University Hospital,
Department of Clinical Genetics, Lund, Sweden INTRODUCTION & OBJECTIVES: Nodal metastasis is diagnosed in 25-30% in large series of patients undergoing radical cystectomy for bladder cancer. Neoadjuvant chemotherapy seems to improve survival in patients with locally advanced disease, but difficulties exist in defining those patients who will benefit from such therapy. We have obtained gene-expression profiles with cDNA micro-array technology and correlated the gene-expression profiles with presence of lymph node metastasis and survival in patients undergoing radical cystectomy and pelvic lymph node dissection to the aortic bifurcation. MATERIAL & METHODS: Tissue from urothelial tumours of the bladder was obtained by transurethral resection or cold cup biopsy and RNA was extracted. of 64 patients undergoing radical cystectomy, 13 were excluded due to low quality or low quantity RNA and 2 were excluded due to over 6 months delay in performing the cystectomy. With microarray technology expression of 35,000 gene sequences were studied using oligonucleotide-arrays. Genes were selected using a variance and a signal to noise filter and by only including genes having values for at least 80% of the tumours, 5921 genes were obtained for final analysis. Significance Analysis of Microarrays (SAM) was used to identify genes that showed significant different gene expression in patients with/without lymph node metastasis and in patients dead/alive. We used a leave-one-out validating methodology to identify 20 discriminatory genes which subsequently were selected as a predictor gene set. RESULTS: Patients were followed 16.5 months (median) from cystectomy. 15 of the 49 patients (31%) died of recurrent disease. Positive pelvic nodes were present in 21 of the patients (43%). The identified 20-gene-set predicted lymph node metastasis in 20 out of the 21 patients (Area under ROC curve = 0.80). Gene expression below 50% of the median expression for these genes significantly increased the risk for bladder cancer death (HR=5,6; p=0.023). CONCLUSIONS: We have identified a gene set that predicts lymph node metastasis
Hakenberg O., Schmidt U., Berdjis N., Meye A., Wawroschek F., Baldauf A., Zastrow S., Wirth M. University Hospital, Urology, Dresden, Germany INTRODUCTION & OBJECTIVES: The urine-based diagnosis of urothelial bladder carcinoma (TCC) is an expanding field of high interest. Conventional urinary cytology is the standard test available, but dependent on investigator experience. Fluorescence-in-situ hybridisation (FISH) is a potentially highly specific method which has been reported to have better diagnostic accuracy than conventional cytology and is available as a commercial kit. In our department, cytology is used routinely for urine-based diagnosis. We compared both methods in a prospective study in a blinded way with each test being assessed by three different examiners independently. MATERIAL & METHODS: 110 consecutive patients scheduled for transurethral biopsy for suspected bladder TCC or symptoms provided voided urine samples preoperatively. These were processed for cytology (Papanicolaou staining) and FISH analysis (Urovysion, Abbott, Germany). All samples were independently examined by three different examiners all blinded to clinical diagnosis and histological results and classed as either negative or positive for TCC. For each method the final assessment was based on agreement of at least 2/3 examiners. RESULTS: Samples with incomplete data were excluded from analysis (n=13). of the 97 remaining patients, 18 had benign conditions and 79 bladder TCC (21 grade 1, 25 grade 2 and 33 grade 3). Sensitivities for TCC detection with FISH were 33%, 76% and 91% for grades 1-3, respectively, and for cytology 38%, 76% and 93% (specificities 72% vs. 66%) and not significantly different. Inter-investigator agreement (3/3 assessments the same) was higher with FISH compared to cytology (75% vs. 61%), however, wrong assessments with all three investigators agreeing occurred in 13 cases with cytology and 16 cases with FISH. These were mostly false assessments in inflammatory conditions or low grade superficial TCC. False negative assessments by all three investigators occurred with FISH for TCC grade 2 in 3 cases and for TCC grade 3 in 1 case, for cytology in TCC grade 2 in 2 cases.
array.
CONCLUSIONS: In a blinded assessment, cytology and FISH yielded essentially equal test results with high interobserver agreement. In view of high labour intensity and costs, the routine use of FISH may be questioned.
P28 ERECTILE DYSFUNCTION: TREATMENT Thursday, 6 April, 14.00-15.30, Room Ternes / Level 1 463 SAFETY AND EFFICACY OF AVANAFIL, A NEW PDE5 INHIBITOR FOR TREATING ERECTILE DYSFUNCTION
HAEMODYNAMIC EFFECTS OF CO-ADMINISTRATION OF AVANAFIL AND GLYCERYL TRINITRATE
(ROC=0.80) and risk of bladder cancer death (HR=5.6; p=0.023) by use of cDNA micro-
Nehra A.1, Swearingen D.2, Dietrich J.3, Peterson C.4
Kaufman J.1, Dietrich J.2 1
2
Advanced Urology, Urology, Aurora, United States, VIVUS Inc., Research and Development, Mountain View, United States INTRODUCTION & OBJECTIVES: This multicentre, double-blind, randomised, paralleldesign Phase II study was conducted to evaluate the efficacy and safety of different doses of avanafil, a new PDE5 inhibitor being developed for the treatment of erectile dysfunction (ED). MATERIAL & METHODS: After a 4-week non-treatment run-in period, 284 men aged 3270 with mild to moderate ED were randomly assigned to 12 weeks of treatment with placebo or avanafil at doses of 50, 100, 200 or 300 mg, taken 30 minutes before initiation of sexual activity. There was no restriction on alcohol or food intake prior to drug ingestion. The mean duration of ED was 66.7 months, and 87% of the subjects had used oral ED medications prior to the study. RESULTS: The primary study outcomes are shown below, including the percentage of sexual attempts in which subjects were able to achieve vaginal penetration (SEP 2); the percentage of sexual attempts in which subjects were able to maintain erections long enough for successful completion of intercourse (SEP 3); and the erectile function (DF) domain score on the International Index of Erectile Function (IIEF) questionnaire by treatment group.
Placebo
Avanafil 50 mg
Avanafil 100 mg
Avanafil 200 mg
Avanafil 300 mg
SEP 2
60.1
76.2*
79.2**
79.8**
83.7***
SEP 3
28.0
53.9***
58.6***
62.1***
64.3***
EF
16.0
19.9**
21.3***
22.0***
22.7***
*p<0.05, **p<0.01, ***p<0.001 vs. placebo Avanafil was associated with significant dose-related increases for all clinical endpoints. The most common dose-related adverse event was headache. CONCLUSIONS: The present Phase II trial demonstrated that the PDE5 inhibitor avanafil produced dose-related, highly significant increases in the ability of men with mild-to moderate ED to successfully complete intercourse. These effects were achieved when treatment was used 30 minutes prior to sexual activity without regard to food intake. Avanafil was effective and well tolerated in this group of patients.
Eur Urol Suppl 2006;5(2):138
464
1
Mayo Clinic, Urology, Rochester, United States, 2MDS, Urology, Phoenix, United States, VIVUS Inc., Research & Development, Mountain View, United States, 4VIVUS Inc., Clinical, Mountain View, United States 3
INTRODUCTION & OBJECTIVES: Avanafil is a rapidly absorbed, highly selective, and rapidly metabolized PDE5 inhibitor under development for treating erectile dysfunction. This study was done to evaluate the effects of avanafil on systolic blood pressure (SBP) and heart rate (HR), when administered concurrently with glyceryl trinitrate (NTG), compared to both placebo and sildenafil. MATERIAL & METHODS: In this double blind crossover-design study, 106 male subjects, aged 30-60 years, were treated at a single-centre. Subjects were distributed among 5 groups based on the interval between PDE5 and NTG administration. Each subject was treated at separate visits with placebo, avanafil (200 mg), and sildenafil (100 mg) in random order. SBPand HR were monitored prior to treatment and for 2 hours after NTG administration. Maximum placebo adjusted changes in standing SBP and HR, for avanafil+NTG and sildenafil+NTG are shown in the table below.
Time from PDE5 to NTG
N
12 hrs
SBP(mmHg)
HR (bpm)
Avanafil
Sildenafil
Avanafil
16
+0.7
-10.4
-5.6
+0.9
8 hrs
16
-1.2
-4.6
+2.7*
+10.8*
4 hrs
26
-6.2*
-9.3*
+0.4
+0.4
1 hr
24
-3.9†
-10.9*
+4.4*†
+10.7*
24
-6.9*
-3.6*
+4.4†
+10.7*
0.5 hrs
Sildenafil
†
* p<0.05 vs. 0 (placebo); p<0.05 vs. sildenafil RESULTS: SBP decreases and HR increases following avanafil were consistently less than similar changes following sildenafil, and differences between these PDE5 inhibitors were statistically significant at some time points. Avanafil had no observable effect on SBP or HR when administered 12 hours prior to NTG. In addition, there were 11 subjects who experienced clinically significant drops in SBP (30 mmHg or more) following placebo, 14 following avanafil, and 28 following sildenafil (p<0.03). CONCLUSIONS: Compared to sildenafil, avanafil+NTG resulted in smaller changes in SBP and HR, a shorter duration of interaction, and fewer subjects with clinically significant hypotension. Avanafil may be a preferable PDE5 inhibitor for patients who are at risk for using NTG.
462
GENE-EXPRESSION PROFILES PREDICT NODAL METASTASIS AND SURVIVAL IN PATIENTS UNDERGOING RADICAL CYSTECTOMY
COMPARISON OF URINARY CYTOLOGY AND FLUORESCENCEIN-SITU HYBRIDISATION ASSAY (FISH) FOR THE DETECTION OF UROTHELIAL BLADDER CARCINOMA
Liedberg F.1, Gudjonsson S.1, Höglund M.2, Lindgren D.2, Månsson W.1 1
Lund University Hospital, Department of Urology, Lund, Sweden, 2Lund University Hospital,
Department of Clinical Genetics, Lund, Sweden INTRODUCTION & OBJECTIVES: Nodal metastasis is diagnosed in 25-30% in large series of patients undergoing radical cystectomy for bladder cancer. Neoadjuvant chemotherapy seems to improve survival in patients with locally advanced disease, but difficulties exist in defining those patients who will benefit from such therapy. We have obtained gene-expression profiles with cDNA micro-array technology and correlated the gene-expression profiles with presence of lymph node metastasis and survival in patients undergoing radical cystectomy and pelvic lymph node dissection to the aortic bifurcation. MATERIAL & METHODS: Tissue from urothelial tumours of the bladder was obtained by transurethral resection or cold cup biopsy and RNA was extracted. of 64 patients undergoing radical cystectomy, 13 were excluded due to low quality or low quantity RNA and 2 were excluded due to over 6 months delay in performing the cystectomy. With microarray technology expression of 35,000 gene sequences were studied using oligonucleotide-arrays. Genes were selected using a variance and a signal to noise filter and by only including genes having values for at least 80% of the tumours, 5921 genes were obtained for final analysis. Significance Analysis of Microarrays (SAM) was used to identify genes that showed significant different gene expression in patients with/without lymph node metastasis and in patients dead/alive. We used a leave-one-out validating methodology to identify 20 discriminatory genes which subsequently were selected as a predictor gene set. RESULTS: Patients were followed 16.5 months (median) from cystectomy. 15 of the 49 patients (31%) died of recurrent disease. Positive pelvic nodes were present in 21 of the patients (43%). The identified 20-gene-set predicted lymph node metastasis in 20 out of the 21 patients (Area under ROC curve = 0.80). Gene expression below 50% of the median expression for these genes significantly increased the risk for bladder cancer death (HR=5,6; p=0.023). CONCLUSIONS: We have identified a gene set that predicts lymph node metastasis
Hakenberg O., Schmidt U., Berdjis N., Meye A., Wawroschek F., Baldauf A., Zastrow S., Wirth M. University Hospital, Urology, Dresden, Germany INTRODUCTION & OBJECTIVES: The urine-based diagnosis of urothelial bladder carcinoma (TCC) is an expanding field of high interest. Conventional urinary cytology is the standard test available, but dependent on investigator experience. Fluorescence-in-situ hybridisation (FISH) is a potentially highly specific method which has been reported to have better diagnostic accuracy than conventional cytology and is available as a commercial kit. In our department, cytology is used routinely for urine-based diagnosis. We compared both methods in a prospective study in a blinded way with each test being assessed by three different examiners independently. MATERIAL & METHODS: 110 consecutive patients scheduled for transurethral biopsy for suspected bladder TCC or symptoms provided voided urine samples preoperatively. These were processed for cytology (Papanicolaou staining) and FISH analysis (Urovysion, Abbott, Germany). All samples were independently examined by three different examiners all blinded to clinical diagnosis and histological results and classed as either negative or positive for TCC. For each method the final assessment was based on agreement of at least 2/3 examiners. RESULTS: Samples with incomplete data were excluded from analysis (n=13). of the 97 remaining patients, 18 had benign conditions and 79 bladder TCC (21 grade 1, 25 grade 2 and 33 grade 3). Sensitivities for TCC detection with FISH were 33%, 76% and 91% for grades 1-3, respectively, and for cytology 38%, 76% and 93% (specificities 72% vs. 66%) and not significantly different. Inter-investigator agreement (3/3 assessments the same) was higher with FISH compared to cytology (75% vs. 61%), however, wrong assessments with all three investigators agreeing occurred in 13 cases with cytology and 16 cases with FISH. These were mostly false assessments in inflammatory conditions or low grade superficial TCC. False negative assessments by all three investigators occurred with FISH for TCC grade 2 in 3 cases and for TCC grade 3 in 1 case, for cytology in TCC grade 2 in 2 cases.
array.
CONCLUSIONS: In a blinded assessment, cytology and FISH yielded essentially equal test results with high interobserver agreement. In view of high labour intensity and costs, the routine use of FISH may be questioned.
P28 ERECTILE DYSFUNCTION: TREATMENT Thursday, 6 April, 14.00-15.30, Room Ternes / Level 1 463 SAFETY AND EFFICACY OF AVANAFIL, A NEW PDE5 INHIBITOR FOR TREATING ERECTILE DYSFUNCTION
HAEMODYNAMIC EFFECTS OF CO-ADMINISTRATION OF AVANAFIL AND GLYCERYL TRINITRATE
(ROC=0.80) and risk of bladder cancer death (HR=5.6; p=0.023) by use of cDNA micro-
Nehra A.1, Swearingen D.2, Dietrich J.3, Peterson C.4
Kaufman J.1, Dietrich J.2 1
2
Advanced Urology, Urology, Aurora, United States, VIVUS Inc., Research and Development, Mountain View, United States INTRODUCTION & OBJECTIVES: This multicentre, double-blind, randomised, paralleldesign Phase II study was conducted to evaluate the efficacy and safety of different doses of avanafil, a new PDE5 inhibitor being developed for the treatment of erectile dysfunction (ED). MATERIAL & METHODS: After a 4-week non-treatment run-in period, 284 men aged 3270 with mild to moderate ED were randomly assigned to 12 weeks of treatment with placebo or avanafil at doses of 50, 100, 200 or 300 mg, taken 30 minutes before initiation of sexual activity. There was no restriction on alcohol or food intake prior to drug ingestion. The mean duration of ED was 66.7 months, and 87% of the subjects had used oral ED medications prior to the study. RESULTS: The primary study outcomes are shown below, including the percentage of sexual attempts in which subjects were able to achieve vaginal penetration (SEP 2); the percentage of sexual attempts in which subjects were able to maintain erections long enough for successful completion of intercourse (SEP 3); and the erectile function (DF) domain score on the International Index of Erectile Function (IIEF) questionnaire by treatment group.
Placebo
Avanafil 50 mg
Avanafil 100 mg
Avanafil 200 mg
Avanafil 300 mg
SEP 2
60.1
76.2*
79.2**
79.8**
83.7***
SEP 3
28.0
53.9***
58.6***
62.1***
64.3***
EF
16.0
19.9**
21.3***
22.0***
22.7***
*p<0.05, **p<0.01, ***p<0.001 vs. placebo Avanafil was associated with significant dose-related increases for all clinical endpoints. The most common dose-related adverse event was headache. CONCLUSIONS: The present Phase II trial demonstrated that the PDE5 inhibitor avanafil produced dose-related, highly significant increases in the ability of men with mild-to moderate ED to successfully complete intercourse. These effects were achieved when treatment was used 30 minutes prior to sexual activity without regard to food intake. Avanafil was effective and well tolerated in this group of patients.
Eur Urol Suppl 2006;5(2):138
464
1
Mayo Clinic, Urology, Rochester, United States, 2MDS, Urology, Phoenix, United States, VIVUS Inc., Research & Development, Mountain View, United States, 4VIVUS Inc., Clinical, Mountain View, United States 3
INTRODUCTION & OBJECTIVES: Avanafil is a rapidly absorbed, highly selective, and rapidly metabolized PDE5 inhibitor under development for treating erectile dysfunction. This study was done to evaluate the effects of avanafil on systolic blood pressure (SBP) and heart rate (HR), when administered concurrently with glyceryl trinitrate (NTG), compared to both placebo and sildenafil. MATERIAL & METHODS: In this double blind crossover-design study, 106 male subjects, aged 30-60 years, were treated at a single-centre. Subjects were distributed among 5 groups based on the interval between PDE5 and NTG administration. Each subject was treated at separate visits with placebo, avanafil (200 mg), and sildenafil (100 mg) in random order. SBPand HR were monitored prior to treatment and for 2 hours after NTG administration. Maximum placebo adjusted changes in standing SBP and HR, for avanafil+NTG and sildenafil+NTG are shown in the table below.
Time from PDE5 to NTG
N
12 hrs
SBP(mmHg)
HR (bpm)
Avanafil
Sildenafil
Avanafil
16
+0.7
-10.4
-5.6
+0.9
8 hrs
16
-1.2
-4.6
+2.7*
+10.8*
4 hrs
26
-6.2*
-9.3*
+0.4
+0.4
1 hr
24
-3.9†
-10.9*
+4.4*†
+10.7*
24
-6.9*
-3.6*
+4.4†
+10.7*
0.5 hrs
Sildenafil
†
* p<0.05 vs. 0 (placebo); p<0.05 vs. sildenafil RESULTS: SBP decreases and HR increases following avanafil were consistently less than similar changes following sildenafil, and differences between these PDE5 inhibitors were statistically significant at some time points. Avanafil had no observable effect on SBP or HR when administered 12 hours prior to NTG. In addition, there were 11 subjects who experienced clinically significant drops in SBP (30 mmHg or more) following placebo, 14 following avanafil, and 28 following sildenafil (p<0.03). CONCLUSIONS: Compared to sildenafil, avanafil+NTG resulted in smaller changes in SBP and HR, a shorter duration of interaction, and fewer subjects with clinically significant hypotension. Avanafil may be a preferable PDE5 inhibitor for patients who are at risk for using NTG.