- Email: [email protected]
MP-03.05 Can Pre-Biopsy Multiparametric MRI Be Used to Detect Significant Prostate Cancer?
MODERATED POSTER SESSIONS
Significantly Enhances the in vivo Antitumor Activity on LNCaP Castration-resistant Prostate Cancer Xenograft Tumors Compared To Single Use of Each Drug Thomas C1,2, Wafa L1, Lamoureux F1, Fazli L1, Rennie P1, Gleave M1 1 The Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada; 2Dept. of Urology, University of Mainz, Germany Introduction and Objective: Response to bicalutamide after castration failure is not durable and treatment options at this stage are limited. Carbidopa, an L-dopa decarboxylase (AR-coactivator) inhibitor, has been shown to retard prostate tumor growth/PSA production in xenografts. Here, we hypothesize that pharmacological targeting of the AR-axis by combination treatment with bicalutamide plus carbidopa significantly enhances antitumoral activity in vitro and in vivo compared to monotherapy with either drug. Methods: Carbidopa was tested for its ability to enhance the effects of bicalutamide on cell growth and PSA transactivation in LNCaP and C4-2 prostate cancer cells. The castration-resistant prostate cancer (CRPC) LNCaP xenograft tumor model was used in vivo. After CRPC progression, mice were treated with carbidopa (50mg/kg) and bicalutamide (50mg/kg) as monotherapy or in combination. Tumor volume and serum PSA were evaluated weekly. Results: Combination treatment of carbidopa plus bicalutamide significantly inhibited cell growth for both cell lines. The combination treatment also decreased androgen-induced PSA transactivation by 2.7-fold in LNCaP cells and by 2.3-fold in C4-2 cells compared to control, while bicalutamide monotherapy reduced PSA levels by only 1.4-fold in each cell line.In vivo, bicalutamide monotherapy delayed LNCaP CRPC tumor growth rate by 3.6fold, while combination treatment reduced tumor growth by 6.4-fold compared to control. Serum PSA was also reduced 3.4-fold with bicalutamide monotherapy, while combination therapy reduced PSA levels by 4.3-fold compared to control. Conclusions: This study demonstrates preclinical proof-of-principle that pharmacological targeting of prostate tumors by combination treatment of bicalutamide plus carbidopa significantly reduces AR activity, and thereby delays CRPC tumor progression in vivo. This work was supported by funding from Prostate Cancer Canada and Deutsche Forschungs-
S42
gemeinschaft (German Research Foundation, TH 1482/2-1). C.Thomas and L.Wafa are equal contributors.
MP-03.05 Can Pre-Biopsy Multiparametric MRI Be Used to Detect Significant Prostate Cancer? Abd Alazeez M1, Moore C2, Ahmed HU2, Arya M1, Freeman A3, Kirkham A4, Allen C4, Emberton M1,2 1 Dept. of Urology, University College Hospitals NHS Foundation Trust, London, UK; 2Division of Surgery and Interventional Science, University College London, London, UK; 3Dept. of Histopathology, University College Hospitals NHS Foundation Trust, London, UK; 4Dept. of Radiology, University College Hospitals NHS Foundation Trust, London, UK Introduction and Objective: The selective detection of clinically significant prostate cancer and avoiding the detection of clinically insignificant disease, may improve the acceptability of both screening and treatment. Multiparametric MRI (MPMRI) has attributes of a diagnostic test which could meet the ideals of such an objective. We compared the detection rates of transperineal prostate mapping (TPM) with targeted transperineal sampling of MRI defined lesions. Materials and Methods: Forty four consecutive men due to undergo TPM had pre-biopsy MP-MRI, which included T2weighted, dynamic contrast enhanced (DCE) and diffusion-weighted imaging (DWI). In addition to 5mm sampling on TPM, additional targeted biopsies (TB) were taken from areas suspicious for cancer on MP-MRI. Significant prostate cancer was defined as cancer core length ⱖ4mm or any Gleason ⱖ 3⫹4. Results: Mean PSA was 6.4ng/ml. Average number of cores taken was 30 for TPM and 4 for TB. Cancer was detected in 34/44 patients, 19 of which had clinically significant disease. On TPM, 29/44 had positive disease; 14 of which were clinically significant. On TB, 23/44 had positive disease; 16 of which were clinically significant. Conclusions: MP-MRI guided biopsies can detect clinically significant prostate cancer with performance characteristics comparable to those of TPM. The use of MP-MRI to define a lesion to target may allow fewer biopsies to be taken in a better fashion whilst reducing the detection of clinically insignificant cancer.
MP-03.05, Table 1. TPM versus TB for the detection of significant cancer TPM TPM positive negative Total TB positive 11 5 16 TB 3 0 3 negative Total 14 5 19
MP-03.05, Table 2. Comparison between results of TPM and TB Item TPM TB Average No. 30 4 of cores % Detection 74% (14/19) 84% (16/19) Significant Disease % Detection 100% (15/15) 47% (7/15) Insignificant Disease Sensitivity, specificity, positive and negative predictive values for TB were 84%, 53%, 70% and 73%, when using the TPM as the reference standard for detection of significant disease.
MP-03.06 Can the Photodynamic Diagnosis Using 5-Aminolevulinic Acid (ALA) Predict how Malignant the Prostate Cancer Cells in the Urine Are, Obtained Following Prostate Massage? Anai S, Nakai Y, Kuwada M, Miyake M, Tanaka N, Fujimoto K, Hirao Y Dept. of Urology, Nara Medical University, Kashihara, Japan Introduction and Objectives: We evaluated the feasibility of photodynamic diagnosis (PDD) using 5-aminolevulinic acid (ALA) for detecting of prostate cancer (PCa) cells in the urine obtained following prostate massage. Material and Methods: Urine samples were collected from 118 men on whom the prostate massage was performed (attentive digital rectal examination) before prostate needle biopsy. Urine sediments were exposed to 5-ALA (1mM) for 2 hours and cytospun onto glass slides. Protoporphyrin IX (PPIX), which is the metabolite of 5-ALA in the heme biosynthetic pathway, was observed using the fluorescent microscope (excitation filter 380-420 nm, emission filter 590 nm) as a positive signal of cancer cell. Any fluorescent signal in the samples was evaluated as positive. After histological diagnosis, the results of 5-ALA-PDD were compared with the histological diagnosis. Results: Prostate cancer cells were successfully visualized by the PPIX. Of the 74 cases with biopsy-proven prostate cancer,
UROLOGY 78 (Supplement 3A), September 2011
Significantly Enhances the in vivo Antitumor Activity on LNCaP Castration-resistant Prostate Cancer Xenograft Tumors Compared To Single Use of Each Drug Thomas C1,2, Wafa L1, Lamoureux F1, Fazli L1, Rennie P1, Gleave M1 1 The Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada; 2Dept. of Urology, University of Mainz, Germany Introduction and Objective: Response to bicalutamide after castration failure is not durable and treatment options at this stage are limited. Carbidopa, an L-dopa decarboxylase (AR-coactivator) inhibitor, has been shown to retard prostate tumor growth/PSA production in xenografts. Here, we hypothesize that pharmacological targeting of the AR-axis by combination treatment with bicalutamide plus carbidopa significantly enhances antitumoral activity in vitro and in vivo compared to monotherapy with either drug. Methods: Carbidopa was tested for its ability to enhance the effects of bicalutamide on cell growth and PSA transactivation in LNCaP and C4-2 prostate cancer cells. The castration-resistant prostate cancer (CRPC) LNCaP xenograft tumor model was used in vivo. After CRPC progression, mice were treated with carbidopa (50mg/kg) and bicalutamide (50mg/kg) as monotherapy or in combination. Tumor volume and serum PSA were evaluated weekly. Results: Combination treatment of carbidopa plus bicalutamide significantly inhibited cell growth for both cell lines. The combination treatment also decreased androgen-induced PSA transactivation by 2.7-fold in LNCaP cells and by 2.3-fold in C4-2 cells compared to control, while bicalutamide monotherapy reduced PSA levels by only 1.4-fold in each cell line.In vivo, bicalutamide monotherapy delayed LNCaP CRPC tumor growth rate by 3.6fold, while combination treatment reduced tumor growth by 6.4-fold compared to control. Serum PSA was also reduced 3.4-fold with bicalutamide monotherapy, while combination therapy reduced PSA levels by 4.3-fold compared to control. Conclusions: This study demonstrates preclinical proof-of-principle that pharmacological targeting of prostate tumors by combination treatment of bicalutamide plus carbidopa significantly reduces AR activity, and thereby delays CRPC tumor progression in vivo. This work was supported by funding from Prostate Cancer Canada and Deutsche Forschungs-
S42
gemeinschaft (German Research Foundation, TH 1482/2-1). C.Thomas and L.Wafa are equal contributors.
MP-03.05 Can Pre-Biopsy Multiparametric MRI Be Used to Detect Significant Prostate Cancer? Abd Alazeez M1, Moore C2, Ahmed HU2, Arya M1, Freeman A3, Kirkham A4, Allen C4, Emberton M1,2 1 Dept. of Urology, University College Hospitals NHS Foundation Trust, London, UK; 2Division of Surgery and Interventional Science, University College London, London, UK; 3Dept. of Histopathology, University College Hospitals NHS Foundation Trust, London, UK; 4Dept. of Radiology, University College Hospitals NHS Foundation Trust, London, UK Introduction and Objective: The selective detection of clinically significant prostate cancer and avoiding the detection of clinically insignificant disease, may improve the acceptability of both screening and treatment. Multiparametric MRI (MPMRI) has attributes of a diagnostic test which could meet the ideals of such an objective. We compared the detection rates of transperineal prostate mapping (TPM) with targeted transperineal sampling of MRI defined lesions. Materials and Methods: Forty four consecutive men due to undergo TPM had pre-biopsy MP-MRI, which included T2weighted, dynamic contrast enhanced (DCE) and diffusion-weighted imaging (DWI). In addition to 5mm sampling on TPM, additional targeted biopsies (TB) were taken from areas suspicious for cancer on MP-MRI. Significant prostate cancer was defined as cancer core length ⱖ4mm or any Gleason ⱖ 3⫹4. Results: Mean PSA was 6.4ng/ml. Average number of cores taken was 30 for TPM and 4 for TB. Cancer was detected in 34/44 patients, 19 of which had clinically significant disease. On TPM, 29/44 had positive disease; 14 of which were clinically significant. On TB, 23/44 had positive disease; 16 of which were clinically significant. Conclusions: MP-MRI guided biopsies can detect clinically significant prostate cancer with performance characteristics comparable to those of TPM. The use of MP-MRI to define a lesion to target may allow fewer biopsies to be taken in a better fashion whilst reducing the detection of clinically insignificant cancer.
MP-03.05, Table 1. TPM versus TB for the detection of significant cancer TPM TPM positive negative Total TB positive 11 5 16 TB 3 0 3 negative Total 14 5 19
MP-03.05, Table 2. Comparison between results of TPM and TB Item TPM TB Average No. 30 4 of cores % Detection 74% (14/19) 84% (16/19) Significant Disease % Detection 100% (15/15) 47% (7/15) Insignificant Disease Sensitivity, specificity, positive and negative predictive values for TB were 84%, 53%, 70% and 73%, when using the TPM as the reference standard for detection of significant disease.
MP-03.06 Can the Photodynamic Diagnosis Using 5-Aminolevulinic Acid (ALA) Predict how Malignant the Prostate Cancer Cells in the Urine Are, Obtained Following Prostate Massage? Anai S, Nakai Y, Kuwada M, Miyake M, Tanaka N, Fujimoto K, Hirao Y Dept. of Urology, Nara Medical University, Kashihara, Japan Introduction and Objectives: We evaluated the feasibility of photodynamic diagnosis (PDD) using 5-aminolevulinic acid (ALA) for detecting of prostate cancer (PCa) cells in the urine obtained following prostate massage. Material and Methods: Urine samples were collected from 118 men on whom the prostate massage was performed (attentive digital rectal examination) before prostate needle biopsy. Urine sediments were exposed to 5-ALA (1mM) for 2 hours and cytospun onto glass slides. Protoporphyrin IX (PPIX), which is the metabolite of 5-ALA in the heme biosynthetic pathway, was observed using the fluorescent microscope (excitation filter 380-420 nm, emission filter 590 nm) as a positive signal of cancer cell. Any fluorescent signal in the samples was evaluated as positive. After histological diagnosis, the results of 5-ALA-PDD were compared with the histological diagnosis. Results: Prostate cancer cells were successfully visualized by the PPIX. Of the 74 cases with biopsy-proven prostate cancer,
UROLOGY 78 (Supplement 3A), September 2011