今日の臨床サポート

前立腺癌

著者: 井手久満 獨協医科大学埼玉医療センター 泌尿器科

監修: 堀江重郎 順天堂大学大学院医学研究科 泌尿器外科学

著者校正済:2022/04/27
現在監修レビュー中
参考ガイドライン:
  1. 日本泌尿器科学会:前立腺癌診療ガイドライン 2016年版
  1. 日本泌尿器科学会:前立腺がん検診ガイドライン 2018年版
患者向け説明資料

概要・推奨   

  1. 前立腺癌罹患数は増加しているが、前立腺癌死亡数は2013年以降わずかに低下している。
  1. 前立腺癌の危険因子として肥満や喫煙、家族歴がある。
  1. 前立腺癌の治療では病期診断やリスク評価がその後の治療法選択や予後予測に大きな影響を与える。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
井手久満 : 特に申告事項無し[2022年]
監修:堀江重郎 : 特許使用料(アステラス製薬,大塚製薬,日本新薬,セティ,アストラゼネカ,杏林製薬,小野薬品,ファイザー),原稿料(キッセイ薬品工業,小野薬品工業,サノフィ,武田薬品工業,中外製薬,アステラス,旭化成ファーマ,ファイザー,日本新薬)[2022年]

改訂のポイント:
  1. 定期レビューを⾏い、診断、治療等、全般的に加筆修正を⾏った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 前立腺癌は、前立腺辺縁領域より発生することが多く、病理組織学的には腺癌がほとんどである。前立腺特異抗原(prostate specific antigen、PSA)検査は、前立腺癌の早期診断に有用であり、また、術後再発、再燃の評価や治療後の経過観察に用いられる。
  1. 前立腺癌は典型的な高齢者の癌であり、年齢別罹患率および死亡率は年齢に伴って増加する。
  1. PSAの正常域は、一般的に4.0ng/mL以下とされているが、それ以下でも約20%程度の前立腺癌が存在しており、60歳以下ではPSAのカットオフ値を2.5ng/mLまで下げることが推奨されている。
  1. PSA検査による前立腺癌検診で発見される癌では進行癌,転移癌の割合が低い。
 
前立腺癌の多発骨転移

前立腺癌では多発骨転移を生じることが多い。椎体、骨盤、肋骨と広範囲に骨転移がみられる。

出典

img1:  著者提供
 
 
 
前立腺癌の多発骨転移

前立腺癌の骨転移の評価には骨シンチグラフィが有用である。

出典

img1:  著者提供
 
 
 
  1. 前立腺癌の骨転移は単純X線写真にて、骨硬化像を示すことが多い。
問診・診察のポイント  
  1. 前立腺癌の家族歴は罹患リスクを2.4~5.6倍に高める。そのため、家族歴の聴取は重要である。

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文献 

G D Steinberg, B S Carter, T H Beaty, B Childs, P C Walsh
Family history and the risk of prostate cancer.
Prostate. 1990;17(4):337-47.
Abstract/Text A case-control study was performed to estimate the relative risk of developing prostate cancer for men with a positive family history. Extensive cancer pedigrees were obtained on 691 men with prostate cancer and 640 spouse controls. Fifteen percent of the cases but only 8% of the controls had a father or brother affected with prostate cancer (P less than .001). Men with a father or brother affected were twice as likely to develop prostate cancer as men with no relatives affected. In addition, there was a trend of increasing risk with increasing number of affected family members such that men with two or three first degree relatives affected had a five and 11-fold increased risk of developing prostate cancer. Recognizing that 9-10% of U.S. men will develop prostate cancer in their lifetime, men with a family history of prostate cancer should be advised of their significantly increased prostate cancer risk and should undergo appropriate screening measures for this disease.

PMID 2251225
E Giovannucci, E B Rimm, G A Colditz, M J Stampfer, A Ascherio, C G Chute, C C Chute, W C Willett
A prospective study of dietary fat and risk of prostate cancer.
J Natl Cancer Inst. 1993 Oct 6;85(19):1571-9.
Abstract/Text BACKGROUND: The strong correlation between national consumption of fat and national rate of mortality from prostate cancer has raised the hypothesis that dietary fat increases the risk of this malignancy. Case-control and cohort studies have not consistently supported this hypothesis.
PURPOSE: We examined prospectively the relationship between prostate cancer and dietary fat, including specific fatty acids and dietary sources of fat. We examined the relationship of fat consumption to the incidence of advanced prostate cancer (stages C, D, or fatal cases) and to the total incidence of prostate cancer.
METHODS: We used data from the Health Professionals Follow-up Study, which is a prospective cohort of 51529 U.S. men, aged 40 through 75, who completed a validated food-frequency questionnaire in 1986. We sent follow-up questionnaires to the entire cohort in 1988 and 1990 to document new cases of a variety of diseases and to update exposure information. As of January 31, 1990, 300 new cases of prostate cancer, including 126 advanced cases, were documented in 47855 participants initially free of diagnosed cancer. The Mantel-Haenszel summary estimator was used to adjust for age and other potentially confounding variables. Multiple logistic regression was used to estimate relative risks (RRs) when controlling simultaneously for more than two covariates.
RESULTS: Total fat consumption was directly related to risk of advanced prostate cancer (age- and energy-adjusted RR = 1.79, with 95% confidence interval [CI] = 1.04-3.07, for high versus low quintile of intake; P [trend] = .06). This association was due primarily to animal fat (RR = 1.63; 95% CI = 0.95-2.78; P [trend] = .08), but not vegetable fat. Red meat represented the food group with the strongest positive association with advanced cancer (RR = 2.64; 95% CI = 1.21-5.77; P = .02). Fat from dairy products (with the exception of butter) or fish was unrelated to risk. Saturated fat, monounsaturated fat, and alpha-linolenic acid, but not linoleic acid, were associated with advanced prostate cancer risk; only the association with alpha-linolenic acid persisted when saturated fat, monounsaturated fat, linoleic acid, and alpha-linolenic acid were modeled simultaneously (multivariate RR = 3.43; 95% CI = 1.67-7.04; P [trend] = .002).
CONCLUSION: The results support the hypothesis that animal fat, especially fat from red meat, is associated with an elevated risk of advanced prostate cancer.
IMPLICATIONS: These findings support recommendations to lower intake of meat to reduce the risk of prostate cancer. The potential roles of carcinogens formed in cooking animal fat and of alpha-linolenic acid in the progression of prostate cancer need to be explored.

PMID 8105097
Stacey A Kenfield, Meir J Stampfer, June M Chan, Edward Giovannucci
Smoking and prostate cancer survival and recurrence.
JAMA. 2011 Jun 22;305(24):2548-55. doi: 10.1001/jama.2011.879.
Abstract/Text CONTEXT: Studies of smoking in relation to prostate cancer mortality or recurrence in prostate cancer patients are limited, with few prostate cancer-specific outcomes.
OBJECTIVE: To assess the relation of cigarette smoking and smoking cessation with overall, prostate cancer-specific, and cardiovascular disease (CVD) mortality and biochemical recurrence among men with prostate cancer.
DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study of 5366 men diagnosed with prostate cancer between 1986 and 2006 in the Health Professionals Follow-Up Study.
MAIN OUTCOME MEASURES: Hazard ratios (HRs) for overall, prostate cancer-specific, and CVD mortality, and biochemical recurrence, defined by an increase in prostate-specific antigen (PSA) levels.
RESULTS: There were 1630 deaths, 524 (32%) due to prostate cancer and 416 (26%) to CVD, and 878 biochemical recurrences. Absolute crude rates for prostate cancer-specific death for never vs current smokers were 9.6 vs 15.3 per 1000 person-years; for all-cause mortality, the corresponding rates were 27.3 and 53.0 per 1000 person-years. In multivariable analysis, current vs never smokers had an increased risk of prostate cancer mortality (HR, 1.61; 95% confidence interval [CI], 1.11-2.32), as did current smokers with clinical stage T1 through T3 (HR, 1.80; 95% CI, 1.04-3.12). Current smokers also had increased risk of biochemical recurrence (HR, 1.61; 95% CI, 1.16-2.22), total mortality (HR, 2.28; 95% CI, 1.87-2.80), and CVD mortality (HR, 2.13; 95% CI, 1.39-3.26). After adjusting for clinical stage and grade (likely intermediates of the relation of smoking with prostate cancer recurrence and survival), current smokers had increased risk of prostate cancer mortality (HR, 1.38; 95% CI, 0.94-2.03), as did current smokers with clinical stage T1 through T3 (HR, 1.41; 95% CI, 0.80-2.49); they also had an increased risk of biochemical recurrence (HR, 1.47; 95% CI, 1.06-2.04). Greater number of pack-years was associated with significantly increased risk of prostate cancer mortality but not biochemical recurrence. Current smokers of 40 or more pack-years vs never smokers had increased prostate cancer mortality (HR, 1.82; 95% CI, 1.03-3.20) and biochemical recurrence (HR, 1.48; 95% CI, 0.88-2.48). Compared with current smokers, those who had quit smoking for 10 or more years (HR, 0.60; 95% CI, 0.42-0.87) or who have quit for less than 10 years but smoked less than 20 pack-years (HR, 0.64; 95% CI, 0.28-1.45) had prostate cancer mortality risks similar to never smokers (HR, 0.61; 95% CI, 0.42-0.88).
CONCLUSIONS: Smoking at the time of prostate cancer diagnosis is associated with increased overall and CVD mortality and prostate cancer-specific mortality and recurrence. Men who have quit for at least 10 years have prostate cancer-specific mortality risks similar to those who have never smoked.

PMID 21693743
Tin C Ngo, J Joy Lee, James D Brooks, Rosie Nolley, Michelle Ferrari, Joseph C Presti
Smoking and adverse outcomes at radical prostatectomy.
Urol Oncol. 2013 Aug;31(6):749-54. doi: 10.1016/j.urolonc.2011.06.013. Epub 2011 Aug 6.
Abstract/Text BACKGROUND: Multiple large epidemiologic studies have examined the relationship between smoking and prostate cancer incidence and mortality only to arrive at contradictory results. In this series, we studied the effect of smoking on pathologic outcomes and biochemical recurrence in a cohort of men undergoing radical prostatectomy.
METHODS: We identified 630 men who underwent radical prostatectomy between 1989 and 2005 who had detailed smoking histories. There were 321 smokers and 309 nonsmokers. Pathologic outcomes included prostate weight, volume of cancer, volume of high grade cancer, margin status, seminal vesicle involvement, extraprostatic extension, perineural invasion, angiolymphatic invasion, and the presence of nodal metastasis. Biochemical recurrence was defined as a postoperative PSA ≥ 0.1 ng/ml. Univariate analysis and multivariate linear and Cox regression were used to study the impact of smoking on these outcomes.
RESULTS: The volume of cancer (2.54 vs. 2.16 ml, P = 0.016) and the volume of high grade cancer (0.58 vs. 0.28 ml, P = 0.004) were greater in smokers compared with nonsmokers. Smoking independently predicted greater volumes of cancer and high grade cancer in multivariate analysis. Heavy smokers (≥20 pack-year history) had a greater risk of biochemical recurrence on univariate survival analysis. Smoking also predicted a greater risk of biochemical recurrence on Cox regression, the magnitude of which was approximately 1% per pack-year smoked.
CONCLUSIONS: Smoking is associated with adverse pathologic features and a higher risk of biochemical recurrence in men undergoing radical prostatectomy. If confirmed by additional studies, smoking history may need to be included into risk assessment models.

Copyright © 2013 Elsevier Inc. All rights reserved.
PMID 21824793
Kosuke Kitamura, Satoru Muto, Isao Yokota, Kazutane Hoshimoto, Tatsuro Kaminaga, Takahiro Noguchi, Syou-Ichiro Sugiura, Hisamitsu Ide, Raizo Yamaguchi, Shigeru Furui, Shigeo Horie
Feasibility of multiparametric prostate magnetic resonance imaging in the detection of cancer distribution: histopathological correlation with prostatectomy specimens.
Prostate Int. 2014 Dec;2(4):188-95. doi: 10.12954/PI.14067. Epub 2014 Dec 30.
Abstract/Text PURPOSE: To prevent overtreatment, it is very important to diagnose the precise distribution and characteristics of all cancer lesions, including small daughter tumors. The purpose of this study was to evaluate the efficacy of T2-weighted magnetic resonance imaging (T2W), diffusion-weighted magnetic resonance imaging (DWI), magnetic resonance spectroscopy ((1)H-MRS), and prostate biopsy (PBx) in the detection of intraprostatic cancer distribution.
METHODS: All patients underwent T2W, DWI, (1)H-MRS, and PBx followed by radical prostatectomy (RP). Individual prostates were divided into 12 segmental regions, each of which was examined for the presence or absence of malignancy on the basis of T2W, DWI, (1)H-MRS, and PBx, respectively. These results were compared with the histopathological findings for RP specimens.
RESULTS: We included 54 consecutive patients with biopsy-proven prostate cancer (mean age, 62.7 years; median prostate-specific antigen level, 5.7 ng/mL) in this study. We could detect cancer in 247 of 540 evaluable lesions. The area under the receiver operator characteristic curve analysis yielded a higher value for DWI (0.68) than for T2W (0.65), (1)H-MRS (0.54), or PBx (0.56). In 180 cancerous regions of RP specimens with false-negative PBx results, T2W+DWI had the highest positive rate (53.3%) compared with that of each sequence alone, including T2W (45.6%), DWI (41.1%), and (1)H-MRS (30.0%).
CONCLUSIONS: Multiparametric magnetic resonance imaging (T2W, (1)H-MRS, DWI) enables the detection of prostate cancer distribution with reasonable sensitivity and specificity. T2W+DWI was particularly effective in detecting cancer distribution with false-negative PBx results.

PMID 25599075
Leonardo Kayat Bittencourt, Daniel Hausmann, Natalia Sabaneeff, Emerson Leandro Gasparetto, Jelle O Barentsz
Multiparametric magnetic resonance imaging of the prostate: current concepts.
Radiol Bras. 2014 Sep-Oct;47(5):292-300. doi: 10.1590/0100-3984.2013.1863.
Abstract/Text Multiparametric MR (mpMR) imaging is rapidly evolving into the mainstay in prostate cancer (PCa) imaging. Generally, the examination consists of T2-weighted sequences, diffusion-weighted imaging (DWI), dynamic contrast-enhanced (DCE) evaluation, and less often proton MR spectroscopy imaging (MRSI). Those functional techniques are related to biological properties of the tumor, so that DWI correlates to cellularity and Gleason scores, DCE correlates to angiogenesis, and MRSI correlates to cell membrane turnover. The combined use of those techniques enhances the diagnostic confidence and allows for better characterization of PCa. The present article reviews and illustrates the technical aspects and clinical applications of each component of mpMR imaging, in a practical approach from the urological standpoint.

PMID 25741104
J E McNeal, E A Redwine, F S Freiha, T A Stamey
Zonal distribution of prostatic adenocarcinoma. Correlation with histologic pattern and direction of spread.
Am J Surg Pathol. 1988 Dec;12(12):897-906.
Abstract/Text For 104 prostate glands obtained at radical prostatectomy for adenocarcinoma, we mapped the tumor outline and determined the tumor volume, grade, and location relative to the transition zone boundary and location of the central zone. Among the 88 cancers whose probable zone of origin could be identified, 68% arose in the peripheral zone, 24% arose in the transition zone, and 8% arose in the central zone. Transition zone carcinomas had usually been diagnosed by transurethral resection (TUR) and often appeared to arise within BPH nodules; only two of 67 non-transition zone carcinomas had been diagnosed at TUR. Two-thirds of 21 transition zone cancers showed a distinctive histologic appearance; they were made up of columnar clear cells lining glands of widely variable size and contour. The transition zone boundary appeared to act as a barrier to the spread of non-transition zone carcinomas. We conclude that carcinoma typically arises in the region of the prostate that is susceptible to benign prostatic hyperplasia and that the great majority of Stage A (TUR) cancers are transition zone cancers. Non-transition zone cancers detectable at TUR are predominantly large tumors that are poorly differentiated and lack the clear cell histologic pattern.

PMID 3202246
Jonathan I Epstein, William C Allsbrook, Mahul B Amin, Lars L Egevad, ISUP Grading Committee
The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma.
Am J Surg Pathol. 2005 Sep;29(9):1228-42.
Abstract/Text
PMID 16096414
D W Keetch, W J Catalona, D S Smith
Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values.
J Urol. 1994 Jun;151(6):1571-4.
Abstract/Text The objective of this study was to determine the need for repeat prostatic biopsies in men whose initial biopsy results revealed no evidence of cancer or atypia. We evaluated 1,136 men who underwent 1 or more prostatic biopsies in a longitudinal prostate specific antigen (PSA) based prostate cancer screening study that called for biopsy if the serum PSA level was greater than 4.0 ng./ml. (Hybritech assay) and findings on rectal examination or ultrasonography were abnormal or suspicious for cancer. Of the 1,136 men who underwent prostatic biopsy 391 (34%) had prostate cancer on the initial biopsy. Of 427 men who had negative initial biopsy results, a persistent serum PSA level of greater than 4.0 ng./ml. and abnormal rectal or ultrasound examination findings 82 (19%) had cancer on biopsy 2. Of 203 men with persistent abnormalities 16 (8%) had cancer on biopsy 3 and 6 of 91 (7%) had cancer on biopsy 4 or later. Thus, 96% of the cancers were detected through either biopsy 1 or 2. The median initial PSA level, followup PSA levels and the yearly rate of change in PSA were significantly greater in men whose cancer was detected compared with those of men whose cancer was not detected (6.4 versus 5.4 ng./ml., 7.4 versus 6.6 ng./ml. and 1.1 versus 0.7 ng./ml. per year, respectively). There was a trend for a higher percentage of tumors detected through serial screening to be pathologically organ confined with those detected through initial screening (73% versus 62%, p = 0.07). We conclude that men with a persistently elevated serum PSA value after an initial negative prostatic biopsy should routinely undergo at least 1 repeat biopsy to exclude adequately the presence of detectable prostate cancer.

PMID 7514690
Roger Chou, Jennifer M Croswell, Tracy Dana, Christina Bougatsos, Ian Blazina, Rongwei Fu, Ken Gleitsmann, Helen C Koenig, Clarence Lam, Ashley Maltz, J Bruin Rugge, Kenneth Lin
Screening for prostate cancer: a review of the evidence for the U.S. Preventive Services Task Force.
Ann Intern Med. 2011 Dec 6;155(11):762-71. doi: 10.7326/0003-4819-155-11-201112060-00375. Epub 2011 Oct 7.
Abstract/Text BACKGROUND: Screening can detect prostate cancer at earlier, asymptomatic stages, when treatments might be more effective.
PURPOSE: To update the 2002 and 2008 U.S. Preventive Services Task Force evidence reviews on screening and treatments for prostate cancer.
DATA SOURCES: MEDLINE (2002 to July 2011) and the Cochrane Library Database (through second quarter of 2011).
STUDY SELECTION: Randomized trials of prostate-specific antigen-based screening, randomized trials and cohort studies of prostatectomy or radiation therapy versus watchful waiting, and large observational studies of perioperative harms.
DATA EXTRACTION: Investigators abstracted and checked study details and quality using predefined criteria.
DATA SYNTHESIS: Of 5 screening trials, the 2 largest and highest-quality studies reported conflicting results. One found that screening was associated with reduced prostate cancer-specific mortality compared with no screening in a subgroup of men aged 55 to 69 years after 9 years (relative risk, 0.80 [95% CI, 0.65 to 0.98]; absolute risk reduction, 0.07 percentage point). The other found no statistically significant effect after 10 years (relative risk, 1.1 [CI, 0.80 to 1.5]). After 3 or 4 screening rounds, 12% to 13% of screened men had false-positive results. Serious infections or urine retention occurred after 0.5% to 1.0% of prostate biopsies. There were 3 randomized trials and 23 cohort studies of treatments. One good-quality trial found that prostatectomy for localized prostate cancer decreased risk for prostate cancer-specific mortality compared with watchful waiting through 13 years of follow-up (relative risk, 0.62 [CI, 0.44 to 0.87]; absolute risk reduction, 6.1%). Benefits seemed to be limited to men younger than 65 years. Treating approximately 3 men with prostatectomy or 7 men with radiation therapy instead of watchful waiting would each result in 1 additional case of erectile dysfunction. Treating approximately 5 men with prostatectomy would result in 1 additional case of urinary incontinence. Prostatectomy was associated with perioperative death (about 0.5%) and cardiovascular events (0.6% to 3%), and radiation therapy was associated with bowel dysfunction.
LIMITATIONS: Only English-language articles were included. Few studies evaluated newer therapies.
CONCLUSION: Prostate-specific antigen-based screening results in small or no reduction in prostate cancer-specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary.
PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

PMID 21984740
Guohua Shen, Houfu Deng, Shuang Hu, Zhiyun Jia
Comparison of choline-PET/CT, MRI, SPECT, and bone scintigraphy in the diagnosis of bone metastases in patients with prostate cancer: a meta-analysis.
Skeletal Radiol. 2014 Nov;43(11):1503-13. doi: 10.1007/s00256-014-1903-9. Epub 2014 May 20.
Abstract/Text Published data on the diagnosis of bone metastases of prostate cancer are conflicting and heterogeneous. We performed a comprehensive meta-analysis to compare the diagnostic performance of choline-PET/CT, MRI, bone SPECT, and bone scintigraphy (BS) in detecting bone metastases in parents with prostate cancer. Pooled sensitivity, specificity, and diagnostic odds ratios (DOR) were calculated both on a per-patient basis and on a per-lesion basis. Summary receiver operating characteristic (SROC) curves were also drawn to obtain the area under curve (AUC) and Q* value. Sixteen articles consisting of 27 studies were included in the analysis. On a per-patient basis, the pooled sensitivities by using choline PET/CT, MRI, and BS were 0.91 [95% confidence interval (CI): 0.83-0.96], 0.97 (95% CI: 0.91-0.99), 0.79 (95% CI: 0.73-0.83), respectively. The pooled specificities for detection of bone metastases using choline PET/CT, MRI, and BS, were 0.99 (95% CI: 0.93-1.00), 0.95 (95% CI: 0.90-0.97), and 0.82 (95% CI: 0.78-0.85), respectively. On a per-lesion basis, the pooled sensitivities of choline PET/CT, bone SPECT, and BS were 0.84 (95% CI: 0.81-0.87), 0.90 (95% CI: 0.86-0.93), 0.59 (95% CI: 0.55-0.63), respectively. The pooled specificities were 0.93 (95% CI: 0.89-0.96) for choline PET/CT, 0.85 (95% CI: 0.80-0.90) for bone SPECT, and 0.75 (95% CI: 0.71-0.79) for BS. This meta-analysis indicated that MRI was better than choline PET/CT and BS on a per-patient basis. On a per-lesion analysis, choline PET/CT with the highest DOR and Q* was better than bone SPECT and BS for detecting bone metastases from prostate cancer.

PMID 24841276
Alberto Briganti, Niccolò Passoni, Matteo Ferrari, Umberto Capitanio, Nazareno Suardi, Andrea Gallina, Luigi Filippo Da Pozzo, Maria Picchio, Valerio Di Girolamo, Andrea Salonia, Liugi Gianolli, Cristina Messa, Patrizio Rigatti, Francesco Montorsi
When to perform bone scan in patients with newly diagnosed prostate cancer: external validation of the currently available guidelines and proposal of a novel risk stratification tool.
Eur Urol. 2010 Apr;57(4):551-8. doi: 10.1016/j.eururo.2009.12.023. Epub 2009 Dec 18.
Abstract/Text BACKGROUND: Several guidelines have indicated that in patients with well-differentiated or moderately well-differentiated prostate cancer (PCa), a staging bone scan may be omitted. However, the guidelines recommendations have not yet been externally validated.
OBJECTIVE: The aim of the study was to externally validate the available guidelines regarding the need for a staging bone scan in patients with newly diagnosed PCa. Moreover, we developed a novel risk stratification tool aimed at improving the accuracy of these guidelines.
DESIGN, SETTING, AND PARTICIPANTS: The study included 853 consecutive patients diagnosed with PCa between January 2003 and June 2008 at a single centre. All patients underwent bone scan using technetium Tc 99m methylene diphosphonate at diagnosis.
MEASUREMENTS: The area under the curve (AUC) of the criteria suggested by the guidelines (European Association of Urology, American Urological Association, National Comprehensive Cancer Network, and American Joint Committee on Cancer) to perform a baseline bone scan was assessed and compared with the accuracy of a classification and regression tree (CART) including prostate-specific antigen (PSA), clinical stage, and biopsy Gleason sum as covariates.
RESULTS AND LIMITATIONS: The AUC of the guidelines ranged between 79.7% and 82.6%. However, the novel CART model, which stratified patients into low risk (biopsy Gleason ≤7, cT1-T3, and PSA <10 ng/ml), intermediate risk (biopsy Gleason ≤7, cT2/T3, and PSA >10 ng/ml), and high risk (biopsy Gleason >7) was significantly more accurate (AUC: 88.0%) than all the guidelines (all p≤0.002). The limitation of this study resides in its retrospective design. Moreover, the proposed risk stratification tool can be considered only for patients who are candidates for radical prostatectomy until validated in other clinical settings.
CONCLUSIONS: This is the first study aimed at externally validating the available guidelines addressing the need for staging baseline bone scans in PCa patients. All guidelines showed high accuracy. However, their accuracy was significantly lower compared with the accuracy of the novel risk stratification tool. According to this tool, staging bone scans might be considered only for patients with a biopsy Gleason score >7 or with a PSA >10 ng/ml and palpable disease (cT2/T3) prior to treatment. However, before recommending its use in clinical practice, our model needs to be externally validated.

Copyright © 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.
PMID 20034730
Roland Palvolgyi, Timothy J Daskivich, Karim Chamie, Lorna Kwan, Mark S Litwin
Bone scan overuse in staging of prostate cancer: an analysis of a Veterans Affairs cohort.
Urology. 2011 Jun;77(6):1330-6. doi: 10.1016/j.urology.2010.12.083. Epub 2011 Apr 13.
Abstract/Text OBJECTIVES: To determine the use and subsequent yield of bone scan imaging in a contemporary Veterans Affairs (VA) cohort of men with prostate cancer. With contemporary widespread prostate-specific antigen (PSA) screening, more patients are being diagnosed with low- and intermediate-risk prostate cancer, reducing the need and yield of bone scan imaging.
METHODS: We retrospectively reviewed the charts of 1598 men diagnosed with prostate cancer from 1998 to 2004 at the Greater Los Angeles and Long Beach VA Medical Centers. We used univariate and multivariate analyses to measure the association between patient (age, race, and comorbidities) and tumor (PSA, clinical stage, Gleason grade) characteristics with bone scan use and subsequent positivity. We conducted the analysis for scans for the entire cohort and those with low and high risk of metastatic disease.
RESULTS: Of 519 men with low-risk disease, 132 (25%) underwent bone scan imaging, none with positive findings. On multivariate analysis for the entire cohort, younger age, Long Beach VA site, increasing PSA level (≥10 ng/mL), clinical stage (cT2 or greater), and Gleason score (≥7) were all positively associated with bone scan use; however, only PSA level ≥20 ng/mL, clinical stage cT3 or greater, and Gleason score ≥4 + 3 corresponded with positivity. A bone scan positivity rate of ≥10% was limited to men with clinical stage cT3 or greater, Gleason score of ≥8, or PSA level of ≥20 ng/mL.
CONCLUSIONS: Although decreasing in incidence with time, our results demonstrate extensive overuse of bone scan imaging among VA patients with low-risk prostate cancer. These patterns of overuse for men with low-risk cancer, yielding no positive findings, result in unnecessary patient anxiety and significant economic waste for the VA Healthcare System.

Copyright © 2011 Elsevier Inc. All rights reserved.
PMID 21492911
Marcin Popiolek, Jennifer R Rider, Ove Andrén, Sven-Olof Andersson, Lars Holmberg, Hans-Olov Adami, Jan-Erik Johansson
Natural history of early, localized prostate cancer: a final report from three decades of follow-up.
Eur Urol. 2013 Mar;63(3):428-35. doi: 10.1016/j.eururo.2012.10.002. Epub 2012 Oct 13.
Abstract/Text BACKGROUND: Most localized prostate cancers are believed to have an indolent course. Within 15 yr of diagnosis, most deaths among men with prostate cancer (PCa) can be attributed to other competing causes. However, data from studies with extended follow-up are insufficient to determine appropriate treatment for men with localized disease.
OBJECTIVE: To investigate the long-term natural history of untreated, early-stage PCa.
DESIGN, SETTING, AND PARTICIPANTS: We conducted a population-based, prospective-cohort study using a consecutive sample of 223 patients with untreated, localized PCa from a regionally well-defined catchment area in central Sweden. All subjects were initially managed with observation. Androgen deprivation therapy was administered when symptomatic tumor progression occurred.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Based on >30 yr of follow-up, the main outcome measures were: progression-free, cause-specific, and overall survival, and rates of progression and mortality per 1000 person-years.
RESULTS AND LIMITATIONS: After 32 yr of follow-up, all but 3 (1%) of the 223 men had died. We observed 90 (41.4%) local progression events and 41 (18.4%) cases of progression to distant metastasis. In total, 38 (17%) men died of PCa. Cause-specific survival decreased between 15 and 20 yr, but stabilized with further follow-up. All nine men with Gleason grade 8-10 disease died within the first 10 yr of follow-up, five (55%) from PCa. Survival for men with well-differentiated, nonpalpable tumors declined slowly through 20 yr, and more rapidly between 20 and 25 yr (from 75.2% [95% confidence interval, 48.4-89.3] to 25% [95% confidence interval, 22.0-72.5]). It is unclear whether these data are relevant for tumors detected by elevated prostate-specific antigen levels.
CONCLUSIONS: Although localized PCa most often has an indolent course, local progression and distant metastasis can develop over the long term, even among patients considered low risk at diagnosis.

Copyright © 2012. Published by Elsevier B.V.
PMID 23084329
Yasutaka Yamada, Himisha Beltran
The treatment landscape of metastatic prostate cancer.
Cancer Lett. 2021 Oct 28;519:20-29. doi: 10.1016/j.canlet.2021.06.010. Epub 2021 Jun 18.
Abstract/Text The treatment landscape of metastatic prostate cancer has evolved significantly over the past two decades. Several landmark phase 3 trials led to new drug approvals and rapid changes in therapy options for patients, including drugs with distinct mechanisms of action (e.g., hormonal, chemotherapy, radionuclide, immunotherapy, and targeted therapies). Therapies initially developed in later stages of the disease (metastatic castration resistant prostate cancer) have started to move earlier in the prostate cancer continuum, with new standards of care for metastatic hormone naive prostate cancer and non-metastatic castration resistant prostate cancer. Overall, patients are living longer with a better quality of life. However, despite these significant advances, prostate cancer remains a leading cause of cancer death globally. Disease heterogeneity and the emergence of therapy resistance remain significant barriers, and the identification and application of molecular biomarkers to guide the choice and sequencing of systemic agents are still in early stages. Here we discuss the current treatment landscape of metastatic prostate cancer, clinical challenges, and the emerging role of molecular biomarkers for targeting biologic subsets of advanced disease and co-targeting heterogenous resistance patterns.

Copyright © 2021 Elsevier B.V. All rights reserved.
PMID 34153403
Matthew R Cooperberg, Peter R Carroll, Laurence Klotz
Active surveillance for prostate cancer: progress and promise.
J Clin Oncol. 2011 Sep 20;29(27):3669-76. doi: 10.1200/JCO.2011.34.9738. Epub 2011 Aug 8.
Abstract/Text Widespread prostate-specific antigen (PSA) -based screening and aggressive treatment of prostate cancer have reduced mortality rates substantially, but both remain controversial in large part because of high rates of overdiagnosis and overtreatment of otherwise indolent tumors. Active surveillance--or close monitoring of PSA levels combined with periodic imaging and repeat biopsies--is gaining acceptance as an alternative initial management strategy for men with low-risk prostate cancer. In reported series, rates of progression to active treatment with intermediate-term follow-up have ranged from 14% to 41%, and likelihood of subsequent cure with surgery or radiation does not seem to be compromised by an initial trial of surveillance. Two related challenges to broader acceptance of surveillance are better characterization at time of diagnosis of the risk of progression (including likelihood that given tumor may have been undersampled by diagnostic biopsy) and validation of optimal end points once surveillance begins. Both are subjects of intense ongoing investigation, with emerging biomarkers and novel imaging tests expected to facilitate decision making substantially. Recent reports have suggested active surveillance can be a cost-effective approach and preserve quality of life, but these questions must be assessed more definitively in prospective cohorts. Ultimately, by minimizing the harms of overtreating low-risk prostate cancer, active surveillance may help settle the controversy surrounding prostate cancer screening and management.

PMID 21825257
Laurence Klotz, Liying Zhang, Adam Lam, Robert Nam, Alexandre Mamedov, Andrew Loblaw
Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer.
J Clin Oncol. 2010 Jan 1;28(1):126-31. doi: 10.1200/JCO.2009.24.2180. Epub 2009 Nov 16.
Abstract/Text PURPOSE We assessed the outcome of a watchful-waiting protocol with selective delayed intervention by using clinical prostate-specific antigen (PSA), or histologic progression as treatment indications for clinically localized prostate cancer. PATIENTS AND METHODS This was a prospective, single-arm, cohort study. Patients were managed with an initial expectant approach. Definitive intervention was offered to those patients with a PSA doubling time of less than 3 years, Gleason score progression (to 4 + 3 or greater), or unequivocal clinical progression. Survival analysis and Cox proportional hazard model were applied to the data. Results A total of 450 patients have been observed with active surveillance. Median follow-up was 6.8 years (range, 1 to 13 years). Overall survival was 78.6%. The 10-year prostate cancer actuarial survival was 97.2%. Overall, 30% of patients have been reclassified as higher risk and have been offered definitive therapy. Of 117 patients treated radically, the PSA failure rate was 50%, which was 13% of the total cohort. PSA doubling time of 3 years or less was associated with an 8.5-times higher risk of biochemical failure after definitive treatment compared with a doubling time of more than 3 years (P < .0001). The hazard ratio for nonprostate cancer to prostate cancer mortality was 18.6 at 10 years. CONCLUSION We observed a low rate of prostate cancer mortality. Among the patients who were reclassified as higher risk and who were treated, PSA failure was relatively common. Other-cause mortality accounted for almost all of the deaths. Additional studies are warranted to improve the identification of patients who harbor more aggressive disease despite favorable clinical parameters at diagnosis.

PMID 19917860
Roderick C N van den Bergh, Stijn Roemeling, Monique J Roobol, Gunnar Aus, Jonas Hugosson, Antti S Rannikko, Teuvo L Tammela, Chris H Bangma, Fritz H Schröder
Outcomes of men with screen-detected prostate cancer eligible for active surveillance who were managed expectantly.
Eur Urol. 2009 Jan;55(1):1-8. doi: 10.1016/j.eururo.2008.09.007. Epub 2008 Sep 17.
Abstract/Text BACKGROUND: The incidence of small, localised, well-differentiated prostate cancer (PCa) is increasing, mainly as a result of screening. Many of these cancers will not progress, and radical therapy may lead to substantial overtreatment. Active surveillance (AS) has emerged as an alternative.
OBJECTIVE: To retrospectively validate the currently used criteria for eligibility for AS.
DESIGN, SETTING, AND PARTICIPANTS: For this cohort study, data from 616 men who were diagnosed with PCa between 1994 and 2007 at a mean age of 66.3 yr in four centres of the European Randomized Study of Screening for Prostate Cancer (ERSPC) were combined. All patients fit the criteria for AS (prostate-specific antigen [PSA] < or = 10.0 ng/ml, PSA-density < 0.2 ng/ml per ml, stage T1C/T2, Gleason score < or = 3 + 3 = 6, and < or = 2 positive biopsy cores), and initially they were managed expectantly. Median follow-up was 3.91 yr.
MEASUREMENTS: Disease specific-, overall-, and treatment-free survival were studied. Present PSA characteristics were assessed and also compared between men who were switching to deferred active therapy during follow-up and men remaining untreated.
RESULTS AND LIMITATIONS: The calculated (Kaplan-Meier) 10-yr PCa-specific survival (21 patients at risk) was 100%, which sharply contrasted with 77% overall survival. Men still alive showed favourable PSA characteristics. Although the calculated 10-yr treatment-free survival was only 43%, objective signs of progression often did not indicate the shift to radical treatment. The cohort consisted of men on AS and those on watchful waiting (WW); information on comorbidity or psychological distress was not available.
CONCLUSIONS: AS seems justified in selected men with screen-detected PCa. Prospective protocol-based AS programs are necessary to optimise selection criteria and to find the appropriate trigger points for switching to active therapy. Possible negative psychological reactions with AS against improved quality of life by withholding side-effects from radical treatment should be considered.

PMID 18805628
Piyush K Agarwal, Jesse Sammon, Akshay Bhandari, Ali Dabaja, Mireya Diaz, Stacey Dusik-Fenton, Ramgopal Satyanarayana, Andrea Simone, Quoc-Dien Trinh, Brad Baize, Mani Menon
Safety profile of robot-assisted radical prostatectomy: a standardized report of complications in 3317 patients.
Eur Urol. 2011 May;59(5):684-98. doi: 10.1016/j.eururo.2011.01.045. Epub 2011 Feb 5.
Abstract/Text BACKGROUND: Previous studies attempting to assess complications after robot-assisted radical prostatectomy (RARP) are limited by their small numbers, short follow-up, or lack of risk factor analysis.
OBJECTIVE: To document complications after RARP by strict application of standardized reporting criteria.
DESIGN, SETTING, AND PARTICIPANTS: Between January 2005 and December 2009, 3317 consecutive patients underwent RARP at a tertiary referral center. Median follow-up was 24.2 mo (interquartile range: 12.4-36.9).
INTERVENTION: Transperitoneal RARP was performed by one of five surgeons-two experienced, three beginners.
MEASUREMENTS: Complications were captured by exhaustive review of multiple datasets, including our prospective prostate cancer database, claims data, and electronic medical and institutional morbidity and mortality records, and reported according to the Martin-Donat criteria. Complications were stratified by type (medical/surgical), Clavien classification, and timing of onset. Multivariable analysis of factors predictive of complications was performed.
RESULTS AND LIMITATIONS: The median hospitalization time was 1 d. There were 368 complications in 326 patients (9.8%), including a transfusion rate of 2.2%. We detected 79 medical complications in 78 patients (2.4%) and 289 surgical complications in 264 patients (8.0%). There were 242 minor (Clavien 1-2) and 126 major (Clavien 3-5) complications. Two hundred ninety-nine (81.3%) complications occurred within 30 d, 17 (4.6%) within 31-90 d, and 52 (14.1%) after 90 d from surgery. On multivariable analysis, preoperative prostate-specific antigen values and cardiac comorbidity were predictive for medical complications, whereas age, gastroesophageal reflux disease, and biopsy Gleason score were predictive of surgical complications. Limitations of this study include representing results from a single high-volume referral center and not including the learning curve of the two most experienced surgeons.
CONCLUSIONS: RARP is a safe operation, with an overall complication rate of 9.8%. Most complications occurred within 30 d of surgery.

Copyright © 2011. Published by Elsevier B.V.
PMID 21324583
Raanan Tal, Hannah H Alphs, Paul Krebs, Christian J Nelson, John P Mulhall
Erectile function recovery rate after radical prostatectomy: a meta-analysis.
J Sex Med. 2009 Sep;6(9):2538-46. doi: 10.1111/j.1743-6109.2009.01351.x. Epub 2009 Jun 9.
Abstract/Text INTRODUCTION: Erectile function recovery (EFR) rates after radical prostatectomy (RP) vary greatly based on a number of factors, such as erectile dysfunction (ED) definition, data acquisition means, time-point postsurgery, and population studied.
AIM: To conduct a meta-analysis of carefully selected reports from the available literature to define the EFR rate post-RP.
MAIN OUTCOME MEASURES: EFR rate after RP.
METHODS: An EMBASE and MEDLINE search was conducted for the time range 1985-2007. Articles were assessed blindly by strict inclusion criteria: report of EFR data post-RP, study population >or=50 patients, >or=1 year follow-up, nerve-sparing status declared, no presurgery ED, and no other prostate cancer therapy. Meta-analysis was conducted to determine the EFR rate and relative risks (RR) for dichotomous subgroups.
RESULTS: A total of 212 relevant studies were identified; only 22 (10%) met the inclusion criteria and were analyzed (9,965 RPs, EFR data: 4,983 subjects). Mean study population size: 226.5, standard deviation = 384.1 (range: 17-1,834). Overall EFR rate was 58%. Single center series publications (k = 19) reported a higher EFR rate compared with multicenter series publications (k = 3): 60% vs. 33%, RR = 1.82, P = 0.001. Studies reporting >or=18-month follow-up (k = 10) reported higher EFR rate vs. studies with <18-month follow-up (k = 12), 60% vs. 56%, RR = 1.07, P = 0.02. Open RP (k = 16) and laparoscopic RP (k = 4) had similar EFR (57% vs. 58%), while robot-assisted RP resulted in a higher EFR rate (k = 2), 73% compared with these other approaches, P = 0.001. Patients <60 years old had a higher EFR rate vs. patients >or=60 years, 77% vs. 61%, RR = 1.26, P = 0.001.
CONCLUSIONS: These data indicate that most of the published literature does not meet strict criteria for reporting post-RP EFR. Single and multiple surgeon series have comparable EFR rates, but single center studies have a higher EFR. Younger men have higher EFR and no significant difference in EFR between ORP and LRP is evident.

PMID 19515209
Eva Haglind, Stefan Carlsson, Johan Stranne, Anna Wallerstedt, Ulrica Wilderäng, Thordis Thorsteinsdottir, Mikael Lagerkvist, Jan-Erik Damber, Anders Bjartell, Jonas Hugosson, Peter Wiklund, Gunnar Steineck, LAPPRO steering committee
Urinary Incontinence and Erectile Dysfunction After Robotic Versus Open Radical Prostatectomy: A Prospective, Controlled, Nonrandomised Trial.
Eur Urol. 2015 Aug;68(2):216-25. doi: 10.1016/j.eururo.2015.02.029. Epub 2015 Mar 12.
Abstract/Text BACKGROUND: Robot-assisted laparoscopic radical prostatectomy (RALP) has become widely used without high-grade evidence of superiority regarding long-term clinical outcomes compared with open retropubic radical prostatectomy (RRP), the gold standard.
OBJECTIVE: To compare patient-reported urinary incontinence and erectile dysfunction 12 mo after RALP or RRP.
DESIGN, SETTING, AND PARTICIPANTS: This was a prospective, controlled, nonrandomised trial of patients undergoing prostatectomy in 14 centres using RALP or RRP. Clinical-record forms and validated patient questionnaires at baseline and 12 mo after surgery were collected.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Odds ratios (ORs) were calculated with logistic regression and adjusted for possible confounders. The primary end point was urinary incontinence (change of pad less than once in 24h vs one time or more per 24h) at 12 mo. Secondary end points were erectile dysfunction at 12 mo and positive surgical margins.
RESULTS AND LIMITATIONS: Of 2625 eligible men, 2431 (93%) could be evaluated for the primary end point. At 12 mo after RALP, 366 men (21.3%) were incontinent, as were 144 (20.2%) after RRP. The adjusted OR was 1.08 (95% confidence interval [CI], 0.87-1.34). Erectile dysfunction was observed in 1200 men (70.4%) 12 mo after RALP and 531 (74.7%) after RRP. The adjusted OR was 0.81 (95% CI, 0.66-0.98). The frequency of positive surgical margins did not differ significantly between groups: 21.8% in the RALP group and 20.9% in the RRP group (adjusted OR: 1.09; 95% CI, 0.87-1.35). The nonrandomised design is a limitation.
CONCLUSIONS: In a Swedish setting, RALP for prostate cancer was modestly beneficial in preserving erectile function compared with RRP, without a statistically significant difference regarding urinary incontinence or surgical margins.
PATIENT SUMMARY: We compared patient-reported urinary incontinence after prostatectomy with two types of surgical technique. There was no statistically significant improvement in the rate of urinary leakage, but there was a small improvement regarding erectile function after robot-assisted operation.

Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
PMID 25770484
Anthony J Costello
Considering the role of radical prostatectomy in 21st century prostate cancer care.
Nat Rev Urol. 2020 Mar;17(3):177-188. doi: 10.1038/s41585-020-0287-y. Epub 2020 Feb 21.
Abstract/Text The practice of radical prostatectomy for treating prostate cancer has evolved remarkably since its general introduction around 1900. Initially described using a perineal approach, the procedure was later popularized using a retropubic one, after it was first described as such in 1948. The open surgical method has now largely been abandoned in favour of the minimally invasive robot-assisted method, which was first described in 2000. Until 1980, the procedure was hazardous, often accompanied by massive blood loss and poor outcomes. For patients in whom surgery is indicated, prostatectomy is increasingly being used as the first step in a multitherapeutic approach in advanced local, and even early metastatic, disease. However, contemporary molecular insights have enabled many men to safely avoid surgical intervention when the disease is phenotypically indolent and use of active surveillance programmes continues to expand worldwide. In 2020, surgery is not recommended in those men with low-grade, low-volume Gleason 6 prostate cancer; previously these men - a large cohort of ~40% of men with newly diagnosed prostate cancer - were offered surgery in large numbers, with little clinical benefit and considerable adverse effects. Radical prostatectomy is appropriate for men with intermediate-risk and high-risk disease (Gleason score 7-9 or Grade Groups 2-5) in whom radical prostatectomy prevents further metastatic seeding of potentially lethal clones of prostate cancer cells. Small series have suggested that it might be appropriate to offer radical prostatectomy to men presenting with small metastatic burden (nodal and or bone) as part of a multimodal therapeutic approach. Furthermore, surgical treatment of prostate cancer has been reported in cohorts of octogenarian men in good health with minimal comorbidities, when 20 years ago such men were rarely treated surgically even when diagnosed with localized high-risk disease. As medical therapies for prostate cancer continue to increase, the use of surgery might seem to be less relevant; however, the changing demographics of prostate cancer means that radical prostatectomy remains an important and useful option in many men, with a changing indication.

PMID 32086498
Francesco Porpiglia, Riccardo Bertolo, Matteo Manfredi, Stefano De Luca, Enrico Checcucci, Ivano Morra, Roberto Passera, Cristian Fiori
Total Anatomical Reconstruction During Robot-assisted Radical Prostatectomy: Implications on Early Recovery of Urinary Continence.
Eur Urol. 2016 Mar;69(3):485-95. doi: 10.1016/j.eururo.2015.08.005. Epub 2015 Aug 19.
Abstract/Text BACKGROUND: The introduction of robotics revolutionized prostate cancer surgery because the magnified three-dimensional vision system and wristed instruments allow microsurgery to be performed. The advantages of robotic surgery could lead to improved continence outcomes in terms of early recovery compared with the traditional surgical methods.
OBJECTIVE: To describe the total anatomical reconstruction (TAR) technique during robot-assisted radical prostatectomy (RARP).
PRIMARY ENDPOINT: evaluation of the continence rate at different time points. Secondary endpoint: evaluation of urine leakage and anastomosis stenosis rates related to the technique.
DESIGN, SETTING, AND PARTICIPANTS: June, 2013 to November, 2014; prospective consecutive series of patients with localized prostate cancer (cT1-3, cN0, cM0).
SURGICAL PROCEDURE: RARP with TAR was performed in all cases. Lymph node dissection was performed if the risk of lymph nodal metastasis was over 5%, according to the Briganti updated nomogram.
MEASUREMENTS: Preoperative, intraoperative, postoperative, and pathological variables were analyzed. Enrolled patients were arbitrarily divided into three groups according to a time criterion. The relationships between the learning curve and the trend of the above-mentioned variables were analyzed using LOESS analysis. Continence was rigorously analyzed preoperatively and at 24h, 1 wk, 4 wk, 12 wk, and 24 wk after catheter removal.
RESULTS AND LIMITATIONS: In total, 252 patients were analyzed. The continence rates immediately after catheter removal and at 1 wk, 4 wk, 12 wk, and 24 wk after RARP were 71.8%, 77.8%, 89.3%, 94.4%, and 98.0%, respectively. Multivariate analysis revealed that the nerve sparing technique, D'Amico risk groups, lymph node dissection, and prostate volume were involved in the early recovery of urinary continence. One ileal perforation requiring reoperation was recorded. The transfusion rate was 0.8%. Thirty-one (12.3%) postoperative complications were recorded up to 6 mo after surgery. Among these, eight acute urinary retentions (3.2%) and three urine leakages (1.2%) were recorded. There was a lack of randomization and comparison with other techniques. Both anatomical dissection of the prostatic apex and TAR were used. The results may not be generalized to low-volume centers.
CONCLUSIONS: The TAR technique showed promising results in the early recovery of urinary continence, as well as watertight anastomosis and a low rate of urine leakage. The oncologic results were not affected. Comparative studies are needed to support the quality of reported results.
PATIENT SUMMARY: On the basis of our findings, it seems that the risk of urinary incontinence following radical prostatectomy can be lowered via meticulous anatomical reconstruction using a robotic system. Comparative studies are required to support the reported results.

Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
PMID 26297603
Christopher U Jones, Daniel Hunt, David G McGowan, Mahul B Amin, Michael P Chetner, Deborah W Bruner, Mark H Leibenhaut, Siraj M Husain, Marvin Rotman, Luis Souhami, Howard M Sandler, William U Shipley
Radiotherapy and short-term androgen deprivation for localized prostate cancer.
N Engl J Med. 2011 Jul 14;365(2):107-18. doi: 10.1056/NEJMoa1012348.
Abstract/Text BACKGROUND: It is not known whether short-term androgen-deprivation therapy (ADT) before and during radiotherapy improves cancer control and overall survival among patients with early, localized prostate adenocarcinoma.
METHODS: From 1994 through 2001, we randomly assigned 1979 eligible patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a prostate-specific antigen (PSA) level of 20 ng per milliliter or less to radiotherapy alone (992 patients) or radiotherapy with 4 months of total androgen suppression starting 2 months before radiotherapy (radiotherapy plus short-term ADT, 987 patients). The primary end point was overall survival. Secondary end points included disease-specific mortality, distant metastases, biochemical failure (an increasing level of PSA), and the rate of positive findings on repeat prostate biopsy at 2 years.
RESULTS: The median follow-up period was 9.1 years. The 10-year rate of overall survival was 62% among patients receiving radiotherapy plus short-term ADT (the combined-therapy group), as compared with 57% among patients receiving radiotherapy alone (hazard ratio for death with radiotherapy alone, 1.17; P=0.03). The addition of short-term ADT was associated with a decrease in the 10-year disease-specific mortality from 8% to 4% (hazard ratio for radiotherapy alone, 1.87; P=0.001). Biochemical failure, distant metastases, and the rate of positive findings on repeat prostate biopsy at 2 years were significantly improved with radiotherapy plus short-term ADT. Acute and late radiation-induced toxic effects were similar in the two groups. The incidence of grade 3 or higher hormone-related toxic effects was less than 5%. Reanalysis according to risk showed reductions in overall and disease-specific mortality primarily among intermediate-risk patients, with no significant reductions among low-risk patients.
CONCLUSIONS: Among patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a PSA level of 20 ng per milliliter or less, the use of short-term ADT for 4 months before and during radiotherapy was associated with significantly decreased disease-specific mortality and increased overall survival. According to post hoc risk analysis, the benefit was mainly seen in intermediate-risk, but not low-risk, men. (Funded by the National Cancer Institute; RTOG 94-08 ClinicalTrials.gov number, NCT00002597.).

PMID 21751904
Karel Odrazka, Martin Dolezel, Jaroslav Vanasek, Miloslava Vaculikova, Milan Zouhar, Jana Sefrova, Petr Paluska, Milan Vosmik, Tereza Kohlova, Iveta Kolarova, Pavel Navratil, Milos Brodak, Petr Prosvic, Petr Hoffmann
Late toxicity after conformal and intensity-modulated radiation therapy for prostate cancer: impact of previous surgery for benign prostatic hyperplasia.
Int J Urol. 2010 Sep;17(9):784-90. doi: 10.1111/j.1442-2042.2010.02592.x. Epub 2010 Jul 6.
Abstract/Text OBJECTIVES: To retrospectively compare late toxicity of conventional-dose three-dimensional conformal radiation therapy (3D-CRT) and high-dose intensity-modulated radiation therapy (IMRT) for prostate cancer.
METHODS: A total of 340 patients with T1-3 prostate cancer were treated with 3D-CRT (n = 228) and IMRT (n = 112). The median follow-up time was 5.9 years and 3.0 years, respectively. The prescription dose was 70 Gy for 3D-CRT and 78 Gy for IMRT. Late gastrointestinal (GI) and genitourinary (GU) toxicities were graded according to the Fox Chase modification of the Radiation Therapy Oncology Group and Late Effects Normal Tissue Task Force criteria.
RESULTS: There was no difference between 3D-CRT and IMRT in the incidence of GI and GU toxicity at 3 years. On multivariate analysis, transurethral resection of prostate/open transvesical prostatectomy (TURP/TVPE) for benign prostatic hyperplasia, carried out before radiotherapy, significantly increased the risk of Grade >or=2 GU toxicity (risk ratio 1.88). Among patients who experienced TURP/TVPE, the 5-year actuarial likelihood of Grade 2-3 urinary incontinence was 23%, compared with 9% for those without prostate surgery (P = 0.01).
CONCLUSIONS: Tolerance of 3D-CRT and IMRT was similar, despite the use of high radiation dose with IMRT. Previous TURP/TVPE increased the risk of GU toxicity.

PMID 20604816
P Hoskin
High dose rate brachytherapy for prostate cancer.
Cancer Radiother. 2008 Nov;12(6-7):512-4. doi: 10.1016/j.canrad.2008.07.012. Epub 2008 Aug 27.
Abstract/Text High dose rate (HDR) afterloading brachytherapy in the management of localised prostate cancer has practical, physical and biological advantages over low dose rate seed brachytherapy. There are no free live sources used, no risk of source loss and since the implant is a temporary procedure following discharge no issues with regard to radioprotection use of existing facilities. Adequate coverage of extracapsular and seminal vesicle tumour is possible for advanced cases and HDR brachytherapy is the most efficient means of obtaining dose escalation in terms of biological dose based on a low alpha/beta ratio. Selection for HDR brachytherapy includes patients with any prostate specific antigen (PSA) level provided there is no demonstrable metastasis, any Gleason score and stages T1B to T3B. The results of a randomised trial show that HDR brachytherapy is an effective means of dose escalation with a favourable therapeutic ratio when compared with standard external beam radiotherapy. Current studies are evaluating HDR brachytherapy as monotherapy delivering a radical dose in two to four fractions. The acute toxicity with HDR brachytherapy is short-lived and far less severe than seen with low dose rate brachytherapy and late toxicity rates are low.

PMID 18755623
D Jeffrey Demanes, Rodney R Rodriguez, Lionel Schour, David Brandt, Gillian Altieri
High-dose-rate intensity-modulated brachytherapy with external beam radiotherapy for prostate cancer: California endocurietherapy's 10-year results.
Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1306-16. doi: 10.1016/j.ijrobp.2004.08.014.
Abstract/Text PURPOSE: To present the long-term outcome and morbidity of high-dose-rate brachytherapy (HDR-BT) combined with external beam radiotherapy (EBRT) for localized prostate cancer.
METHODS AND MATERIALS: Between September 1991 and December 1998, 209 consecutive patients with no prior androgen suppression were treated with HDR-BT plus EBRT. The median follow-up was 7.25 years (range, 5-12 years). The patients were stratified into three risk groups: low (Stage T2a or less, Gleason score 20). Four definitions of PSA progression were compared with the general clinical failure outcome: the American Society for Therapeutic Radiology and Oncology (ASTRO) definition, nadir plus 2.0 ng/mL, two consecutive rises >/=0.5 ng/mL, and PSA level >0.2 ng/mL. Morbidity was scored using Radiation Therapy Oncology Group criteria.
RESULTS: The general clinical control rate was 90% (188 of 209), and the general clinical failure rate was 10% (21 of 209). The overall survival rate was 79%, and the cause-specific survival rate was 97%. The PSA progression-free survival (ASTRO definition) rate was 90%, 87%, and 69% for the low-, intermediate-, and high-risk groups, respectively. The nadir plus 2 ng/mL and two rises >/=0.5 definitions correlated better with the actual clinical outcome than did the ASTRO and PSA >0.2 ng/mL definitions. The rate of Grade 3 and 4 late urinary morbidity was 6.7% and 1%, respectively, mostly occurring in patients who had undergone post-RT transurethral prostate resection. No late Grade 3 or 4 rectal morbidity developed. The sexual potency preservation rate was 67%.
CONCLUSION: Our 10-year results have demonstrated HDR-BT plus EBRT is a proven treatment for all stages of localized prostate cancer. The morbidity was low, but post-RT transurethral resection should be avoided.

PMID 15817332
Y S Chin, J Bullard, L Bryant, P Bownes, P Ostler, P J Hoskin
High dose rate iridium-192 brachytherapy as a component of radical radiotherapy for the treatment of localised prostate cancer.
Clin Oncol (R Coll Radiol). 2006 Aug;18(6):474-9.
Abstract/Text AIMS: To assess the treatment outcomes and toxicity of conformal high dose rate (HDR) brachytherapy boost as a means of radiation dose escalation in patients with localised prostate cancer.
MATERIALS AND METHODS: Between December 1998 and July 2004, 65 consecutive patients with localised prostate cancer (magnetic resonance imaging-staged T1-3 N0 M0) were treated with external beam radiation therapy (EBRT) followed by two fractions of HDR iridium-192 brachytherapy. The patients selected this treatment modality in preference to entering an ongoing randomised phase 3 trial. Any pre-treatment serum prostate-specific antigen (PSA) and Gleason score were included. The primary end point was biochemical disease-free progression. Late treatment-related morbidity was graded according to the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer criteria.
RESULTS: The median patient age was 67.3 years (range 47.9-80). Sixty patients (92.3%) had intermediate- to high-risk disease defined by clinical stage, presenting PSA and Gleason score/World Health Organisation (WHO) grade. With a median follow-up of 3.5 years (range 0.6-5.8), two patients had died of metastatic disease and another four patients had PSA relapse, giving a 3-year actuarial biochemical disease-free progression of 90.8%. Three patients (4.6%) had acute grade 3 genitourinary toxicity, in the form of urinary retention. Late grade 3 and 4 genitourinary toxicities occurred in four patients (6.2%) and one patient (1.5%), respectively. No late gastrointestinal toxicities were observed.
CONCLUSIONS: These results suggest that the combined modality of conformal HDR brachytherapy and EBRT is a feasible treatment modality with acceptable acute and late toxicities, comparable with those of EBRT alone. It offers an attractive conformal treatment modality with the potential of further dose escalation in the treatment of localised prostate cancer.

PMID 16909971
Abstract/Text PURPOSE: We have been treating localized prostate cancer with high-dose-rate (HDR) brachytherapy combined with hypofractionated external beam radiation therapy (EBRT) at our institution. We recently reported the existence of a correlation between the severity of acute genitourinary (GU) toxicity and the urethral radiation dose in HDR brachytherapy by using different fractionation schema. The purpose of this study was to evaluate the role of the urethral dose in the development of acute GU toxicity more closely than in previous studies. For this purpose, we conducted an analysis of patients who had undergone HDR brachytherapy with a fixed fractionation schema combined with hypofractionated EBRT.
METHODS AND MATERIALS: Among the patients with localized prostate cancer who were treated by 192-iridium HDR brachytherapy combined with hypofractionated EBRT at Gunma University Hospital between August 2000 and November 2004, we analyzed 67 patients who were treated by HDR brachytherapy with the fractionation schema of 9 Gy x two times combined with hypofractionated EBRT. Hypofractionated EBRT was administered at a fraction dose of 3 Gy three times weekly, and a total dose of 51 Gy was delivered to the prostate gland and seminal vesicles using the four-field technique. No elective pelvic irradiation was performed. After the completion of EBRT, all the patients additionally received transrectal ultrasonography-guided HDR brachytherapy. The planning target volume was defined as the prostate gland with a 5-mm margin all around, and the planning was conducted based on computed tomography images. The tumor stage was T1c in 13 patients, T2 in 31 patients, and T3 in 23 patients. The Gleason score was 2-6 in 12 patients, 7 in 34 patients, and 8-10 in 21 patients. Androgen ablation was performed in all the patients. The median follow-up duration was 11 months (range 3-24 months). The toxicities were graded based on the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer toxicity criteria.
RESULTS: The main symptoms of acute GU toxicity were dysuria and increase in the urinary frequency or nocturia. The grade distribution of acute GU toxicity in the patients was as follows: Grade 0-1, 42 patients (63%); Grade 2-3, 25 patients (37%). The urethral dose in HDR brachytherapy was determined using the following dose-volume histogram (DVH) parameters: V30 (percentage of the urethral volume receiving 30% of the prescribed radiation dose), V80, V90, V100, V110, V120, V130, and V150. In addition, the D5 (dose covering 5% of the urethral volume), D10, D20, and D50 of the urethra were also estimated. The V30-V150 values in the patients with Grade 2-3 acute GU toxicity were significantly higher than those in patients with Grade 0-1 toxicity. The D10 and D20, but not D5 and D50, values were also significantly higher in the patients with Grade 2-3 acute GU toxicity than in those with Grade 0-1 toxicity. Regarding the influence of the number of needles implanted, there was no correlation between the number of needles implanted and the severity of acute GU toxicity or the V30-V150 values and D5-D50 values.
CONCLUSIONS: It was concluded that HDR brachytherapy combined with hypofractionated EBRT is feasible for localized prostate cancer, when considered from the viewpoint of acute toxicity. However, because the urethral dose was closely associated with the grade of severity of the acute GU toxicity, the urethral dose in HDR brachytherapy must be kept low to reduce the severity of acute GU toxicity.

PMID 16168839
Olufemi Babalola, Joyce Ting-Hsuan Lee, Charles Viviano
Prostate Ablation Using High Intensity Focused Ultrasound: The Potential Role for Patient Preference Information - A Literature Review.
J Urol. 2018 Apr 24;. doi: 10.1016/j.juro.2018.04.066. Epub 2018 Apr 24.
Abstract/Text PURPOSE: The Food and Drug Administration (FDA) recently allowed marketing of two HIFU devices for prostate tissue ablation indications after previous rejections for a prostate cancer indication due to insufficient data on clinical effectiveness or direct patient benefit. A review of the safety and effectiveness of HIFU and knowledge regarding patient preferences, such as tolerance for adverse events associated with HIFU ablation of tissue in men with prostate cancer, may inform decision-making for device developers and the FDA.
MATERIALS AND METHODS: We searched PubMed and Grey literature including FDA reports for relevant data on: 1. The safety and effectiveness of primary and salvage HIFU treatment for localized prostate cancer in studies performed either within or outside the united states (US), and 2. Patient preference information (PPI) on HIFU-related safety and effectiveness outcomes.
RESULTS: We found that there are no HIFU effectiveness data relevant to clinical decision-making such as overall survival or prostate-cancer-specific survival in the US. Long-term effectiveness data from outside the US are sparse and outcomes are variable. We found no patient preference data on HIFU treatment in men with prostate cancer.
CONCLUSION: The lack of long term HIFU oncological data in a United States population has brought new challenges to prostate cancer stakeholders including clinicians, patients, and the FDA. PPI from future patient studies on HIFU could provide additional information to patients, clinicians, and current and prospective device developers. In addition, it can be used by regulators in their risk-benefit evaluation for this class of treatment devices.

Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
PMID 29702099
Louis Potters, Eric A Klein, Michael W Kattan, Chandana A Reddy, Jay P Ciezki, Alwyn M Reuther, Patrick A Kupelian
Monotherapy for stage T1-T2 prostate cancer: radical prostatectomy, external beam radiotherapy, or permanent seed implantation.
Radiother Oncol. 2004 Apr;71(1):29-33. doi: 10.1016/j.radonc.2003.12.011.
Abstract/Text BACKGROUND AND PURPOSE: To review the freedom from biochemical recurrence (FBR) rates after permanent prostate brachytherapy (PPB), external beam radiotherapy (RT) to a minimum 70Gy, or radical prostatectomy (RP) for clinically localized stage T1-T2 adenocarcinoma of the prostate.
PATIENTS AND METHODS: The study cohort consisted of 1819 consecutively treated clinical stage T1-T2 (AJCC 1997) localized prostate cancer patients between 1992 and 1998. All patients received monotherapy treatment without additional adjuvant therapy. The distribution by treatment modality was as follows: RT for 340, RP for 746, and PPB for 733 cases. The median follow-up time was 58 months for all cases (51 months for PPB cases, 56 months for RT cases, and 64 months for RP cases). Biochemical relapse was defined as to be detectable PSA levels in RP cases, and the ASTRO consensus panel definition for the RT and PPB cases.
RESULTS: The 7-year FBR rates for PPB vs EBRT vs RP were 74, 77, and 79%, respectively. Multivariate analysis identified iPSA (P < 0.001) and bGS (P < 0.001) as independent predictors of relapse. Treatment modality, age, clinical T-stage, and race were not independent predictors of failure.
CONCLUSIONS: Pretreatment PSA levels, and biopsy Gleason score determined outcome in this study cohort. Biochemical failure rates in this study cohort are similar between PPB, RT, and RP as monotherapy for clinically localized prostate cancer.

PMID 15066293
Gunes Gundem, Peter Van Loo, Barbara Kremeyer, Ludmil B Alexandrov, Jose M C Tubio, Elli Papaemmanuil, Daniel S Brewer, Heini M L Kallio, Gunilla Högnäs, Matti Annala, Kati Kivinummi, Victoria Goody, Calli Latimer, Sarah O'Meara, Kevin J Dawson, William Isaacs, Michael R Emmert-Buck, Matti Nykter, Christopher Foster, Zsofia Kote-Jarai, Douglas Easton, Hayley C Whitaker, ICGC Prostate Group, David E Neal, Colin S Cooper, Rosalind A Eeles, Tapio Visakorpi, Peter J Campbell, Ultan McDermott, David C Wedge, G Steven Bova
The evolutionary history of lethal metastatic prostate cancer.
Nature. 2015 Apr 16;520(7547):353-357. doi: 10.1038/nature14347. Epub 2015 Apr 1.
Abstract/Text Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones. Here we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.

PMID 25830880
Christopher J Sweeney, Yu-Hui Chen, Michael Carducci, Glenn Liu, David F Jarrard, Mario Eisenberger, Yu-Ning Wong, Noah Hahn, Manish Kohli, Matthew M Cooney, Robert Dreicer, Nicholas J Vogelzang, Joel Picus, Daniel Shevrin, Maha Hussain, Jorge A Garcia, Robert S DiPaola
Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer.
N Engl J Med. 2015 Aug 20;373(8):737-46. doi: 10.1056/NEJMoa1503747. Epub 2015 Aug 5.
Abstract/Text BACKGROUND: Androgen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in longer overall survival than that with ADT alone.
METHODS: We assigned men with metastatic, hormone-sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone.
RESULTS: A total of 790 patients (median age, 63 years) underwent randomization. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P<0.001). In the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%.
CONCLUSIONS: Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00309985.).

PMID 26244877
Karim Fizazi, NamPhuong Tran, Luis Fein, Nobuaki Matsubara, Alfredo Rodriguez-Antolin, Boris Y Alekseev, Mustafa Özgüroğlu, Dingwei Ye, Susan Feyerabend, Andrew Protheroe, Peter De Porre, Thian Kheoh, Youn C Park, Mary B Todd, Kim N Chi, LATITUDE Investigators
Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer.
N Engl J Med. 2017 Jul 27;377(4):352-360. doi: 10.1056/NEJMoa1704174. Epub 2017 Jun 4.
Abstract/Text BACKGROUND: Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer.
METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival.
RESULTS: After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group.
CONCLUSIONS: The addition of abiraterone acetate and prednisone to androgen-deprivation therapy significantly increased overall survival and radiographic progression-free survival in men with newly diagnosed, metastatic, castration-sensitive prostate cancer. (Funded by Janssen Research and Development; LATITUDE ClinicalTrials.gov number, NCT01715285 .).

PMID 28578607
T Tsushima, Y Nasu, T Saika, Y Maki, M Noda, B Suyama, T Yamato, H Kumon
Optimal starting time for flutamide to prevent disease flare in prostate cancer patients treated with a gonadotropin-releasing hormone agonist.
Urol Int. 2001;66(3):135-9. doi: 56592.
Abstract/Text OBJECTIVE: Flare-up phenomena, such as an increase in prostate-specific antigen (PSA) and/or deterioration of symptoms, are observed in some patients undergoing gonadotropin-releasing hormone (GnRH) agonist therapy. This study was carried out to determine the optimal time for starting the administration of flutamide to prevent flare-up phenomena.
PATIENTS AND METHODS: Twenty-six patients with prostate cancer and elevated serum levels of PSA were randomly assigned to 5 groups. Group A patients (n = 6) were treated with a subcutaneous injection of 3.75 mg leuprorelin acetate depot alone. Group B, C, D and E patients (5 patients in each group) were treated with 375 mg/day of orally administered flutamide combined with leuprorelin. Flutamide was initiated on the day of leuprorelin injection in group B, and at 1, 2 and 4 weeks before leuprorelin injection in groups C, D and E, respectively. Serum PSA and testosterone levels were measured in each patient.
RESULTS: Pretreatment with flutamide increased the serum testosterone level, but the testosterone surge after leuprorelin administration was almost the same in all 5 treatment groups. In patients who had been treated with flutamide in combination with leuprorelin, the mean PSA level did not exceed the pretreatment levels after leuprorelin administration. The rate of decrease in PSA in the group receiving simultaneous administration of flutamide with leuprorelin showed a decline comparable to that during the period before leuprorelin administration in the flutamide pretreatment groups.
CONCLUSION: Simultaneous administration of flutamide with a GnRH agonist is sufficient to prevent flare-up phenomena.

Copyright 2001 S. Karger AG, Basel
PMID 11316974
F Boccardo, A Rubagotti, M Battaglia, P Di Tonno, F P Selvaggi, G Conti, G Comeri, A Bertaccini, G Martorana, P Galassi, F Zattoni, A Macchiarella, A Siragusa, G Muscas, F Durand, D Potenzoni, A Manganelli, V Ferraris, F Montefiore
Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer.
J Clin Oncol. 2005 Feb 1;23(4):808-15. doi: 10.1200/JCO.2005.12.013.
Abstract/Text PURPOSE: To determine whether tamoxifen or anastrozole prevents gynecomastia and breast pain caused by bicalutamide (150 mg) without compromising efficacy, safety, or sexual functioning.
PATIENTS AND METHODS: A double-blind, placebo-controlled trial was performed in patients with localized, locally advanced, or biochemically recurrent prostate cancer. Patients (N = 114) were randomly assigned to either bicalutamide (150 mg/d) plus placebo or in combination with tamoxifen (20 mg/d) or anastrozole (1 mg/d) for 48 weeks. Gynecomastia, breast pain, prostate-specific antigen (PSA), sexual functioning, and serum levels of hormones were assessed.
RESULTS: Gynecomastia developed in 73% of patients in the bicalutamide group, 10% of patients in the bicalutamide-tamoxifen group, and 51% of patients in the bicalutamide-anastrozole group (P < .001); breast pain developed in 39%, 6%, and 27% of patients, respectively (P = .006). Baseline PSA level decreased by > or = 50% in 97%, 97%, and 83% of patients in the bicalutamide, bicalutamide-tamoxifen, and bicalutamide-anastrozole groups, respectively (P = .07); and adverse events were reported in 37%, 35%, and 69% of patients, respectively (P = .004). There were no major differences among treatments in sexual functioning parameters from baseline to month 6. Elevated testosterone levels occurred in each group; however, free testosterone levels remained unchanged in the bicalutamide-tamoxifen group because of increased sex hormone-binding globulin levels.
CONCLUSION: Anastrozole did not significantly reduce the incidence of bicalutamide-induced gynecomastia and breast pain. In contrast, tamoxifen was effective, without increasing adverse events, at least in the short-term follow-up. These data support the need for a larger study to determine any effect on mortality.

PMID 15681525
M Wirth, C Tyrrell, M Wallace, K P Delaere, M Sánchez-Chapado, J Ramon, J Hetherington, F Pina, C F Heynes, T M Borchers, T Morris, A Stone
Bicalutamide (Casodex) 150 mg as immediate therapy in patients with localized or locally advanced prostate cancer significantly reduces the risk of disease progression.
Urology. 2001 Aug;58(2):146-51.
Abstract/Text OBJECTIVES: To investigate the efficacy and tolerability of bicalutamide (Casodex) as immediate therapy, either alone or as adjuvant to treatment of curative intent, in patients with localized or locally advanced (T1b-T4, any nodal status, M0) prostate cancer.
METHODS: This was a multicenter, prospective, randomized, double-blind, placebo-controlled trial in Europe, South Africa, Australia, and Mexico and is part of the Casodex Early Prostate Cancer program.
RESULTS: A total of 3603 men were randomized to receive bicalutamide (n = 1798) or placebo (n = 1805). The patient demographics were well balanced between the two groups. Prior therapy of curative intent had been given to 64% of the patients (prostatectomy [44%], radiotherapy [18%], and prostatectomy and radiotherapy [2%]) and 36% had been monitored with watchful waiting. After a median follow-up of 2.6 years and a median exposure to the study drug of 2.2 years, a significant 43% reduction in the risk of objective progression was observed for the bicalutamide group compared with the placebo group (hazard ratio 0.57, 95% confidence interval 0.48 to 0.69, P < 0.0001). The time to prostate-specific antigen doubling was significantly delayed for the bicalutamide group compared with the placebo group (hazard ratio 0.37, 95% confidence interval 0.32 to 0.43, P < 0.001). The survival data were immature, with 7.2% overall mortality. The most frequently reported adverse events with bicalutamide were gynecomastia alone (17.4%), breast pain alone (17.6%), and gynecomastia with breast pain (47.5%).
CONCLUSIONS: Bicalutamide 150 mg daily as immediate therapy, alone or as adjuvant to treatment of curative intent, significantly reduced the risk of disease progression in patients with localized or locally advanced prostate cancer. Longer follow-up is underway to assess any benefit in overall survival.

PMID 11489683
W See, P Iversen, M Wirth, D McLeod, L Garside, T Morris
Immediate treatment with bicalutamide 150mg as adjuvant therapy significantly reduces the risk of PSA progression in early prostate cancer.
Eur Urol. 2003 Nov;44(5):512-7; discussion 517-8.
Abstract/Text OBJECTIVE: To evaluate the effect of bicalutamide ('Casodex') 150mg (in addition to standard care), on the risk of prostate-specific antigen (PSA) progression, in patients with early prostate cancer.
METHODS: The bicalutamide 150mg Early Prostate Cancer (EPC) programme is the largest clinical trial programme in the treatment of prostate cancer to date. This paper reports the PSA progression data from the EPC programme at a median of 3years' follow-up, for the overall study population, and across the radical prostatectomy and radiotherapy primary therapy strategies. PSA progression was predefined as the earliest occurrence of PSA doubling from baseline, objective progression, or death from any cause.
RESULT: Overall, bicalutamide 150 mg in addition to standard care significantly reduced the risk of PSA progression by 59% compared with standard care alone (HR 0.41; 95% CI 0.38, 0.45; p<0.0001). Significant reductions were observed following radical prostatectomy (51%; HR 0.49; 95% CI 0.43, 0.56; p<0.0001) and radiotherapy (58%; HR 0.42; 95% CI 0.33, 0.53; p<0.0001). Further exploration of the data by disease stage, nodal status, Gleason score and pre-treatment PSA level revealed significant reductions in the risk of PSA progression across most prognostic risk factor subgroups.
CONCLUSIONS: Bicalutamide 150mg significantly reduces the risk of PSA progression, irrespective of whether patients received radical prostatectomy or radiotherapy as standard care. The EPC programme is ongoing and further progression and survival data are awaited.

PMID 14572747
Peter Iversen, Jan-Erik Johansson, Pär Lodding, Olavi Lukkarinen, Per Lundmo, Peter Klarskov, Teuvo L J Tammela, Ilker Tasdemir, Tom Morris, Kevin Carroll, Scandinavian Prostatic Cancer Group
Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6.
J Urol. 2004 Nov;172(5 Pt 1):1871-6.
Abstract/Text PURPOSE: We evaluated the benefits of adding 150 mg bicalutamide to standard care, that is radical prostatectomy, radiotherapy or watchful waiting (WW), in patients with localized or locally advanced prostate cancer.
MATERIALS AND METHODS: A total of 1,218 men with T1-4, M0, any N prostate cancer were recruited from 62 Scandinavian centers and randomized 1:1 to 150 mg bicalutamide or placebo plus standard care. Primary end points were progression-free survival (PFS) and overall survival.
RESULTS: At a median 5.3-year followup patients with locally advanced disease had improved survival with bicalutamide (HR 0.68, 95% CI 0.50 to 0.92), while those with localized disease had decreased survival with bicalutamide (HR 1.47, 95% CI 1.06 to 2.03). Bicalutamide significantly improved PFS, decreasing the risk of disease progression by 43% compared with placebo (HR 0.57, 95% CI 0.48 to 0.68, p<0.0001). The rate of events was 35.4% for bicalutamide and 46.2% for placebo. Patients with locally advanced disease gained the greatest PFS benefits with bicalutamide (HR 0.40, 95% CI 0.31 to 0.52). Since 81% of the trial population were untreated before entry and would otherwise have undergone WW, the findings essentially reflect the results of immediate hormone therapy vs WW.
CONCLUSIONS: Bicalutamide (150 mg) provides significant benefit in patients with locally advanced disease. In previously untreated patients there may be a tumor burden below which endocrine therapy provides no benefit or may even decrease survival.

PMID 15540741
F Labrie, A Dupont, A Belanger, M Giguere, Y Lacoursiere, J Emond, G Monfette, V Bergeron
Combination therapy with flutamide and castration (LHRH agonist or orchiectomy) in advanced prostate cancer: a marked improvement in response and survival.
J Steroid Biochem. 1985 Nov;23(5B):833-41.
Abstract/Text Eighty-seven previously untreated patients with clinical stage D2 (bone metastases) prostate cancer have received the combination therapy with a pure antiandrogen and an LHRH agonist (or orchiectomy) as first treatment in a multicentre study for up to 34 months (average = 16.2 months). A positive objective response assessed according to the criteria of the US NPCP has been observed in all cases. Pain disappeared in all patients within 1 month and performance become normal in all (including 2 bedridden patients) within 4 months. Progression of the disease after a period of remission has been observed in only 8 patients. Only one patient has died from prostate cancer while 3 have died from other causes. The probability of continuing response and survival at 2 years for the patients who receive the combination treatment (Kaplan-Meier's method) is 81 and 91%, respectively. By contrast, in the randomized group who had orchiectomy alone, 4 of 7 have died from prostate cancer (P less than 0.05 as compared to combination therapy). In addition to a marked improvement in the remission rate and survival, combination therapy maintains a good quality of life, hot flashes and a decrease or loss of libido being the only side-effects.

PMID 2934579
Hideyuki Akaza, Shiro Hinotsu, Michiyuki Usami, Yoichi Arai, Hiroshi Kanetake, Seiji Naito, Yoshihiko Hirao, Study Group for the Combined Androgen Blockade Therapy of Prostate Cancer
Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival.
Cancer. 2009 Aug 1;115(15):3437-45. doi: 10.1002/cncr.24395.
Abstract/Text BACKGROUND: A previously reported, double-blind, randomized, multicenter phase 3 trial in 205 patients with stage C/D prostate cancer compared combined androgen blockade (CAB) with luteinizing hormone-releasing hormone agonist (LHRH-A) plus bicalutamide 80 mg versus LHRH-A plus bicalutamide-matching placebo (LHRH-A monotherapy). The analysis at a median follow-up of 2.4 years indicated that CAB significantly (P<.001) prolonged the time to progression and the time to treatment failure. In the current report, survival data from a long-term follow-up (median, 5.2 years) were analyzed.
METHODS: All deaths irrespective of cause and all prostate cancer-specific deaths were recorded. The data were analyzed using Cox regression analysis and the log-rank test.
RESULTS: At a median follow-up of 5.2 years, a significant overall survival advantage was observed in favor of CAB over LHRH-A monotherapy (Cox regression analysis: hazard ratio, 0.78; 95% confidence interval, 0.60-0.99; P=.0498; log-rank test: P=.0425). The difference in cause-specific survival between the 2 groups was not significant. The achievement of a prostate-specific antigen (PSA) nadir concentrationCONCLUSIONS: CAB with bicalutamide 80 mg offered a significant overall survival benefit compared with LHRH-A monotherapy without reducing tolerability in patients with locally advanced or metastatic prostate cancer.

Copyright (c) 2009 American Cancer Society.
PMID 19536889
Abstract/Text BACKGROUND: In advanced prostate cancer, androgen suppression (AS) by surgery or drugs controls testicular hormone secretion, and the further addition of an antiandrogen such as nilutamide, flutamide, or cyproterone acetate is referred to as maximum androgen blockade (MAB). The aim of this overview was to compare the effects on the duration of survival of MAB and of AS alone.
METHODS: The collaborative meta-analysis of 27 randomised trials involved central reanalysis of the data on each of 8275 men (98% of those ever randomised in trials of MAB vs AS) with metastatic (88%) or locally advanced (12%) prostate cancer. Half were over 70 years of age, and follow-up was typically for about 5 years.
FINDINGS: 5932 (72%) men have died; of the deaths for which causes were provided, about 80% were attributed to prostate cancer. 5-year survival was 25.4% with MAB versus 23.6% with AS alone, a non-significant gain of 1.8% (SE 1.3; logrank 2p=0.11). There was no significant heterogeneity in the treatment effect (MAB vs AS) with respect to age or disease stage. The results for cyproterone acetate, which accounted for only a fifth of the evidence, appeared slightly unfavourable to MAB (5-year survival 15.4% MAB vs 18.1% AS alone; difference -2.8% [SE 2.4]; logrank 2p=0.04 adverse), whereas those for nilutamide and flutamide appeared slightly favourable (5-year survival 27.6% MAB vs 24.7% AS alone; difference 2.9% [SE 1.3]; logrank 2p=0.005). Non-prostate-cancer deaths (although not clearly significantly affected by treatment) accounted for some of the apparently adverse effects of cyproterone acetate.
INTERPRETATION: In advanced prostate cancer, addition of an antiandrogen to AS improved the 5-year survival by about 2% or 3% (depending on whether the analysis includes or excludes the cyproterone acetate trials), but the range of uncertainty as to the true size of this benefit runs from about 0% to about 5%.

PMID 10801170
L Klotz, P Schellhammer, K Carroll
A re-assessment of the role of combined androgen blockade for advanced prostate cancer.
BJU Int. 2004 Jun;93(9):1177-82. doi: 10.1111/j.1464-410x.2004.04803.x.
Abstract/Text
PMID 15180600
Howard I Scher, Karim Fizazi, Fred Saad, Mary-Ellen Taplin, Cora N Sternberg, Kurt Miller, Ronald de Wit, Peter Mulders, Kim N Chi, Neal D Shore, Andrew J Armstrong, Thomas W Flaig, Aude Fléchon, Paul Mainwaring, Mark Fleming, John D Hainsworth, Mohammad Hirmand, Bryan Selby, Lynn Seely, Johann S de Bono, AFFIRM Investigators
Increased survival with enzalutamide in prostate cancer after chemotherapy.
N Engl J Med. 2012 Sep 27;367(13):1187-97. doi: 10.1056/NEJMoa1207506. Epub 2012 Aug 15.
Abstract/Text BACKGROUND: Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy.
METHODS: In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival.
RESULTS: The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; P<0.001). The superiority of enzalutamide over placebo was shown with respect to all secondary end points: the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs. 2%, P<0.001), the soft-tissue response rate (29% vs. 4%, P<0.001), the quality-of-life response rate (43% vs. 18%, P<0.001), the time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25; P<0.001), radiographic progression-free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and the time to the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001). Rates of fatigue, diarrhea, and hot flashes were higher in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide.
CONCLUSIONS: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy. (Funded by Medivation and Astellas Pharma Global Development; AFFIRM ClinicalTrials.gov number, NCT00974311.).

PMID 22894553
Tomasz M Beer, Andrew J Armstrong, Dana E Rathkopf, Yohann Loriot, Cora N Sternberg, Celestia S Higano, Peter Iversen, Suman Bhattacharya, Joan Carles, Simon Chowdhury, Ian D Davis, Johann S de Bono, Christopher P Evans, Karim Fizazi, Anthony M Joshua, Choung-Soo Kim, Go Kimura, Paul Mainwaring, Harry Mansbach, Kurt Miller, Sarah B Noonberg, Frank Perabo, De Phung, Fred Saad, Howard I Scher, Mary-Ellen Taplin, Peter M Venner, Bertrand Tombal, PREVAIL Investigators
Enzalutamide in metastatic prostate cancer before chemotherapy.
N Engl J Med. 2014 Jul 31;371(5):424-33. doi: 10.1056/NEJMoa1405095. Epub 2014 Jun 1.
Abstract/Text BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy.
METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival.
RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment.
CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).

PMID 24881730
S Sørensen, S Helweg-Larsen, H Mouridsen, H H Hansen
Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: a randomised trial.
Eur J Cancer. 1994;30A(1):22-7.
Abstract/Text We performed a randomised single blind trial of high-dose dexamethasone as an adjunct to radiotherapy in patients with metastatic spinal cord compression from solid tumours. After stratification for primary tumour and gait function, 57 patients were allocated randomly to treatment with either high-dose dexamethasone or no steroidal treatment. Dexamethasone was administered as a bolus of 96 mg intravenously, followed by 96 mg orally for 3 days and then tapered in 10 days. A successful treatment result defined as gait function after treatment was obtained in 81% of the patients treated with dexamethasone compared to 63% of the patients receiving no dexamethasone therapy. Six months after treatment, 59% of the patients in the dexamethasone group were still ambulatory compared to 33% in the no dexamethasone group. Life table analysis of patients surviving with gait function showed a significantly better course in patients treated with dexamethasone (P < 0.05). Median survival was identical in the two treatment groups. Similar results were found in subgroup analysis of 34 patients with breast cancer as the primary malignancy. Significant side-effects were reported in 3 (11%) of the patients receiving glucocorticoids, 2 of whom discontinued the treatment. We conclude that high-dose glucocorticoid therapy should be given as adjunct treatment in patients with metastatic epidural spinal cord compression.

PMID 8142159
R F Young, E M Post, G A King
Treatment of spinal epidural metastases. Randomized prospective comparison of laminectomy and radiotherapy.
J Neurosurg. 1980 Dec;53(6):741-8. doi: 10.3171/jns.1980.53.6.0741.
Abstract/Text Metastases to the spinal epidural space with compression of the spinal cord or cauda equina are commonly encountered by physicians in a variety of clinical field. In the recent past, decompressive laminectomy followed by radiotheray was thought to be the best available treatment. More recently, radiotherapy alone has been advocated as an alternative treatment mode with a similar rate of effectiveness. This study compares laminectomy followed by radiotherapy to radiotherapy alone in the treatment of spinal epidural metastases in a randomized, prospective clinical trial. No significant difference was found in the effectiveness of the two treatment methods in regard to pain relief, improved ambulation, or improved sphincter function. Patients with an incomplete myelographic block fared well regardless of treatment, and those with a complete block fared poorly. Because of the limited size of this study and because of certain unforeseen design defects, the results are suggestive but not conclusive. Suggestions are made for a future randomized, prospective multicenter study that would conclusively answer the perplexing question as to the most efficacious method for treating spinal epidural metastases.

PMID 7441333
Charles J Ryan, Matthew R Smith, Karim Fizazi, Fred Saad, Peter F A Mulders, Cora N Sternberg, Kurt Miller, Christopher J Logothetis, Neal D Shore, Eric J Small, Joan Carles, Thomas W Flaig, Mary-Ellen Taplin, Celestia S Higano, Paul de Souza, Johann S de Bono, Thomas W Griffin, Peter De Porre, Margaret K Yu, Youn C Park, Jinhui Li, Thian Kheoh, Vahid Naini, Arturo Molina, Dana E Rathkopf, COU-AA-302 Investigators
Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study.
Lancet Oncol. 2015 Feb;16(2):152-60. doi: 10.1016/S1470-2045(14)71205-7. Epub 2015 Jan 16.
Abstract/Text BACKGROUND: Abiraterone acetate plus prednisone significantly improved radiographic progression-free survival compared with placebo plus prednisone in men with chemotherapy-naive castration-resistant prostate cancer at the interim analyses of the COU-AA-302 trial. Here, we present the prespecified final analysis of the trial, assessing the effect of abiraterone acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent therapies.
METHODS: In this placebo-controlled, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology performance status (0 vs 1) were randomly assigned with a permuted block allocation scheme via a web response system in a 1:1 ratio to receive either abiraterone acetate (1000 mg once daily) plus prednisone (5 mg twice daily; abiraterone acetate group) or placebo plus prednisone (placebo group). Coprimary endpoints were radiographic progression-free survival and overall survival analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00887198.
FINDINGS: At a median follow-up of 49.2 months (IQR 47.0-51.8), 741 (96%) of the prespecified 773 death events for the final analysis had been observed: 354 (65%) of 546 patients in the abiraterone acetate group and 387 (71%) of 542 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received abiraterone acetate plus prednisone as crossover per protocol (93 patients) or as subsequent therapy (145 patients). Overall, 365 (67%) patients in the abiraterone acetate group and 435 (80%) in the placebo group received subsequent treatment with one or more approved agents. Median overall survival was significantly longer in the abiraterone acetate group than in the placebo group (34.7 months [95% CI 32.7-36.8] vs 30.3 months [28.7-33.3]; hazard ratio 0.81 [95% CI 0.70-0.93]; p=0.0033). The most common grade 3-4 adverse events of special interest were cardiac disorders (41 [8%] of 542 patients in the abiraterone acetate group vs 20 [4%] of 540 patients in the placebo group), increased alanine aminotransferase (32 [6%] vs four [<1%]), and hypertension (25 [5%] vs 17 [3%]).
INTERPRETATION: In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant. These results further support the favourable safety profile of abiraterone acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer.
FUNDING: Janssen Research & Development.

Copyright © 2015 Elsevier Ltd. All rights reserved.
PMID 25601341
Karim Fizazi, Howard I Scher, Arturo Molina, Christopher J Logothetis, Kim N Chi, Robert J Jones, John N Staffurth, Scott North, Nicholas J Vogelzang, Fred Saad, Paul Mainwaring, Stephen Harland, Oscar B Goodman, Cora N Sternberg, Jin Hui Li, Thian Kheoh, Christopher M Haqq, Johann S de Bono, COU-AA-301 Investigators
Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study.
Lancet Oncol. 2012 Oct;13(10):983-92. doi: 10.1016/S1470-2045(12)70379-0. Epub 2012 Sep 18.
Abstract/Text BACKGROUND: Abiraterone acetate improved overall survival in metastatic castration-resistant prostate cancer at a preplanned interim analysis of the COU-AA-301 double-blind, placebo-controlled phase 3 study. Here, we present the final analysis of the study before crossover from placebo to abiraterone acetate (after 775 of the prespecified 797 death events).
METHODS: Between May 8, 2008, and July 28, 2009, this study enrolled 1195 patients at 147 sites in 13 countries. Patients were eligible if they had metastatic castration-resistant prostate cancer progressing after docetaxel. Patients were stratified according to baseline Eastern Cooperative Oncology Group (ECOG) performance status, worst pain over the past 24 h on the Brief Pain Inventory-Short Form, number of previous chemotherapy regimens, and type of progression. Patients were randomly assigned (ratio 2:1) to receive either abiraterone acetate (1000 mg, once daily and orally) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone with a permuted block method via an interactive web response system. The primary endpoint was overall survival, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00091442.
FINDINGS: Of the 1195 eligible patients, 797 were randomly assigned to receive abiraterone acetate plus prednisone (abiraterone group) and 398 to receive placebo plus prednisone (placebo group). At median follow-up of 20·2 months (IQR 18·4-22·1), median overall survival for the abiraterone group was longer than in the placebo group (15·8 months [95% CI 14·8-17·0] vs 11·2 months [10·4-13·1]; hazard ratio [HR] 0·74, 95% CI 0·64-0·86; p<0·0001). Median time to PSA progression (8·5 months, 95% CI 8·3-11·1, in the abiraterone group vs 6·6 months, 5·6-8·3, in the placebo group; HR 0·63, 0·52-0·78; p<0·0001), median radiologic progression-free survival (5·6 months, 5·6-6·5, vs 3·6 months, 2·9-5·5; HR 0·66, 0·58-0·76; p<0·0001), and proportion of patients who had a PSA response (235 [29·5%] of 797 patients vs 22 [5·5%] of 398; p<0·0001) were all improved in the abiraterone group compared with the placebo group. The most common grade 3-4 adverse events were fatigue (72 [9%] of 791 patients in the abiraterone group vs 41 [10%] of 394 in the placebo group), anaemia (62 [8%] vs 32 [8%]), back pain (56 [7%] vs 40 [10%]), and bone pain (51 [6%] vs 31 [8%]).
INTERPRETATION: This final analysis confirms that abiraterone acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment. No new safety signals were identified with increased follow-up.

Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID 22995653
Ian F Tannock, Ronald de Wit, William R Berry, Jozsef Horti, Anna Pluzanska, Kim N Chi, Stephane Oudard, Christine Théodore, Nicholas D James, Ingela Turesson, Mark A Rosenthal, Mario A Eisenberger, TAX 327 Investigators
Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.
N Engl J Med. 2004 Oct 7;351(15):1502-12. doi: 10.1056/NEJMoa040720.
Abstract/Text BACKGROUND: Mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced, hormone-refractory prostate cancer, but it does not improve survival. We compared such treatment with docetaxel plus prednisone in men with this disease.
METHODS: From March 2000 through June 2002, 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and were randomly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks, 75 mg of docetaxel per square meter every three weeks, or 30 mg of docetaxel per square meter weekly for five of every six weeks. The primary end point was overall survival. Secondary end points were pain, prostate-specific antigen (PSA) levels, and the quality of life. All statistical comparisons were against mitoxantrone.
RESULTS: As compared with the men in the mitoxantrone group, men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 (95 percent confidence interval, 0.62 to 0.94; P=0.009 by the stratified log-rank test) and those given weekly docetaxel had a hazard ratio for death of 0.91 (95 percent confidence interval, 0.75 to 1.11; P=0.36). The median survival was 16.5 months in the mitoxantrone group, 18.9 months in the group given docetaxel every 3 weeks, and 17.4 months in the group given weekly docetaxel. Among these three groups, 32 percent, 45 percent, and 48 percent of men, respectively, had at least a 50 percent decrease in the serum PSA level (P<0.001 for both comparisons with mitoxantrone); 22 percent, 35 percent (P=0.01), and 31 percent (P=0.08) had predefined reductions in pain; and 13 percent, 22 percent (P=0.009), and 23 percent (P=0.005) had improvements in the quality of life. Adverse events were also more common in the groups that received docetaxel.
CONCLUSIONS: When given with prednisone, treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain, serum PSA level, and quality of life, as compared with mitoxantrone plus prednisone.

Copyright 2004 Massachusetts Medical Society.
PMID 15470213
Daniel P Petrylak, Catherine M Tangen, Maha H A Hussain, Primo N Lara, Jeffrey A Jones, Mary Ellen Taplin, Patrick A Burch, Donna Berry, Carol Moinpour, Manish Kohli, Mitchell C Benson, Eric J Small, Derek Raghavan, E David Crawford
Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer.
N Engl J Med. 2004 Oct 7;351(15):1513-20. doi: 10.1056/NEJMoa041318.
Abstract/Text BACKGROUND: Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive androgen-independent prostate cancer. We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormone-independent prostate cancer.
METHODS: We randomly assigned 770 men to one of two treatments, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg of docetaxel per square meter of body-surface area on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel, or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily. The primary end point was overall survival; secondary end points were progression-free survival, objective response rates, and post-treatment declines of at least 50 percent in serum prostate-specific antigen (PSA) levels.
RESULTS: Of 674 eligible patients, 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone. In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02 by the log-rank test), and the corresponding hazard ratio for death was 0.80 (95 percent confidence interval, 0.67 to 0.97). The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P<0.001 by the log-rank test). PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients, respectively (P<0.001), and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease, respectively (P=0.30). Grade 3 or 4 neutropenic fevers (P=0.01), nausea and vomiting (P<0.001), and cardiovascular events (P=0.001) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone. Pain relief was similar in both groups.
CONCLUSIONS: The improvement in median survival of nearly two months with docetaxel and estramustine, as compared with mitoxantrone and prednisone, provides support for this approach in men with metastatic, androgen-independent prostate cancer.

Copyright 2004 Massachusetts Medical Society.
PMID 15470214
Ronald de Wit, Johann de Bono, Cora N Sternberg, Karim Fizazi, Bertrand Tombal, Christian Wülfing, Gero Kramer, Jean-Christophe Eymard, Aristotelis Bamias, Joan Carles, Roberto Iacovelli, Bohuslav Melichar, Ásgerður Sverrisdóttir, Christine Theodore, Susan Feyerabend, Carole Helissey, Ayse Ozatilgan, Christine Geffriaud-Ricouard, Daniel Castellano, CARD Investigators
Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer.
N Engl J Med. 2019 Dec 26;381(26):2506-2518. doi: 10.1056/NEJMoa1911206. Epub 2019 Sep 30.
Abstract/Text BACKGROUND: The efficacy and safety of cabazitaxel, as compared with an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel and had progression within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) are unclear.
METHODS: We randomly assigned, in a 1:1 ratio, patients who had previously received docetaxel and an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide) to receive cabazitaxel (at a dose of 25 mg per square meter of body-surface area intravenously every 3 weeks, plus prednisone daily and granulocyte colony-stimulating factor) or the other androgen-signaling-targeted inhibitor (either 1000 mg of abiraterone plus prednisone daily or 160 mg of enzalutamide daily). The primary end point was imaging-based progression-free survival. Secondary end points of survival, response, and safety were assessed.
RESULTS: A total of 255 patients underwent randomization. After a median follow-up of 9.2 months, imaging-based progression or death was reported in 95 of 129 patients (73.6%) in the cabazitaxel group, as compared with 101 of 126 patients (80.2%) in the group that received an androgen-signaling-targeted inhibitor (hazard ratio, 0.54; 95% confidence interval [CI], 0.40 to 0.73; P<0.001). The median imaging-based progression-free survival was 8.0 months with cabazitaxel and 3.7 months with the androgen-signaling-targeted inhibitor. The median overall survival was 13.6 months with cabazitaxel and 11.0 months with the androgen-signaling-targeted inhibitor (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.89; P = 0.008). The median progression-free survival was 4.4 months with cabazitaxel and 2.7 months with an androgen-signaling-targeted inhibitor (hazard ratio for progression or death, 0.52; 95% CI, 0.40 to 0.68; P<0.001), a prostate-specific antigen response occurred in 35.7% and 13.5% of the patients, respectively (P<0.001), and tumor response was noted in 36.5% and 11.5% (P = 0.004). Adverse events of grade 3 or higher occurred in 56.3% of patients receiving cabazitaxel and in 52.4% of those receiving an androgen-signaling-targeted inhibitor. No new safety signals were observed.
CONCLUSIONS: Cabazitaxel significantly improved a number of clinical outcomes, as compared with the androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling-targeted agent (abiraterone or enzalutamide). (Funded by Sanofi; CARD ClinicalTrials.gov number, NCT02485691.).

Copyright © 2019 Massachusetts Medical Society.
PMID 31566937
Kim N Chi, Neeraj Agarwal, Anders Bjartell, Byung Ha Chung, Andrea J Pereira de Santana Gomes, Robert Given, Álvaro Juárez Soto, Axel S Merseburger, Mustafa Özgüroğlu, Hirotsugu Uemura, Dingwei Ye, Kris Deprince, Vahid Naini, Jinhui Li, Shinta Cheng, Margaret K Yu, Ke Zhang, Julie S Larsen, Sharon McCarthy, Simon Chowdhury, TITAN Investigators
Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer.
N Engl J Med. 2019 Jul 4;381(1):13-24. doi: 10.1056/NEJMoa1903307. Epub 2019 May 31.
Abstract/Text BACKGROUND: Apalutamide is an inhibitor of the ligand-binding domain of the androgen receptor. Whether the addition of apalutamide to androgen-deprivation therapy (ADT) would prolong radiographic progression-free survival and overall survival as compared with placebo plus ADT among patients with metastatic, castration-sensitive prostate cancer has not been determined.
METHODS: In this double-blind, phase 3 trial, we randomly assigned patients with metastatic, castration-sensitive prostate cancer to receive apalutamide (240 mg per day) or placebo, added to ADT. Previous treatment for localized disease and previous docetaxel therapy were allowed. The primary end points were radiographic progression-free survival and overall survival.
RESULTS: A total of 525 patients were assigned to receive apalutamide plus ADT and 527 to receive placebo plus ADT. The median age was 68 years. A total of 16.4% of the patients had undergone prostatectomy or received radiotherapy for localized disease, and 10.7% had received previous docetaxel therapy; 62.7% had high-volume disease, and 37.3% had low-volume disease. At the first interim analysis, with a median of 22.7 months of follow-up, the percentage of patients with radiographic progression-free survival at 24 months was 68.2% in the apalutamide group and 47.5% in the placebo group (hazard ratio for radiographic progression or death, 0.48; 95% confidence interval [CI], 0.39 to 0.60; P<0.001). Overall survival at 24 months was also greater with apalutamide than with placebo (82.4% in the apalutamide group vs. 73.5% in the placebo group; hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P = 0.005). The frequency of grade 3 or 4 adverse events was 42.2% in the apalutamide group and 40.8% in the placebo group; rash was more common in the apalutamide group.
CONCLUSIONS: In this trial involving patients with metastatic, castration-sensitive prostate cancer, overall survival and radiographic progression-free survival were significantly longer with the addition of apalutamide to ADT than with placebo plus ADT, and the side-effect profile did not differ substantially between the two groups. (Funded by Janssen Research and Development; TITAN ClinicalTrials.gov number, NCT02489318.).

Copyright © 2019 Massachusetts Medical Society.
PMID 31150574
Chunling Hu, Steven N Hart, Eric C Polley, Rohan Gnanaolivu, Hermela Shimelis, Kun Y Lee, Jenna Lilyquist, Jie Na, Raymond Moore, Samuel O Antwi, William R Bamlet, Kari G Chaffee, John DiCarlo, Zhong Wu, Raed Samara, Pashtoon M Kasi, Robert R McWilliams, Gloria M Petersen, Fergus J Couch
Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.
JAMA. 2018 Jun 19;319(23):2401-2409. doi: 10.1001/jama.2018.6228.
Abstract/Text Importance: Individuals genetically predisposed to pancreatic cancer may benefit from early detection. Genes that predispose to pancreatic cancer and the risks of pancreatic cancer associated with mutations in these genes are not well defined.
Objective: To determine whether inherited germline mutations in cancer predisposition genes are associated with increased risks of pancreatic cancer.
Design, Setting, and Participants: Case-control analysis to identify pancreatic cancer predisposition genes; longitudinal analysis of patients with pancreatic cancer for prognosis. The study included 3030 adults diagnosed as having pancreatic cancer and enrolled in a Mayo Clinic registry between October 12, 2000, and March 31, 2016, with last follow-up on June 22, 2017. Reference controls were 123 136 individuals with exome sequence data in the public Genome Aggregation Database and 53 105 in the Exome Aggregation Consortium database.
Exposures: Individuals were classified based on carrying a deleterious mutation in cancer predisposition genes and having a personal or family history of cancer.
Main Outcomes and Measures: Germline mutations in coding regions of 21 cancer predisposition genes were identified by sequencing of products from a custom multiplex polymerase chain reaction-based panel; associations of genes with pancreatic cancer were assessed by comparing frequency of mutations in genes of pancreatic cancer patients with those of reference controls.
Results: Comparing 3030 case patients with pancreatic cancer (43.2% female; 95.6% non-Hispanic white; mean age at diagnosis, 65.3 [SD, 10.7] years) with reference controls, significant associations were observed between pancreatic cancer and mutations in CDKN2A (0.3% of cases and 0.02% of controls; odds ratio [OR], 12.33; 95% CI, 5.43-25.61); TP53 (0.2% of cases and 0.02% of controls; OR, 6.70; 95% CI, 2.52-14.95); MLH1 (0.13% of cases and 0.02% of controls; OR, 6.66; 95% CI, 1.94-17.53); BRCA2 (1.9% of cases and 0.3% of controls; OR, 6.20; 95% CI, 4.62-8.17); ATM (2.3% of cases and 0.37% of controls; OR, 5.71; 95% CI, 4.38-7.33); and BRCA1 (0.6% of cases and 0.2% of controls; OR, 2.58; 95% CI, 1.54-4.05).
Conclusions and Relevance: In this case-control study, mutations in 6 genes associated with pancreatic cancer were found in 5.5% of all pancreatic cancer patients, including 7.9% of patients with a family history of pancreatic cancer and 5.2% of patients without a family history of pancreatic cancer. Further research is needed for replication in other populations.

PMID 29922827
Vérane Achard, Paul Martin Putora, Aurelius Omlin, Thomas Zilli, Stefanie Fischer
Metastatic Prostate Cancer: Treatment Options.
Oncology. 2022;100(1):48-59. doi: 10.1159/000519861. Epub 2021 Nov 15.
Abstract/Text BACKGROUND: Metastatic prostate cancer (PCa) is associated with considerable diminished overall survival (OS). Standard treatment for metastatic PCa has long been androgen deprivation therapy alone, with patients initially responding to this treatment and then progressing to a castration-resistant phase.
SUMMARY: The advent of novel therapeutic agents has changed this paradigm, with high-level evidence that upfront combination therapy with either docetaxel or new hormonal agents results in improved OS for patients with metastatic hormone-sensitive PCa. In the absence of a comprehensive clinical trial investigating the comparative efficacy and safety of all agents, clinicians are responsible for choosing the most appropriate therapy in close coordination with patients. Furthermore, the same therapeutic agents are also efficient in the castration-resistant phase, leading to the issue of the best therapeutic sequence. Finally, along with systemic therapy and molecular imaging advancements, radiotherapy was investigated in the oligometastatic setting, whether it is to treat the primary tumour or metastases. Key Messages: In this complex landscape, where providers have multiple effective therapeutic options to treat metastatic PCa patients, priority must be given to determine which treatment combination and sequence is best suited to a particular patient, given his comorbidities and preferences.

© 2021 S. Karger AG, Basel.
PMID 34781285
Gwenaelle Gravis, Karim Fizazi, Florence Joly, Stéphane Oudard, Franck Priou, Benjamin Esterni, Igor Latorzeff, Remy Delva, Ivan Krakowski, Brigitte Laguerre, Fréderic Rolland, Christine Théodore, Gael Deplanque, Jean Marc Ferrero, Damien Pouessel, Loïc Mourey, Philippe Beuzeboc, Sylvie Zanetta, Muriel Habibian, Jean François Berdah, Jerome Dauba, Marjorie Baciuchka, Christian Platini, Claude Linassier, Jean Luc Labourey, Jean Pascal Machiels, Claude El Kouri, Alain Ravaud, Etienne Suc, Jean Christophe Eymard, Ali Hasbini, Guilhem Bousquet, Michel Soulie
Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial.
Lancet Oncol. 2013 Feb;14(2):149-58. doi: 10.1016/S1470-2045(12)70560-0. Epub 2013 Jan 8.
Abstract/Text BACKGROUND: Early chemotherapy might improve the overall outcomes of patients with metastatic non-castrate (ie, hormone-sensitive) prostate cancer. We investigated the effects of the addition of docetaxel to androgen-deprivation therapy (ADT) for patients with metastatic non-castrate prostate cancer.
METHODS: In this randomised, open-label, phase 3 study, we enrolled patients in 29 centres in France and one in Belgium. Eligible patients were older than 18 years and had histologically confirmed adenocarcinoma of the prostate and radiologically proven metastatic disease; a Karnofsky score of at least 70%; a life expectancy of at least 3 months; and adequate hepatic, haematological, and renal function. They were randomly assigned to receive to ADT (orchiectomy or luteinising hormone-releasing hormone agonists, alone or combined with non-steroidal antiandrogens) alone or in combination with docetaxel (75 mg/m(2) intravenously on the first day of each 21-day cycle; up to nine cycles). Patients were randomised in a 1:1 ratio, with dynamic minimisation to minimise imbalances in previous systemic treatment with ADT, chemotherapy for local disease or isolated rising concentration of serum prostate-specific antigen, and Glass risk groups. Patients, physicians, and data analysts were not masked to treatment allocation. The primary endpoint was overall survival. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00104715.
FINDINGS: Between Oct 18, 2004, and Dec 31, 2008, 192 patients were randomly allocated to receive ADT plus docetaxel and 193 to receive ADT alone. Median follow-up was 50 months (IQR 39-63). Median overall survival was 58·9 months (95% CI 50·8-69·1) in the group given ADT plus docetaxel and 54·2 months (42·2-not reached) in that given ADT alone (hazard ratio 1·01, 95% CI 0·75-1·36). 72 serious adverse events were reported in the group given ADT plus docetaxel, of which the most frequent were neutropenia (40 [21%]), febrile neutropenia (six [3%]), abnormal liver function tests (three [2%]), and neutropenia with infection (two [1%]). Four treatment-related deaths occurred in the ADT plus docetaxel group (two of which were neutropenia-related), after which the data monitoring committee recommended treatment with granulocyte colony-stimulating factor. After this recommendation, no further treatment-related deaths occurred. No serious adverse events were reported in the ADT alone group.
INTERPRETATION: Docetaxel should not be used as part of first-line treatment for patients with non-castrate metastatic prostate cancer.
FUNDING: French Health Ministry and Institut National du Cancer (PHRC), Sanofi-Aventis, AstraZeneca, and Amgen.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23306100
Nicholas D James, Matthew R Sydes, Noel W Clarke, Malcolm D Mason, David P Dearnaley, Melissa R Spears, Alastair W S Ritchie, Christopher C Parker, J Martin Russell, Gerhardt Attard, Johann de Bono, William Cross, Rob J Jones, George Thalmann, Claire Amos, David Matheson, Robin Millman, Mymoona Alzouebi, Sharon Beesley, Alison J Birtle, Susannah Brock, Richard Cathomas, Prabir Chakraborti, Simon Chowdhury, Audrey Cook, Tony Elliott, Joanna Gale, Stephanie Gibbs, John D Graham, John Hetherington, Robert Hughes, Robert Laing, Fiona McKinna, Duncan B McLaren, Joe M O'Sullivan, Omi Parikh, Clive Peedell, Andrew Protheroe, Angus J Robinson, Narayanan Srihari, Rajaguru Srinivasan, John Staffurth, Santhanam Sundar, Shaun Tolan, David Tsang, John Wagstaff, Mahesh K B Parmar, STAMPEDE investigators
Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.
Lancet. 2016 Mar 19;387(10024):1163-77. doi: 10.1016/S0140-6736(15)01037-5. Epub 2015 Dec 21.
Abstract/Text BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.
METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).
FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.
INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.
FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Copyright © 2016 James et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.
PMID 26719232
Andrew J Armstrong, Russell Z Szmulewitz, Daniel P Petrylak, Jeffrey Holzbeierlein, Arnauld Villers, Arun Azad, Antonio Alcaraz, Boris Alekseev, Taro Iguchi, Neal D Shore, Brad Rosbrook, Jennifer Sugg, Benoit Baron, Lucy Chen, Arnulf Stenzl
ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer.
J Clin Oncol. 2019 Nov 10;37(32):2974-2986. doi: 10.1200/JCO.19.00799. Epub 2019 Jul 22.
Abstract/Text PURPOSE: Enzalutamide, a potent androgen-receptor inhibitor, has demonstrated significant benefits in metastatic and nonmetastatic castration-resistant prostate cancer. We evaluated the efficacy and safety of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC).
METHODS: ARCHES (ClinicalTrials.gov identifier: NCT02677896) is a multinational, double-blind, phase III trial, wherein 1,150 men with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg/day) or placebo, plus androgen deprivation therapy (ADT), stratified by disease volume and prior docetaxel chemotherapy. The primary end point was radiographic progression-free survival.
RESULTS: As of October 14, 2018, the risk of radiographic progression or death was significantly reduced with enzalutamide plus ADT versus placebo plus ADT (hazard ratio, 0.39; 95% CI, 0.30 to 0.50; P < .001; median not reached v 19.0 months). Similar significant improvements in radiographic progression-free survival were reported in prespecified subgroups on the basis of disease volume and prior docetaxel therapy. Enzalutamide plus ADT significantly reduced the risk of prostate-specific antigen progression, initiation of new antineoplastic therapy, first symptomatic skeletal event, castration resistance, and reduced risk of pain progression. More men achieved an undetectable prostate-specific antigen level and/or an objective response with enzalutamide plus ADT (P < .001). Patients in both treatment groups reported a high baseline level of quality of life, which was maintained over time. Grade 3 or greater adverse events were reported in 24.3% of patients who received enzalutamide plus ADT versus 25.6% of patients who received placebo plus ADT, with no unexpected adverse events.
CONCLUSION: Enzalutamide with ADT significantly reduced the risk of metastatic progression or death over time versus placebo plus ADT in men with mHSPC, including those with low-volume disease and/or prior docetaxel, with a safety analysis that seems consistent with the safety profile of enzalutamide in previous clinical trials in castration-resistant prostate cancer.

PMID 31329516
Ian D Davis, Andrew J Martin, Martin R Stockler, Stephen Begbie, Kim N Chi, Simon Chowdhury, Xanthi Coskinas, Mark Frydenberg, Wendy E Hague, Lisa G Horvath, Anthony M Joshua, Nicola J Lawrence, Gavin Marx, John McCaffrey, Ray McDermott, Margaret McJannett, Scott A North, Francis Parnis, Wendy Parulekar, David W Pook, M Neil Reaume, Shahneen K Sandhu, Alvin Tan, T Hsiang Tan, Alastair Thomson, Emily Tu, Francisco Vera-Badillo, Scott G Williams, Sonia Yip, Alison Y Zhang, Robert R Zielinski, Christopher J Sweeney, ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer.
N Engl J Med. 2019 Jul 11;381(2):121-131. doi: 10.1056/NEJMoa1903835. Epub 2019 Jun 2.
Abstract/Text BACKGROUND: Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer.
METHODS: In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events.
RESULTS: A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group.
CONCLUSIONS: Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).

Copyright © 2019 Massachusetts Medical Society.
PMID 31157964
Ian M Thompson, Donna Pauler Ankerst, Chen Chi, M Scott Lucia, Phyllis J Goodman, John J Crowley, Howard L Parnes, Charles A Coltman
Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower.
JAMA. 2005 Jul 6;294(1):66-70. doi: 10.1001/jama.294.1.66.
Abstract/Text CONTEXT: Three fourths of US men older than 50 years have been screened with prostate-specific antigen (PSA) for prostate cancer.
OBJECTIVE: To estimate the receiver operating characteristic (ROC) curve for PSA.
DESIGN, SETTING, AND PARTICIPANTS: Calculation of PSA ROC curves in the placebo group of the Prostate Cancer Prevention Trial, a randomized, prospective study conducted from 1993 to 2003 at 221 US centers. Participants were 18 882 healthy men aged 55 years or older without prostate cancer and with PSA levels less than or equal to 3.0 ng/mL and normal digital rectal examination results, followed up for 7 years with annual PSA measurement and digital rectal examination. If PSA level exceeded 4.0 ng/mL or rectal examination result was abnormal, a prostate biopsy was recommended. After 7 years of study participation, an end-of-study prostate biopsy was recommended in all cancer-free men.
MAIN OUTCOME MEASURES: Operating characteristics of PSA for prostate cancer detection, including sensitivity, specificity, and ROC curve.
RESULTS: Of 8575 men in the placebo group with at least 1 PSA measurement and digital rectal examination in the same year, 5587 (65.2%) had had at least 1 biopsy; of these, 1225 (21.9%) were diagnosed with prostate cancer. Of 1213 cancers with Gleason grade recorded, 250 (20.6%) were Gleason grade 7 or greater and 57 (4.7%) were Gleason grade 8 or greater. The areas under the ROC curve (AUC) for PSA to discriminate any prostate cancer vs no cancer, Gleason grade 7 or greater cancer vs no or lower-grade cancer, and Gleason grade 8 or greater cancer vs no or lower-grade cancer were 0.678 (95% confidence interval [CI], 0.666-0.689), 0.782 (95% CI, 0.748-0.816), and 0.827 (95% CI, 0.761-0.893), respectively (all P values <.001 for AUC vs 50%). For detecting any prostate cancer, PSA cutoff values of 1.1, 2.1, 3.1, and 4.1 ng/mL yielded sensitivities of 83.4%, 52.6%, 32.2%, and 20.5%, and specificities of 38.9%, 72.5%, 86.7%, and 93.8%, respectively. Age-stratified analyses showed slightly better performance of PSA in men younger than 70 years vs those 70 years or older with AUC values of 0.699 (SD, 0.013) vs 0.663 (SD, 0.013) (P = .03).
CONCLUSION: There is no cutpoint of PSA with simultaneous high sensitivity and high specificity for monitoring healthy men for prostate cancer, but rather a continuum of prostate cancer risk at all values of PSA.

PMID 15998892
Benny Holmström, Mattias Johansson, Anders Bergh, Ulf-Håkan Stenman, Göran Hallmans, Pär Stattin
Prostate specific antigen for early detection of prostate cancer: longitudinal study.
BMJ. 2009 Sep 24;339:b3537. Epub 2009 Sep 24.
Abstract/Text OBJECTIVE: To evaluate if prostate specific antigen test attains validity standards required for screening in view of recent prostate cancer screening trial results.
DESIGN: Case-control study nested in longitudinal cohort.
SETTING: Västerbotten Intervention Project cohort, Umeå, Sweden.
PARTICIPANTS: 540 cases and 1034 controls matched for age and date of blood draw.
MAIN OUTCOME MEASURE: Validity of prostate specific antigen for prediction of subsequent prostate cancer diagnosis by record linkage to cancer registry.
RESULTS: Blood samples were drawn on average 7.1 (SD 3.7) years before diagnosis. The area under the curve for prostate specific antigen was 0.84 (95% confidence interval 0.82 to 0.86). At prostate specific antigen cut-off values of 3, 4, and 5 ng/ml, sensitivity estimates were 59%, 44%, and 33%, and specificity estimates were 87%, 92%, and 95%. The positive likelihood ratio commonly considered to "rule in disease" is 10; in this study the positive likelihood ratios were 4.5, 5.5, and 6.4 for prostate specific antigen cut-off values of 3, 4, and 5 ng/ml. The negative likelihood ratio commonly considered to "rule out disease" is 0.1; in this study the negative likelihood ratios were 0.47, 0.61, and 0.70 for prostate specific antigen cut-off values of 3, 4, and 5 ng/ml. For a cut-off of 1.0 ng/ml, the negative likelihood ratio was 0.08.
CONCLUSIONS: No single cut-off value for prostate specific antigen concentration attained likelihood ratios formally required for a screening test. Prostate specific antigen concentrations below 1.0 ng/ml virtually ruled out a prostate cancer diagnosis during the follow-up. Additional biomarkers for early detection of prostate cancer are needed before population based screening for prostate cancer should be introduced.

PMID 19778969
Jeffrey La Rochelle, Christopher L Amling
Prostate cancer screening: what we have learned from the PLCO and ERSPC trials.
Curr Urol Rep. 2010 May;11(3):198-201. doi: 10.1007/s11934-010-0109-5.
Abstract/Text Two large randomized trials on prostate cancer screening have recently reported their 10-year results with somewhat differing conclusions. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) study found a slightly higher risk of a prostate cancer diagnosis in the screening cohort, but no cancer-specific survival advantage was seen for this group. However, the study had widespread screening contamination in the control arm that significantly weakens the study's ability to reach a valid conclusion about the benefits of screening. The European Randomized Study of Screening in Prostate Cancer (ERSPC) was less affected by screening contamination of the control arm, and a cancer-specific survival benefit for the screening arm was seen by 7-8 years (RR, 0.70-0.80). Based on these studies, it is reasonable to conclude that there is a survival benefit for screening, but it may not extend to older men (>75 years) who have undergone prior screening.

PMID 20425627
Gerald L Andriole, E David Crawford, Robert L Grubb, Saundra S Buys, David Chia, Timothy R Church, Mona N Fouad, Edward P Gelmann, Paul A Kvale, Douglas J Reding, Joel L Weissfeld, Lance A Yokochi, Barbara O'Brien, Jonathan D Clapp, Joshua M Rathmell, Thomas L Riley, Richard B Hayes, Barnett S Kramer, Grant Izmirlian, Anthony B Miller, Paul F Pinsky, Philip C Prorok, John K Gohagan, Christine D Berg, PLCO Project Team
Mortality results from a randomized prostate-cancer screening trial.
N Engl J Med. 2009 Mar 26;360(13):1310-9. doi: 10.1056/NEJMoa0810696. Epub 2009 Mar 18.
Abstract/Text BACKGROUND: The effect of screening with prostate-specific-antigen (PSA) testing and digital rectal examination on the rate of death from prostate cancer is unknown. This is the first report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial on prostate-cancer mortality.
METHODS: From 1993 through 2001, we randomly assigned 76,693 men at 10 U.S. study centers to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended. The numbers of all cancers and deaths and causes of death were ascertained.
RESULTS: In the screening group, rates of compliance were 85% for PSA testing and 86% for digital rectal examination. Rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41 to 46% for digital rectal examination. After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group (rate ratio, 1.22; 95% confidence interval [CI], 1.16 to 1.29). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years were 67% complete and consistent with these overall findings.
CONCLUSIONS: After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups. (ClinicalTrials.gov number, NCT00002540.)

2009 Massachusetts Medical Society
PMID 19297565
Fritz H Schröder, Jonas Hugosson, Monique J Roobol, Teuvo L J Tammela, Stefano Ciatto, Vera Nelen, Maciej Kwiatkowski, Marcos Lujan, Hans Lilja, Marco Zappa, Louis J Denis, Franz Recker, Antonio Berenguer, Liisa Määttänen, Chris H Bangma, Gunnar Aus, Arnauld Villers, Xavier Rebillard, Theodorus van der Kwast, Bert G Blijenberg, Sue M Moss, Harry J de Koning, Anssi Auvinen, ERSPC Investigators
Screening and prostate-cancer mortality in a randomized European study.
N Engl J Med. 2009 Mar 26;360(13):1320-8. doi: 10.1056/NEJMoa0810084. Epub 2009 Mar 18.
Abstract/Text BACKGROUND: The European Randomized Study of Screening for Prostate Cancer was initiated in the early 1990s to evaluate the effect of screening with prostate-specific-antigen (PSA) testing on death rates from prostate cancer.
METHODS: We identified 182,000 men between the ages of 50 and 74 years through registries in seven European countries for inclusion in our study. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and ended on December 31, 2006.
RESULTS: In the screening group, 82% of men accepted at least one offer of screening. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio for death from prostate cancer in the screening group, as compared with the control group, was 0.80 (95% confidence interval [CI], 0.65 to 0.98; adjusted P=0.04). The absolute risk difference was 0.71 death per 1000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. The analysis of men who were actually screened during the first round (excluding subjects with noncompliance) provided a rate ratio for death from prostate cancer of 0.73 (95% CI, 0.56 to 0.90).
CONCLUSIONS: PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis. (Current Controlled Trials number, ISRCTN49127736.)

2009 Massachusetts Medical Society
PMID 19297566
E David Crawford, Robert Grubb, Amanda Black, Gerald L Andriole, Ming-Hui Chen, Grant Izmirlian, Christine D Berg, Anthony V D'Amico
Comorbidity and mortality results from a randomized prostate cancer screening trial.
J Clin Oncol. 2011 Feb 1;29(4):355-61. doi: 10.1200/JCO.2010.30.5979. Epub 2010 Nov 1.
Abstract/Text PURPOSE: Estimates of prostate cancer-specific mortality (PCSM) were similar for men randomly assigned to intervention compared with usual care on the Prostate, Lung, Colorectal and Ovarian PC screening study. However, results analyzed by comorbidity strata remain unknown.
PATIENTS AND METHODS: Between 1993 and 2001, of 76,693 men who were randomly assigned to usual care or intervention at 10 US centers, 73,378 (96%) completed a questionnaire that inquired about comorbidity and prostate-specific antigen (PSA) testing before random assignment. Fine and Gray's multivariable analysis was performed to assess whether the randomized screening arm was associated with the risk of PCSM in men with no or minimal versus at least one significant comorbidity, adjusting for age and prerandomization PSA testing.
RESULTS: After 10 years of follow-up, 9,565 deaths occurred, 164 from PC. A significant decrease in the risk of PCSM (22 v 38 deaths; adjusted hazard ratio [AHR], 0.56; 95% CI, 0.33 to 0.95; P = .03) was observed in men with no or minimal comorbidity randomly assigned to intervention versus usual care, and the additional number needed to treat to prevent one PC death at 10 years was five. Among men with at least one significant comorbidity, those randomly assigned to intervention versus usual care did not have a decreased risk of PCSM (62 v 42 deaths; AHR, 1.43; 95% CI, 0.96 to 2.11; P = .08).
CONCLUSION: Selective use of PSA screening for men in good health appears to reduce the risk of PCSM with minimal overtreatment.

PMID 21041707
Jonas Hugosson, Sigrid Carlsson, Gunnar Aus, Svante Bergdahl, Ali Khatami, Pär Lodding, Carl-Gustaf Pihl, Johan Stranne, Erik Holmberg, Hans Lilja
Mortality results from the Göteborg randomised population-based prostate-cancer screening trial.
Lancet Oncol. 2010 Aug;11(8):725-32. doi: 10.1016/S1470-2045(10)70146-7. Epub 2010 Jul 2.
Abstract/Text BACKGROUND: Prostate cancer is one of the leading causes of death from malignant disease among men in the developed world. One strategy to decrease the risk of death from this disease is screening with prostate-specific antigen (PSA); however, the extent of benefit and harm with such screening is under continuous debate.
METHODS: In December, 1994, 20,000 men born between 1930 and 1944, randomly sampled from the population register, were randomised by computer in a 1:1 ratio to either a screening group invited for PSA testing every 2 years (n=10,000) or to a control group not invited (n=10,000). Men in the screening group were invited up to the upper age limit (median 69, range 67-71 years) and only men with raised PSA concentrations were offered additional tests such as digital rectal examination and prostate biopsies. The primary endpoint was prostate-cancer specific mortality, analysed according to the intention-to-screen principle. The study is ongoing, with men who have not reached the upper age limit invited for PSA testing. This is the first planned report on cumulative prostate-cancer incidence and mortality calculated up to Dec 31, 2008. This study is registered as an International Standard Randomised Controlled Trial ISRCTN54449243.
FINDINGS: In each group, 48 men were excluded from the analysis because of death or emigration before the randomisation date, or prevalent prostate cancer. In men randomised to screening, 7578 (76%) of 9952 attended at least once. During a median follow-up of 14 years, 1138 men in the screening group and 718 in the control group were diagnosed with prostate cancer, resulting in a cumulative prostate-cancer incidence of 12.7% in the screening group and 8.2% in the control group (hazard ratio 1.64; 95% CI 1.50-1.80; p<0.0001). The absolute cumulative risk reduction of death from prostate cancer at 14 years was 0.40% (95% CI 0.17-0.64), from 0.90% in the control group to 0.50% in the screening group. The rate ratio for death from prostate cancer was 0.56 (95% CI 0.39-0.82; p=0.002) in the screening compared with the control group. The rate ratio of death from prostate cancer for attendees compared with the control group was 0.44 (95% CI 0.28-0.68; p=0.0002). Overall, 293 (95% CI 177-799) men needed to be invited for screening and 12 to be diagnosed to prevent one prostate cancer death.
INTERPRETATION: This study shows that prostate cancer mortality was reduced almost by half over 14 years. However, the risk of over-diagnosis is substantial and the number needed to treat is at least as high as in breast-cancer screening programmes. The benefit of prostate-cancer screening compares favourably to other cancer screening programs.
FUNDING: The Swedish Cancer Society, the Swedish Research Council, and the National Cancer Institute.

2010 Elsevier Ltd. All rights reserved.
PMID 20598634
G P Haas, J E Montie, J E Pontes
The state of prostate cancer screening in the United States.
Eur Urol. 1993;23(3):337-47.
Abstract/Text
PMID 8508885
H Grönberg, L Damber, J E Damber
Familial prostate cancer in Sweden. A nationwide register cohort study.
Cancer. 1996 Jan 1;77(1):138-43. doi: 10.1002/(SICI)1097-0142(19960101)77:1<138::AID-CNCR23>3.0.CO;2-5.
Abstract/Text BACKGROUND: Although prostate carcinoma is not widely recognized as a familial cancer, familial aggregation of this disease has been shown in some retrospective case-control studies. To study familial prostate cancer in Sweden, a population-based cohort study was performed, that attempted to avoid possible bias connected with some earlier studies of familial prostate cancer.
METHODS: A nationwide register cohort study was conducted using an unselected study population. The study cohort of 5496 sons of Swedish men found to have prostate cancer between 1959 and 1963 was identified through parish offices. All prostate cancer patients reported between 1958 and 1990 in this cohort were identified through linkage to the Swedish Cancer Register. The expected number of prostate cancer patients was calculated using incidence rates obtained from the same register.
RESULTS: A highly significant increased overall standardized incidence ratio (SIR) of 1.70 (95% confidence interval, 1.51-1.90) was obtained for prostate cancer in this cohort, with 302 observed cases compared with 178 expected prostate cancers. The SIR was 3.38 among patients aged 45-49 years at diagnosis, with the risk gradually decreasing to a SIR of 1.35 among patients older than 80 years (trend, P = 0.013). Among sons with a father whose prostate cancer was diagnosed at an early age (< 70 years), a significant trend (P = 0.01) for prostate cancer risk was observed due to early onset of the disease.
CONCLUSIONS: This cohort study provides further evidence that a positive family history of prostate cancer is a risk factor for developing the disease in an unselected population. The increased risk was found for all ages, but was more pronounced in younger men.

PMID 8630920
Rinaa S Punglia, Anthony V D'Amico, William J Catalona, Kimberly A Roehl, Karen M Kuntz
Effect of verification bias on screening for prostate cancer by measurement of prostate-specific antigen.
N Engl J Med. 2003 Jul 24;349(4):335-42. doi: 10.1056/NEJMoa021659.
Abstract/Text BACKGROUND: The sensitivity and specificity of a screening test are biased when disease status is not verified in all subjects and when the likelihood of confirmation depends on the test result itself. We assessed the screening characteristics of the prostate-specific antigen (PSA) measurement after correction for verification bias.
METHODS: Between 1995 and 2001, 6691 men underwent PSA-based screening for prostate cancer. Of these men, 705 (11 percent) subsequently underwent biopsy of the prostate. Under the assumption that the chance of undergoing a biopsy depends only on the PSA-test result and other observed clinical variables, we used a mathematical model to estimate adjusted receiver-operating-characteristic (ROC) curves.
RESULTS: Adjusting for verification bias significantly increased the area under the ROC curve (i.e., the overall diagnostic performance) of the PSA test, as compared with an unadjusted analysis (0.86 vs. 0.69, P<0.001, for men less than 60 years of age; 0.72 vs. 0.62, P=0.008, for men 60 years of age or older). If the threshold PSA value for undergoing biopsy were set at 4.1 ng per milliliter, 82 percent of cancers in younger men and 65 percent of cancers in older men would be missed. A digital rectal examination that is abnormal but not suspicious for cancer does not affect the overall performance characteristics of the test.
CONCLUSIONS: A lower threshold level of PSA for recommending prostate biopsy, particularly in younger men, may improve the clinical value of the PSA test.

Copyright 2003 Massachusetts Medical Society
PMID 12878740
Andrew J Vickers, Angel M Cronin, Thomas Björk, Jonas Manjer, Peter M Nilsson, Anders Dahlin, Anders Bjartell, Peter T Scardino, David Ulmert, Hans Lilja
Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study.
BMJ. 2010 Sep 14;341:c4521. Epub 2010 Sep 14.
Abstract/Text OBJECTIVE: To determine the relation between concentrations of prostate specific antigen at age 60 and subsequent diagnosis of clinically relevant prostate cancer in an unscreened population to evaluate whether screening for prostate cancer and chemoprevention could be stratified by risk.
DESIGN: Case-control study with 1:3 matching nested within a highly representative population based cohort study.
SETTING: General population of Sweden taking part in the Malmo Preventive Project. Cancer registry at the National Board of Health and Welfare.
PARTICIPANTS: 1167 men aged 60 who provided blood samples in 1981 and were followed up to age 85.
MAIN OUTCOME MEASURES: Metastasis or death from prostate cancer.
RESULTS: The rate of screening during the course of the study was low. There were 43 cases of metastasis and 35 deaths from prostate cancer. Concentration of prostate specific antigen at age 60 was associated with prostate cancer metastasis (area under the curve 0.86, 95% confidence interval 0.79 to 0.92; P<0.001) and death from prostate cancer (0.90, 0.84 to 0.96; P<0.001). The greater the number for the area under the curve (values from 0 to 1) the better the test. Although only a minority of the men with concentrations in the top quarter (>2 ng/ml) develop fatal prostate cancer, 90% (78% to 100%) of deaths from prostate cancer occurred in these men. Conversely, men aged 60 with concentrations at the median or lower (≤1 ng/ml) were unlikely to have clinically relevant prostate cancer (0.5% risk of metastasis by age 85 and 0.2% risk of death from prostate cancer).
CONCLUSIONS: The concentration of prostate specific antigen at age 60 predicts lifetime risk of metastasis and death from prostate cancer. Though men aged 60 with concentrations below the median (≤1 ng/ml) might harbour prostate cancer, it is unlikely to become life threatening. Such men could be exempted from further screening, which should instead focus on men with higher concentrations.

PMID 20843935
Stacy Loeb, H Ballentine Carter, William J Catalona, Judd W Moul, Fritz H Schroder
Baseline prostate-specific antigen testing at a young age.
Eur Urol. 2012 Jan;61(1):1-7. doi: 10.1016/j.eururo.2011.07.067. Epub 2011 Aug 10.
Abstract/Text CONTEXT: Prostate cancer screening is highly controversial, including the age to begin prostate-specific antigen (PSA) testing. Several studies have evaluated the usefulness of baseline PSA measurements at a young age.
OBJECTIVE: Review the literature on baseline PSA testing at a young age (≤60 yr) for the prediction of prostate cancer risk and prognosis.
EVIDENCE ACQUISITION: PubMed was searched for English-language publications on baseline PSA and prostate cancer for the period ending April 2011.
EVIDENCE SYNTHESIS: In most published series, median PSA levels in the general male population range from approximately 0.4 to 0.7 ng/ml in men in their 40s and from approximately 0.7 to 1.0 ng/ml in men in their 50s. Evidence from both nonscreening and screening populations has demonstrated the predictive value of a single baseline PSA measurement for prostate cancer risk assessment. Specifically, men with baseline PSA levels above the age-group-specific median have a greater risk of prostate cancer diagnosis during the next 20-25 yr. Additional studies confirmed that higher baseline PSA levels at a young age are also associated with a greater risk of aggressive disease, metastasis, and disease-specific mortality many years later.
CONCLUSIONS: Baseline PSA measurements at a young age are significant predictors of later prostate cancer diagnosis and disease-specific outcomes. Thus baseline PSA testing may be used for risk stratification and to guide screening protocols.

Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.
PMID 21862205

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