625 THE SPECIFIC CLINICAL CHARACTERISTICS OF DUCTAL PROSTATE CANCER

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The specific clinical characteristics of ductal prostate cancer

Does neoadjuvant sorafenib treatment affect microvessel density count in prostate cancer?

Leibovici D.1, Tu S.M.2, Lopez A.3, Pagliaro L.C.2, Kuban D.A.4, Logothetis C.J.2, Pisters L.L.5

Mamoulakis C.1, Wijkstra De La Rosette J.J.M.C.H.1

Assaf-Harofeh Medical Center, Dept. of Urology, Zerifin, Israel, 2University of Texas, M.D. Anderson Cancer Center, Dept. of Gu Medical Oncology, Houston, United States of America, 3 University of Texas, M.D. Anderson Cancer Center, Dept. of Pathology, Houston, United States of America, 4University of Texas, M.D. Anderson Cancer Center, Dept. of Radiation Oncology, Houston, United States of America, 5University of Texas, M.D. Anderson Cancer Center, Dept. of Urology, Houston, United States of America 1

Introduction & Objectives: Ductal adenocarcinoma is an uncommon variant of prostate cancer. Patients with this subtype of cancer may have a distinct symptom pattern and clinical course that differ from those associated with the typical acinar type. We present the largest series of ductal prostate cancer patients to date, and describe the clinical presentation and sites of metastasis in these patients. Material & Methods: Using an oracle®-based modularly patient database, we detected 154 patients with ductal prostate cancer between the years 2000-2007 who were treated at the University of Texas M.D. Anderson Cancer Center. Histology slides were reviewed and the diagnosis was confirmed our pathologists in all cases. Charts were reviewed and data were retrieved regarding symptoms at the time of presentation, serum PSA level, Gleason’s score, sites of metastasis, and disease specific survival. The local ethical committee approved this study. Results: Of the 154 patients, 76 underwent radical prostatectomy and 32 received radiation therapy as their primary form of treatment, whereas 46 others had metastatic disease at the time of presentation to our center. Forty-three patients (28%) presented with local symptoms including urine retention necessitating transurethral resection, lower urinary tract symptoms, hematuria, tenesmus and pelvic pain. The median Gleason score of the entire group was 9 (7-10), 25 patients (16%) had a PSA<4.0 and 35% of the metastatic patients had a PSA level<10.0. Seventy-nine (51%) of all patients progressed to metastasis. Sites of metastasis included: Bone in 60 (39%) cases, lung in 31 (20%), liver in 9 (6%), brain in 8 (5%), peritoneal spread and retroperitoneal lymphadenopathy in 6 (4%), respectively, penis in 2 (2%) and kidney, spleen, soft tissue and skin – one in each. Extra-skeletal metastases were noted in 36 (24%) cases. Ten patients (6%) developed visceral metastasis in the absence of skeletal involvement. The median disease-specific survival was 137 months, 98 months, and 61 months in patients who had undergone radical prostatectomy, radiation therapy, or presented with metastasis, respectively. Conclusions: Ductal prostate cancer is a distinct subtype with specific manifestations and clinical course. Its typical characteristics include the propensity of local morbidity, uncommon sites of visceral metastasis, and relative long-term survival.



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M30 and M65 as novel biomarkers in advanced prostate cancer Liew M.P.C.1, Greystoke A.2, Dive C.2, Clarke N.W.1 Paterson Institute for Cancer Research, Genito- Urinary Research Group, Manchester, United Kingdom, 2Paterson Institute for Cancer Research, Dept. of Medical Oncology, Clinical and Experimental Pharmacology Group, Manchester, United Kingdom 1

Introduction & Objectives: Due to variations in the natural history, decisions on management of prostate cancer (CaP) can be difficult. Prostate specific antigen (PSA) is the biomarker of prognosis and treatment response. But it is not a reliable predictor of natural history in all cases. Cytokeratin 18 (CK18) is a major component of the cytoskeleton of epithelial cells, with high levels in normal prostate and prostate cancer specimens. CK18 is a novel serum biomarker of cell death in epithelial cells (Greystoke 2008) and during cell death its products are released into the circulation where they can be detected by validated M30 and M65 ELISA assays (Cummings 2008). M30 detects caspasecleaved CK18 fragments (apoptosis); M65 detects both cleaved (apoptosis) and intact (necrosis) CK18. Recent reports confirm prognostic significance in lung and testicular tumour (Ulakaya 2007 and de Haas 2008) and these assays have been used to assess response to other cancer treatments (Kramer, 2006). This pilot study aimed to assess utility of these markers in CaP. Material & Methods: M30 and M60 was measured retrospectively in 134 patients with T3 (114) and T4 (20) CaP. Data obtained included age, stage, PSA, Gleason score and overall survival. We examined the correlations with these cell death biomarkers and these factors. Results: M65 but not M30 was elevated compared to controls in patients with prostate cancer (median 283 vs. 241 U/l; 138 vs. 155). Additionally, M65 correlated with PSA (r 0.24, p=0.0068). In contrast, M30 did not correlate with PSA, stage and Gleason score. Patients with the lowest 25% levels of M30 had the best overall survival (3 year OS 85% vs. 58%, p=0.03). Of particular interest was the ability of M30 to predict survival in patients with lower PSA levels (<21 ng/ml). In these patients, those with low M30 (<136 U/l) levels had a much better prognosis (see graph) when compared to high M30 (>136U/l) levels (3 year OS 80% vs. 62%, p=0.02). Conclusions: This pilot study is the first report of the prognostic impact of M30 and M65 in patients with advanced prostate cancer. Elevated levels of M65 confirm its potential validity as a marker of disease burden in future therapeutic trials. Low M30 levels predict better survival, particularly in patients with low PSA: those with high M30 have poorer survival than those with low M30 levels. These results suggest that the M30 levels may allow better prognostication in patients diagnosed with advanced prostate cancer.

1 2

H.1,

Kuilman

L.1,

Visser

M.2,

Laguna

M.P.1,

De

Reijke

T.M.1,

Academic Medical Center, University of Amsterdam, Dept. of Urology, Amsterdam, The Netherlands, Academic Medical Center, University of Amsterdam, Dept. of Pathology, Amsterdam, The Netherlands

Introduction & Objectives: Results from a Medical Ethics Committee approved, single-center, open-label, one-armed phase II clinical trial of neoadjuvant sorafenib treatment prior to radical prostatectomy (RP) are presented for the first time. The aim of the study was to evaluate changes in angiogenesis based on microvascular density count (MVDC) determination in biopsy material compared to RP specimens. Material & Methods: Between June 2006-August 2007, 7 patients with biopsy-proven prostate cancer (PCa) eligible for laparoscopic RP signed informed consent to receive 400 mg sorafenib bid for an 8-week preoperative period. MVDC was randomly-blindly determined by an experienced observer, in benign and tumor foci of the biopsy and RP specimens after topographical correlation. A vessel-staining technique combined with manual assessment of the microvessel characteristics was employed. Student’s t test was used to compare mean MVDC of benign and malignant foci a) in the biopsy material and b) in the RP specimens. A general linear model for repeated measure design was defined to compare mean MVDC of a) benign foci and b) malignant foci between biopsy material and RP specimens, taking into account the effect of total sorafenib dose consumption. Results: Mean patients’ age was 56.8±7.4 years. Six patients completed the trial: 1 under full and 5 after switching to half daily dose due to side effects. 1 patient dropped-out 10 days after full dose treatment. Median treatment duration was 55 (10-56) days. Mean total sorafenib dose consumption was 25.0±10.8 g. Tumor stage was pT2c, pT3a and pT3b in 1, 5 and 1 patient, respectively (median Gleason score: 7 (6-7)). MVDC data are presented in the figure. Mean MVDC was significantly higher in malignant than benign biopsy material foci (456.9 vs. 222.5 microvessels/mm2; P=0.024). No difference was detected in RP specimens (malignant vs. benign foci: 254.9 vs. 213.6 microvessels/mm2; P=0.263). Mean MVDC of benign foci was not significantly decreased (P=0.128) but mean MVDC of malignant foci was significantly decreased (P=0.029) after sorafenib treatment. Total dose was not proven to be a significant predictor of this reduction (P=0.119), possibly due to the small sample of patients. Conclusions: Neoadjuvant sorafenib treatment reduces significantly MVDC in PCa. In this pilot study, total dose consumption was not associated with this effect.

P39 OUTCOMES OF RADICAL PROSTATECTOMY Thursday, 19 March, 15.45-17.15, Room A5

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The length of positive surgical margins correlates with biochemical recurrence after radical prostatectomy Van Oort I.M.1, Bruins H.M.1, Kiemeney L.A.L.M.2, Hulsbergen-Van De Kaa C.A.3, Witjes J.A.1 Radboud University Nijmegen Medical Centre, Dept. of Urology, Nijmegen, The Netherlands, Radboud University Nijmegen Medical Centre, Dept. of Epidemiology and Biostatistics, Nijmegen, The Netherlands, 3Radboud University Nijmegen Medical Centre, Dept. of Pathology, Nijmegen, The Netherlands

1

2

Introduction & Objectives: The presence of positive surgical margins in a radical prostatectomy (RP) specimen is an important negative prognostic factor, although the length of the positive margins was not an independent predictive factor for biochemical recurrence (BCR) in most studies. The aim of this study is to correlate the length and the Gleason grade of the positive resection margin with BCR after RP. Material & Methods: Data of 267 consecutive RP specimens with positive surgical margins were analyzed. All RP specimens were sectioned at 4-mm intervals and completely embedded. Evaluation was done by one uropathologist with regard to the length of the positive margins (mm) and the highest Gleason grade in the positive margins. BCR was defined as two consecutive PSA levels above 0,10 ng/mL. Data were analyzed using Kaplan-Meier survival analysis and proportional hazards models. Results: In the group of 267 patients, the length of positive margins ranged from 0.4 to 174.5 mm (median 11.2 mm; mean 21.9 mm) and was associated with preoperative PSA (p< 0.001), pathologic stage (p < 0.001), tumor volume (p = 0.001), number of positive sites (p <0.001) and Gleason grade at the positive margin (p < 0.001) and with Gleason score (p = 0.042). The distribution of the locations of positive margins was dorsal (42.7%), anterior (34.8%), apical (33.0%), posterolateral (20.6%), basal (19.5%) and at the seminal vesicles (5.2%). In 34 patients the post-operative PSA did not drop to zero and another 59 patients received adjuvant hormonal treatment or radiotherapy, leaving a group of 174 patients to be analyzed for BCR with a median follow-up of 36.2 months. The mean length of positive margins of the 93 patients with persistent increased postoperative PSA levels or adjuvant therapy was significantly higher than the rest (32.6 mm vs. 15.4 mm; p < 0.001). In the group of 174 patients with an undetectable postoperative PSA level and no direct adjuvant therapy, the 5-years BCR was 29%. The BCR for patients with positive margins ≤ 10 mm and > 10 mm was 21% and 39% respectively (logrank p=0.011). In multivariate analyses BCR was associated with increasing length (≤ 10mm vs. >10 mm; HR 2.15; 95% CI 1.12-4.15; p = 0.022), but not with preoperative PSA, pathological stage, Gleason score, tumor volume or Gleason grade at the resection margin. Conclusions: The length of positive margins is an independent predictive factor for PSA recurrence.

Eur Urol Suppl 2009;8(4):277