Hein Van Poppel

Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup.

PURPOSE Nonsteroidal antiandrogen monotherapy may be a treatment option for some patients with advanced prostate cancer. We report a survival and safety update from an analysis of 2 studies in which patients with nonmetastatic (M0) locally advanced disease were treated with either 150 mg. bicalutamide monotherapy or castration. MATERIALS AND METHODS Data from 2 open label, multicenter studies of identical design were pooled according to protocol. Patients with stage T3/4 prostate cancer were randomized to receive 150 mg. bicalutamide daily or castration (orchiectomy or 3.6 mg. goserelin acetate every 28 days) in a 2:1 ratio. RESULTS A total of 480 patients with locally advanced prostate cancer were randomized to treatment. After a median followup of 6.3 years mortality was 56%. There was no statistically significant difference between the 2 groups in overall survival (hazard ratio 1.05, upper 1-sided 95% confidence limit 1.31, p = 0.70) or time to progression (1.20, 1.45, p = 0.11). There were statistically significant benefits in the bicalutamide monotherapy group in the 2 quality of life parameters of sexual interest (p = 0.029) and physical capacity (p = 0.046). The highest incidences of adverse events were the pharmacological side effects of hot flashes in the castration group, and breast pain and gynecomastia in the bicalutamide group. The incidences of other types of adverse events were low. Bicalutamide was well tolerated, with few drug related withdrawals from study, and no new safety issues were identified during this longer followup. CONCLUSIONS Monotherapy with 150 mg. bicalutamide is an attractive alternative to castration in patients with locally advanced prostate cancer for whom immediate hormone therapy is indicated.

Overexpression of fatty acid synthase is an early and common event in the development of prostate cancer

The expression of fatty acid synthase (FAS), a key lipogenic enzyme and potential target for antineoplastic therapy, was analyzed in 87 frozen needle biopsies of prostate cancer using a highly sensitive immunohistochemical detection technique (Envision). In comparison to normal or benign, hyperplastic glandular structures, which were all negative for FAS staining, immunohistochemical signal was evident in 24/25 low grade prostatic epithelial neoplasia (PIN) lesions, in 26/26 high grade PIN lesions and in 82/87 invasive carcinomas. Staining intensity tended to increase from low grade to high grade PIN to invasive carcinoma. Cancers with a high FAS expression had an overall high proliferative index. No correlation was found between FAS expression and lipid accumulation. These findings indicate that increased FAS expression is one of the earliest and most common events in the development of prostate cancer, suggesting that FAS may be used as a general prostate cancer marker and that antineoplastic therapy based on FAS inhibition may be an option for chemoprevention or curative treatment for nearly all prostate cancers.

The contribution of magnetic resonance imaging to the three-dimensional treatment planning of localized prostate cancer.

PURPOSE To investigate whether the use of transaxial and coronal MR imaging improves the ability to localize the apex of the prostate and the anterior part of the rectum compared to the use of transaxial CT alone, and whether the incorporation of MR could improve the coverage of the prostate by the radiotherapy field and change the volume of rectum irradiated. METHODS AND MATERIALS Ten consecutive patients with localized prostate carcinoma underwent a CT and an axial and coronal MR scan in treatment position. The CT and MR images were mathematically aligned, and three observers were asked to contour independently the prostate and the rectum on CT and on MR. The interobserver variability of the prostatic apex location and of the delineation of the anterior rectal wall were assessed for each image modality. A dosimetry study was performed to evaluate the dose to the rectum when MR was used in addition to CT to localize the pelvic organs. RESULTS The interobserver variation of the prostatic apex location was largest on CT ranging from 0.54 to 1.07 cm, and smallest on coronal MR ranging from 0.17 to 0.25 cm. The interobserver variation of the delineation of the anterior rectum on MR was small and constant along the whole length of the prostate (0.09+/-0.02 cm), while for CT it was comparable to that for the MR delineation at the base of the prostate, but it increased gradually towards the apex, where the variation reached 0.39 cm. The volume of MR rectum receiving more than 80% of the prescribed dose was on average reduced by 23.8+/-11.2% from the CT to the MR treatment plan. CONCLUSION It can be concluded that the additional use of axial and coronal MR scans, in designing the treatment plan for localized prostate carcinoma, improves substantially the localization accuracy of the prostatic apex and the anterior aspect of the rectum, resulting in a better coverage of the prostate and a potential to reduce the volume of the rectum irradiated to a high dose.

Selective activation of the fatty acid synthesis pathway in human prostate cancer

A substantial subset of breast, colorectal, ovarian, endometrial and prostatic cancers displays markedly elevated expression of immunohistochemically detectable fatty acid synthase, a feature that has been associated with poor prognosis and that may be exploited in anti‐neoplastic therapy. Here, using an RNA array hybridisation technique complemented by in situ hybridisation, we report that in prostate cancer fatty acid synthase expression is up‐regulated at the mRNA level together with other enzymes of the same metabolic pathway. Contrary to the observations that in many cell systems (including androgen‐stimulated LNCaP prostate cancer cells) fatty acid and cholesterol metabolism are co‐ordinately regulated so as to supply balanced amounts of lipids for membrane biosynthesis, storage or secretion, no changes in the expression of genes involved in cholesterol synthesis were found. These findings point to selective activation of the fatty acid synthesis pathway and suggest a shift in the balance of lipogenic gene expression in a subgroup of prostate cancers. Int. J. Cancer 88:176–179, 2000.

Neoadjuvant Hormonal Therapy Before Radical Prostatectomy Decreases the Number of Positive Surgical Margins in Stage T2 Prostate Cancer: Interim Results of a Prospective Randomized Trial

PURPOSE We investigated the effect of neoadjuvant treatment before radical prostatectomy for clinically localized prostate cancer. MATERIALS AND METHODS A total of 130 patients with stages T2b and T3 prostate cancer was randomized in a multicenter study: 62 underwent immediate radical prostatectomy and 65 received 560 mg. estramustine phosphate daily for 6 weeks preoperatively. RESULTS For clinical stage T2b tumors the neoadjuvant treatment resulted in a significant decrease in positive surgical margins compared to the nonpretreated group. This difference was not found for clinical stage T3 tumors. The impact on progression and survival still must be analyzed. CONCLUSIONS Neoadjuvant treatment can be beneficial for clinical stage T2 prostate cancer. Optimal treatment for stage T3 tumors remains controversial.

Mapping of Pelvic Lymph Node Metastases in Prostate Cancer

BACKGROUND Opinions about the optimal lymph node dissection (LND) template in prostate cancer differ. Drainage and dissemination patterns are not necessarily identical. OBJECTIVE To present a precise overview of the lymphatic drainage pattern and to correlate those findings with dissemination patterns. We also investigated the relationship between the number of positive lymph nodes (LN+) and resected lymph nodes (LNs) per region. DESIGN, SETTING, AND PARTICIPANTS Seventy-four patients with localized prostate adenocarcinoma were prospectively enrolled. Patients did not show suspect LNs on computed tomography scan and had an LN involvement risk of ≥ 10% but ≤ 35% (Partin tables) or a cT3 tumor. INTERVENTION After intraprostatic technetium-99m nanocolloid injection, patients underwent planar scintigraphy and single-photon emission computed tomography imaging. Then surgery was performed, starting with a sentinel node (SN) procedure and a superextended lymphadenectomy followed by radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Distribution of scintigraphically detected SNs and removed SNs per region were registered. The number of LN+, as well as the percentage LN+ of the total number of removed LNs per region, was demonstrated in combining data of all patients. The impact of the extent of LND on N-staging and on the number of LN+ removed was calculated. RESULTS AND LIMITATIONS A total of 470 SNs were scintigraphically detected (median: 6; interquartile range [IQR]: 3-9), of which 371 SNs were removed (median: 4; IQR: 2.25-6). In total, 91 LN+ (median: 2; IQR: 1-3) were found in 34 of 74 patients. The predominant site for LN+ was the internal iliac region. An extended LND (eLND) would have correctly staged 32 of 34 patients but would have adequately removed all LN+ in only 26 of 34 patients. When adding the presacral region, these numbers increased to 33 of 34 and 30 of 34 patients, respectively. CONCLUSIONS Standard eLND would have correctly staged the majority of LN+ patients, but 13% of the LN+ would have been missed. Adding the presacral LNs to the template should be considered to obtain a minimal template with maximal gain. NOTE: This manuscript was invited based on the 2011 European Association of Urology meeting in Vienna.

MICROSCOPIC VASCULAR INVASION IS THE MOST RELEVANT PROGNOSTICATOR AFTER RADICAL NEPHRECTOMY FOR CLINICALLY NONMETASTATIC RENAL CELL CARCINOMA

PURPOSE Although many factors have been considered to predict the outcome after radical nephrectomy, renal cell carcinoma continues to behave unpredictably. In a retrospective study the correlation between microvascular tumor invasion and disease-free survival after surgery for renal cell carcinoma was analyzed. MATERIALS AND METHODS Between 1980 and 1993, 180 patients (mean age 60 years) were followed for a mean of 52 months after radical or partial nephrectomy for clinically localized renal cell carcinoma. The relevance of microscopic vascular invasion was compared to classical tumor staging, grade and tumor diameter. RESULTS Microscopic vascular invasion was found in 51 patients (28.3%), including 20 (39.2%) with progression (mean interval to progression 72 months). Of 129 patients with no pathological evidence of microscopic vascular invasion only 8 (6.2%) showed progression at a mean interval of more than 160 months. The difference in disease-free survival as a function of microvascular invasion was statistically highly significant (log rank p < 0.00001) and on multivariate analysis this parameter was by far the most relevant predictor of progression. CONCLUSIONS In patients who underwent radical nephrectomy for clinically nonmetastatic renal cell carcinoma with microvascular invasion but without lymph node involvement or macroscopic vascular invasion the chance of disease progression is estimated at 45% within 1 year. Microvascular invasion is the single most relevant prognosticator after presumed curative radical nephrectomy for renal cell carcinoma.

Early Salvage Radiation Therapy Does Not Compromise Cancer Control in Patients with pT3N0 Prostate Cancer After Radical Prostatectomy: Results of a Match-controlled Multi-institutional Analysis

BACKGROUND Previous randomised trials demonstrated that adjuvant radiation therapy (aRT) improves cancer control in patients with pT3 prostate cancer (PCa). However, there is currently no evidence supporting early salvage radiation therapy (eSRT) as equivalent to aRT in improving freedom from biochemical recurrence (BCR) after radical prostatectomy (RP). OBJECTIVE To evaluate BCR-free survival for aRT versus observation followed by eSRT in cases of relapse in patients undergoing RP for pT3pN0, R0-R1 PCa. DESIGN, SETTING, AND PARTICIPANTS Using a European multi-institutional cohort, 890 men with pT3pN0, R0-R1 PCa were identified. INTERVENTION All patients underwent RP. Subsequently, patients were stratified into two groups: aRT versus initial observation followed by eSRT in cases of relapse. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Propensity-matched analysis was employed, and patients were stratified into two groups: aRT versus observation and eventual eSRT, defined as RT given at a postoperative serum prostate-specific antigen (PSA) ≤ 0.5 ng/ml at least 6 mo after RP. BCR, defined as PSA >0.20 ng/ml and rising after administration of RT, was compared between aRT and initial observation followed by eSRT in cases of relapse using Kaplan-Meier and Cox regression methods. RESULTS AND LIMITATIONS Overall, 390 (43.8%) and 500 (56.2%) patients were treated with aRT and initial observation, respectively. Within the latter group, 225 (45.0%) patients experienced BCR and underwent eSRT. In the postpropensity-matched cohort, the 2- and 5-yr BCR-free survival rates were 91.4% and 78.4% in aRT versus 92.8% and 81.8% in patients who underwent initial observation and eSRT in cases of relapse, respectively (p=0.9). No differences in the 2- and 5-yr BCR-free survival rates were found, even when patients were stratified according to pT3 substage and surgical margin status (all p ≥ 0.4). These findings were also confirmed in multivariable analyses (p=0.6). Similar results were achieved when the cut-off to define eSRT was set at 0.3 ng/ml (all p ≥ 0.5). CONCLUSIONS The current study suggests that timely administration of eSRT is comparable to aRT in improving BCR-free survival in the majority of pT3pN0 PCa patients. Therefore, eSRT may not compromise cancer control but significantly reduces overtreatment associated with aRT.

High-level expression of fatty acid synthase in human prostate cancer tissues is linked to activation and nuclear localization of Akt/PKB.

Many human epithelial cancers, particularly those with a poor prognosis, express high levels of fatty acid synthase (FAS), a key metabolic enzyme linked to the synthesis of membrane phospholipids in cancer cells. In view of the recent finding that in the human prostate cancer cell line LNCaP, overexpression of FAS can be largely attributed to constitutive activation of the phosphatidylinositol‐3 (PI3) kinase/Akt kinase pathway, the activation status of the Akt pathway, and whether this activation coincides with increased FAS expression, was examined in clinical prostate cancer tissues. Using well‐preserved frozen prostatic needle biopsies and a sensitive Envision detection technique, S473‐phosphorylated Akt (pAkt) was found in 11/23 low‐grade prostatic intraepithelial neoplasia (PIN) lesions, in all (36/36) high‐grade PINs, and in all (86/86) invasive carcinomas. Non‐neoplastic tissues were negative. Interestingly, in low‐grade PINs and low‐grade carcinomas, pAkt was mainly cytoplasmic or membrane‐bound and was associated with moderate elevation of FAS expression. In 24/36 high‐grade PINs and 82/88 invasive carcinomas, pAkt was found at least partly in the nucleus. Greater nuclear pAkt staining, and higher FAS expression, correlated with a higher Gleason score. In the light of previous findings that pAkt plays a causative role in the overexpression of FAS in cancer cells in culture, these data strongly suggest that high‐level expression of FAS in prostate cancer tissues is linked to phosphorylation and nuclear accumulation of Akt. Copyright

Is a 1-cm margin necessary during nephron-sparing surgery for renal cell carcinoma?

OBJECTIVES To determine whether a 1-cm margin is necessary for cancer control during nephron-sparing surgery (NSS) for renal cell carcinoma (RCC). METHODS A retrospective review of 67 patients who underwent NSS for RCC between 1990 and 2000 was conducted. The data collected included patient demographics, tumor size and location, histologic type and grade, margin status (positive or negative), and the shortest distance of normal parenchyma (in millimeters) around the tumor in the final pathologic specimen. Recurrence was determined from the clinical follow-up, which included physical examination, ultrasonography or computed tomography, and various laboratory tests. RESULTS Fifty-five cases were performed open and 12 laparoscopically. The mean follow-up was 60 months (range 5 to 124). The mean tumor size was 3.0 cm (range 0.9 to 11.0). Seven patients were found to have a positive margin; 1 died of metastatic RCC, 1 was alive with systemic recurrence, and 5 had no evidence of disease. Of 11 patients with a negative margin distance of less than 1 mm, 9 were recurrence free, 1 had simultaneous local and pulmonary relapse, and the other had pulmonary recurrence only. The remainder of the study patients (n = 49) had negative margins greater than 1 mm, and all were alive without evidence of disease at the last follow-up. CONCLUSIONS This review questions the necessity of a 1-cm margin to prevent recurrence after NSS for RCC. Additional studies to determine the optimal margin distance should be conducted.