E U R O P E A N U R O L O G Y 5 8 ( 2 0 1 0 ) 4 6 2 – 4 6 6464

however it is more useful to measure of urinary leakage

which is calculated by the weight of pads. Phone or personal

interviews, validated questionnaires are useful in assessing

continence conditions.

Preoperatively the role of older age, obesity, erectile

dysfunction voiding difficulty, previous TURP, enlarged

prostate, pathological tumour stage and the efficacy of

preoperative physiotherapy were examined.

Different intraoperative factors were investigated in the

literature (blood loss, anastomotic stricture, nerve sparing

technique, length of urethral stump, preservation of bladder

neck and puboprostatic ligaments, surgical experience)

regarding their effect on postoperative continence.

Expert’s comments:

This is an important paper, which gives a good summary of

possible factors that may influence the results of post-pros-

tatectomy continence. However we should supplement two

points.

Firstly the definition of postoperative continence. We

know that different definitions exist. Some of the authors

declare, that those patients, who use maximum one pad per

day are continent as well [1]. According to our opinion the

pre and postoperative definition of continence must be the

same. Only the patients who are completely dry without

any pads can be characterized as continent patients.

The second question is whether the decreased preoper-

ative pelvic floor muscle function has a role in the

development of serious postoperative urinary incontinence

or preoperative biofeedback, pelvic floor muscle training

may improve continence [2]. A study using anal sphinc-

terometry proved, that in case of serious post-prostatec-

tomy incontinence an impaired pelvic floor muscle function

was even founded preoperatively. In a well organised,

randomized, prospective study, the positive effect of pelvic

floor muscle training completed with preoperative biofeed-

back, in the earlier continence recovery and reduction of

several incontinence was proved [3].

References

[1] Sacco E, Prayer-Galetti T, Pinto F, Fracalanza S, Betto G, Pagano F,

et al. Urinary incontinence after radical prostatectomy: incidence by

definition, risk factors and temporal trend in a large series with long

term follow up. BJU Int 2006;97:1234–41.

[2] Majoros A, Asztalos I, Keszthelyi A, Hamvas A, Romics I. Could it be

possible predict the urinary incontinence after radical retropubic

prostatectomy by the help of the preoperative anal sphincterometry ?

(prospective pilot study). Eur Urol Suppl 2007;6:73.

[3] Burgio KL, Goode PS, Urban DA, Umlauf MG, Locher JL, Bueschen A,

et al. Preoperative biofeedback assisted behavioral training to de-

crease post-prostatectomy incontinence: a randomized, controlled

trial. J Urol 2006;175:196–201.

Imre Romics, Attila Majoros

Semmelweis University, Budapest, H-1082 Hungary

DOI:10.1016/j.eururo.2010.06.017

Re: Antitumour Activity of MDV3100 in Castration-Resistant Prostate Cancer: A Phase 1–2 Study

Scher HI, Beer TM, Higano CS, et al. Prostate Cancer

Foundation/Department of Defense Prostate Cancer Clinical

Trials Consortium

Lancet 2010;375:1437–46

Expert’s summary:

In a phase 1/2 study, Scher et al evaluated the safety and

efficacy of MDV3100 in 140 patients with castration-resistant

prostate cancer (CRPC). MDV3100 is a novel antiandrogen. It

has a higher affinity for the androgen receptor (AR) than

previous antiandrogens like bicalutamide. It has further

effects like impairment of nuclear translocation of the AR,

DNA binding, and coactivator recruitment, and it induces

apoptosis. MDV3100 was tested in different doses, ranging

from 30 to 600 mg.

Patients in this study have undergone from one line to

more than four lines of hormonal manipulation: 46% were

chemotherapy naive, and 54% had previous chemotherapy.

Seventy-eight percent of the patients had bone metastases,

54% had lymph node metastases, and 5% were classified as

M0.

Prostate-specific antigen responses (decrease > 50% from

baseline) were seen in 62% of the chemotherapy-naive

patients and in 51% of the patients with previous chemo-

therapy. According to Response Evaluation Criteria in Solid

Tumors (RECIST criteria), 36% of the chemotherapy-naive

patients and 12% of the postchemotherapy patients showed a

partial response. These effects were dose dependent for doses

up to 150 mg with no additional benefit for increased doses.

The median time to radiologic progression was 47 wk for the

entire cohort.

Fatigue was the most common side effect, particularly

for doses >240 mg. No grade 3/4 fatigue was seen for doses

up to 150 mg. Other side effects were anemia and arthralgia.

Of the patients with doses up to 240 mg (n = 87), 1%

discontinued treatment for an adverse event.

Expert’s comments:

Since the advent of docetaxel in 2004 [1], no relevant progress

has been made in the treatment of CRPC. Combination trials of

docetaxel with Calcitriol and, more recently, with bevacizu-

mab were negative [2]. The same was true for the GVAX phase

3 vaccination studies [3]. In contrast, the phase 3 study with

sipuleucel-T, reported at the 2009 American Urological Asso-

ciation meeting [4], has shown a significant overall survival

advantage. Sipuleucel-T is now approved by the US Food and

Drug Administration.

Other promising compounds are in phase 3 testing.

Abiraterone has shown results very similar to MDV3100 in

phase 1/2 testing [5,6]; however, abiraterone has a

different, possibly more pronounced side-effect profile.

Two phase 3 studies with abiraterone have finished accrual,

and first results are expected in autumn 2010.

E U R O P E A N U R O L O G Y 5 8 ( 2 0 1 0 ) 4 6 2 – 4 6 6 465

ZD4054, an endothelin antagonist, has shown a signifi-

cant overall survival advantage in a randomized phase 2

study [7]. The results of the first phase 3 trial are about to be

reported in September 2010.

I agree with Scher et al that the results with MDV3100

are encouraging, particularly in view of the mild side

effects. The phase 3 AFFIRM trial in postchemotherapy

patients is under way, with the first results probably

expected in 2012.

These are exciting times for clinical research in CRPC.

Even with all due caution, the prediction seems warranted

that CRPC will be treated differently within the next 2–4 yr.

MDV3100 may likely play a relevant role in this context.

Conflicts of interest: The author has nothing to disclose.

References

[1] Tannock IF, et al. N Engl J Med 2004;351:1502–12.

[2] Kelly WK, et al. J Clin Oncol 2010;28(Suppl):7s, abs. LBA4511.

[3] Scher HI, et al. J Clin Oncol 2010;28(Suppl):7s, abs. 4509.

[4] Lassi K, Dawson NA. Curr Opin Oncol 2010;22:263–7.

[5] Attard G, et al. J Clin Oncol 2009;27:3742–8.

[6] Attard G, et al. J Clin Oncol 2008;26:4563–71.

[7] James ND, et al. Eur Urol 2009;55:1112–23.

Kurt Miller

Department of Urology, Charite Berlin, Hindenburgdamm 30,

12200 Berlin, Germany

E-mail address: miller@medizin.fu-berlin.de

DOI:10.1016/j.eururo.2010.06.018

Re: Effect of Dutasteride on the Risk of Prostate Cancer

Andriole GL, Bostwick DG, Brawley OW, et al.

N Engl J Med 2010;363:1192–202

Experts’ summary:

This is a large, multicentre, placebo-controlled, randomised,

controlled trial of 0.5 mg dutasteride daily in >6000 men at

high risk of but without diagnosed prostate cancer. Appropriate

exclusion criteria were applied. Biopsies were taken at 2 yr and

4 yr; patients found to have cancer at these protocol-directed

biopsies or at non-protocol-directed biopsies did not continue

the study treatment. All pathology was rigorously validated

with external review. The primary end point was prostate

cancer diagnosis after 2 yr and 4 yr of treatment. Other end

points related to the volume and grading of the disease, pres-

ence of preneoplastic lesions, and benign prostate hyperplasia

(BPH) progression parameters such as acute urinary retention.

The seminal findings were that dutasteride led to a 22.8%

relative risk reduction and a 5.1% absolute risk reduction in

prostate cancer diagnosis compared to placebo. This effect

was most pronounced for lower grade tumours, and overall

there was no difference at 4 yr for Gleason grade 8–10

tumours. Dutasteride also resulted in fewer diagnoses of

preneoplastic lesions (high-grade prostatic intraepithelial

neoplasia and atypical small acinar proliferation) compared

with placebo. Dutasteride was also associated with an

improvement of BPH progression parameters and had a

dropout rate of <5%.

Experts’ comments:

It is unsurprising and was reported previously that dutaste-

ride reduced prostate volume and BPH progression events,

with little overall morbidity and a low dropout rate. The

headline of this study is that dutasteride reduced the inci-

dence of prostate cancer for low-grade tumours but not high-

grade (Gleason 8–10) tumours, which actually increased in

years 3 and 4. This increase, similar in nature to that found for

finasteride in the Prostate Cancer Prevention Trial [1], is likely

explained by the sampling effect of prostate volume reduction

and the fact that more prostate cancer diagnoses were made in

the placebo cohort, and those subjects were then removed

from the study and thus did not enter the later time points. In

other words, these low-grade tumours in the placebo group

were not left to become higher grade tumours that could

be picked up at the end-of-study biopsies. In any case, the

overall difference between dutasteride and placebo in Gleason

8–10 tumours over the entire study time period was not

significant.

The reduction in prostate cancer incidence for high-risk

patients with dutasteride remained after adjustment for

age, body mass index (BMI), prostate volume, family history

of prostate cancer, and prostate-specific antigen

(PSA) levels. Prostate cancer risk was also reduced by

dutasteride by a similar extent (range: 16.1–32.0%) across

all prespecified subgroups, based on age, family history of

prostate cancer, PSA, prostate volume, International Pros-

tate Symptom Score (<8 or �8), and BMI. Whether

dutasteride caused greater risk reductions in prostate

cancer based on race or ethnicity was not analysed.

Dutasteride also reduced the incidence of known

preneoplastic lesions; this finding supports the inference

that the drug has a real effect at the early stages of prostate

carcinogenesis but not at its later stages. There is significant

basic scientific rationale for this, with the known effects of

5a-reductase inhibitors on tumour apoptosis [2] and

angiogenesis [3,4]. Our take-home word of wisdom from

this paper is that dutasteride is useful in preventing

prostate cancer in men at high risk of developing the

disease without causing significant adverse effects in

the majority of these men. What is still unknown is

whether the disease that dutasteride helps prevent is

clinically significant, why it does not seem to have any

significant beneficial effect on disease we know for sure is

clinically important (ie, high-grade disease), and whether

dutasteride would help prevent prostate cancer in a more

general population rather than just in men at high risk of

developing prostate cancer.

Conflicts of interest: The authors have nothing to disclose.