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249 (82%) were significant PCa, and 53 (18%) were nonsignificant PCa. The detection accuracy of significant PCa by targeted
biopsies was higher than the detection accuracy of extended
systematic biopsies ( p < 0.001). Targeted biopsies also
detected 16% more grade IV/V cases. A targeted biopsiesonly
strategy without extended systematic biopsies would have
necessitated a mean of 3.8 cores performed in only 63% of
patients with positive MRI and avoided the potentially unnecessary diagnosis of 13% (53 of 302) of nonsignificant PCa.
Experts comments:
In the era of overdetection of insignificant PCas, this study is
of major interest and draws attractive perspectives. As many
as half of the PCas in men aged >50 yr may be insignificant
[1]. As suggested by the authors, MRI-targeted biopsies may
avoid unnecessary biopsies in almost 40% of patients and may
avoid unnecessary diagnosis in >10% of patients harboring
insignificant cancers. Also, decreasing from 12 cores to 34
cores in a biopsy procedure may affect morbidity, especially
by decreasing the risk of urinary tract infections [2].
Notwithstanding the quality of this work, some comments should be made on the methodology. From our point
of view, choosing predictors of insignificancy on biopsy as a
surrogate for true insignificant cancers diagnosed on
whole-mount analysis may engender significant bias in
the results. As previously reported in many studies,
prostate biopsies are subject to understaging. The detection of a low-grade microfocal cancer on biopsy is
correlated with insignificant cancer in <60% of cases
[3,4]. With this fact in mind, how can one choose biopsy as a
verification for MRI evaluation? Among the 302 cancers
detected in this series, at least some must have been treated
with radical prostatectomy, and we are somewhat frustrated at not finding a proper correlation analysis with the
specimen histologic findings.

Re: A Prospective, Randomized Pilot Study Evaluating

the Effects of Metformin and Lifestyle Intervention on
Patients With Prostate Cancer Receiving Androgen
Deprivation Therapy
Nobes JB, Langley SE, Klopper T, Russell-Jones D, Laing RW
BJU Int. In press. doi:10.1111/j.1464-410X.2011.10555.x
Experts summary:
This randomized 6-mo interventional versus standard-of-care
(controls) preliminary trial included in each arm 20 men with
a mean age of 70 yr who were on androgen deprivation
therapy (ADT) for prostate cancer (PCa). The intervention
was a combination of metformin (850 mg daily for 2 wk
and then 850 mg twice daily thereafter) with a low glycemic
index diet and exercise encouragement.
After 6 mo, men in the intervention arm experienced
significant reductions in waist circumference (WC), overall
weight, body mass index, and systolic blood pressure
compared to controls. Men in the intervention arm
also experienced a significant within-group reduction in

Another point of discussion concerns the population

itself. Should prebiopsy MRI be performed for all patients
with suspected localized PCa? The authors did not exclude
patients with intermediate- or high-risk cancers. Some of
these patients even had PSA values up to 100 ng/ml. The
concept of biopsy-based insignificant cancer in these
patients is highly questionable. Prebiopsy MRI and targeted
biopsies should probably be restricted to selected patients
with suspicion of low-risk PCa, who are really the patients at
risk of overdetection and overtreatment.
Conicts of interest: The authors have nothing to disclose.

References
[1] Haas GP, Delongchamps NB, Jones RF, et al. Needle biopsies on
autopsy prostates: sensitivity of cancer detection based on true
prevalence. J Natl Cancer Inst 2007;99:14849.
[2] Nam RK, Saskin R, Lee Y, et al. Increasing hospital admission rates
for urological complications after transrectal ultrasound guided
prostate biopsy. J Urol 2010;183:9638.
[3] Allan RW, Sanderson H, Epstein JI. Correlation of minute (05 mm or
less) focus of prostate adenocarcinoma on needle biopsy with
radical prostatectomy specimen: role of prostate specic antigen
density. J Urol 2003;170:3702.
[4] Boccon-Gibod LM, Dumonceau O, Toublanc M, Ravery V, BocconGibod LA. Micro-focal prostate cancer: a comparison of biopsy and
radical prostatectomy specimen features. Eur Urol 2005;48:8959.
Nicolas Barry Delongchamps, Marc Zerbib*
Urology Department, Cochin Hospital, Paris Descartes University,
27 Fg St Jacques 75014, Paris, France
*Corresponding author.
E-mail address: marc.zerbib@cch.aphp.fr (M. Zerbib)
DOI: 10.1016/j.eururo.2011.12.038

hemoglobin A1c that did not occur within the control arm.
Other parameters including markers of lipids and insulin
resistance were not significantly different.
Experts comments:
Hundreds of millions, perhaps billions, of dollars have been
spent over the past decade on attempting to discover the best
novel prescription or dietary supplement interventions for
prevention of PCa and biochemical recurrence and to mollify
side effects of PCa treatment. It is fascinating that it may turn
out that generic cost-effective (ie, cheap), heart-healthy, and
safe medications may have the optimal benefit to risk ratio
compared to anything else proffered to patients [1]. Indeed,
heart health appears tantamount to prostate health.
Metformin and lifestyle changes have a wonderful history
of safe and moderately effective weight loss in men and
women and show an ability to reduce the risk of other
metabolic syndromerelated issues and even diabetes [2].
These beneficial effects are still being observed long term, for
at least a decade, with these simplistic and cost-effective

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interventions. Metformin inhibits gluconeogenesis and

glucose absorption, controls insulin levels, and promotes
AMP-activated protein kinase, which discourages uncontrolled tumor growth [3]. Thus metformin is also being tested
in multiple clinical trials as a potential neoadjuvant and
adjuvant medication, and this includes a phase 3 trial in
breast cancer with survival as a primary end point.
Nobes et al should be praised not only for utilizing such a
heart-healthy, safe, comprehensive lifestyle and medication
approach with ADT patients (no compliance or adverse
events were observed) but also for precisely mimicking the
specific metformin dosage that was effective from past
cardiovascular clinical trials. Interestingly, past noteworthy
cardiovascular studies have demonstrated that lifestyle
changes were actually more effective than metformin [2],
and this is one of the unanswered questions of this current
preliminary study by Nobes et al. The intervention was a
combination of metformin and lifestyle changes, so the
relative efficacy of each approach individually in men on
ADT is not known at this time. Past short-term studies of
moderate lifestyle changes alone on ADT have been
impressive [4], but long-term changes may require medication such as Metformin to promote adequate synergy and
tangible clinical efficacy. Regardless, Nobes et al should
again be commended because their research team will also
apparently investigate the impact of these interventions
individually in a future, larger multicenter trial.
The study by Nobes et al may be harbinger of a steady
paradigm shift in PCa research that is exciting. A past
obsession with novel and expensive agents in multiple
areas of PCa has potentially led to an approach in which we
cant see the forest for the trees, and this has not been
healthy. Because cardiovascular disease is the number 1
cause of mortality in men with and without PCa, the ideal
preventive or side effectameliorating agent should be one
that, in the worst-case scenario, reduces the risk of the
number 1 cause of death in men and, in the best-case
scenario, provides a 2-for-1 benefit and beyond, so to speak.
Sitting at my computer and writing this review produces a

limitless smile because if one were to peruse the medical

literature right now, diet, exercise and lifestyle changes,
aspirin, cholesterol-lowering agents, and now metformin
appear to be some of the more promising agents in PCa.
They are all cost effective and safe, operate under some
unique and common heart-healthy mechanisms, and may
give clinicians and patients that much needed 2-for-1
benefit. Indeed, heart health is tantamount to prostate
health, and it seems that researchers are beginning to see
multiple diverse forests over a few trees! Perhaps this
approach will reverberate to such an extent that it may even
resolve the controversy over prostate-specific antigen
screening [5].

Re: Dutasteride Improves Outcomes of Benign Prostatic

Hyperplasia When Evaluated for Prostate Cancer Risk
Reduction: Secondary Analysis of the Reduction by
Dutasteride of Prostate Cancer Events Trial
Roehrborn CG, Nickel JC, Andriole GL, et al

enrollment [1]. The article reviewed in this section of European

Urology was a secondary analysis of men participating in the
REDUCE trial. In this particular cohort it evaluated the following benign prostatic hyperplasia (BPH) outcome parameters:
changes of prostate volume, lower urinary tract symptoms
assessed by IPSS, symptom burden assessed by IPSS question
8, and BPH Impact Index (BII), as well as the incidence of
acute urinary retention, BPH-related surgery, and urinary tract
infection.
At baseline, mean values of the investigated men were
age 63 yr, total IPSS 8.6, question 8 of the IPSS questionnaire
2.1, BII 2.2, prostate volume 46 cm3, serum PSA 5.9 ng/ml,
maximum flow rate 15.3 ml/s, and postvoid residuals 46 ml.
Of the 8122 men investigated in this study, 3896 (48%) had
no or only mild symptoms (IPSS 07), and 1581 (20%) had a
prostate volume <30 cm3. At 4 yr, the following values were
noted:

Urology 2011;78:6417
Experts summary:
The Reduction by Dutasteride of Prostate Cancer Events
(REDUCE) trial, an international multicenter randomized, double-blind 4-yr trial to determine the risk of incident prostate
cancer in men treated with dutasteride 0.5 mg or placebo once
daily, included male volunteers between 50 and 75 yr of age,
with a serum prostate-specific antigen (PSA) concentration of
2.510 ng/ml, prostate volume 80 cm3, International Prostate Symptom Score (IPSS) <25 (or <20 when using a1-blockers), and negative biopsies for prostate cancer before trial

Conicts of interest: Mark A. Moyad has received lecture and consulting

honoraria from Abbott Labs.

References
[1] Solomon KR, Freeman MR. The complex interplay between cholesterol and prostate malignancy. Urol Clin North Am 2011;38:24359.
[2] Diabetes Prevention Program Research Group. 10-year follow-up of
diabetes incidence and weight loss in the Diabetes Prevention
Program Outcomes Study. Lancet 2009;373:167786.
[3] Jalving M, Gietema JA, Lefrandt JD, et al. Metformin: taking away the
candy for cancer? Eur J Cancer 2010;46:236980.
[4] Galvao DA, Taaffe DR, Spry N, Joseph D, Newton RU. Combined
resistance and aerobic exercise program reverses muscle loss in
men undergoing androgen suppression therapy for prostate cancer
without bone metastases: a randomized controlled trial. J Clin
Oncol 2010;28:3407.
[5] Crawford ED, Grubb III R, Black A, et al. Comorbidity and mortality
results from a randomized prostate cancer screening trial. J Clin
Oncol 2011;29:35561.
Mark A. Moyad
University of Michigan Medical Center, Department of Urology,
Ann Arbor, MI 48109-0330, USA
E-mail address: moyad@umich.edu
DOI: 10.1016/j.eururo.2011.12.039