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EUROPEAN UROLOGY 63 (2013) 1128–1133
A total of 731 men agreed to participate in the trial; 364
were randomized to RP, and 367 were randomized to
observation. At median follow-up of 10.0 yr, RP provided no
benefit with respect to ACM (hazard ratio [HR]: 0.88; 95%
confidence interval [CI], 0.71–1.08; p = 0.22; absolute risk
reduction, 2.9 percentage points) or PCSM (HR: 0.63; 95%
CI, 0.36–1.09; p = 0.09; absolute risk reduction, 2.6 percentage
points). For men with PSA >10 ng/ml, subgroup analysis
demonstrated that RP was associated with decreased ACM
(HR: 0.67; 95% CI, 0.48–0.94) and PCSM (HR: 0.36; 95%
CI, 0.15–0.89).
overall and PCa-specific survival. The study also demonstrated higher rates of non-PCSM than had been previously
suggested by other studies over similar time frames [2].
Such information is crucial when counseling men about the
benefits of treatment. This study adds to mounting evidence
that low-risk tumors may safely be observed and high-risk
tumors should be treated.
Conflicts of interest: The authors have nothing to disclose.
References
Experts’ comments:
This study is truly pivotal because it is the first randomized
trial to assess the impact of RP versus observation in the PSA
era, an issue that remains important and unclear >17 yr after
the study first opened. A prior Scandinavian trial largely
performed in the pre-PSA era demonstrated improved
PCa-specific survival [1] and, with longer follow-up, improved
overall survival [2] in patients who received RP. However, the
generalizability of this Scandinavian trial has been questioned
because >80% of study participants were diagnosed by digital
rectal examination.
Although the PIVOT study is flawed (accrual goals were
not met, and the investigators failed to account for
differences in outcomes based on provider [3]), Wilt et al.
report their results with 10 yr of median follow-up and
demonstrate clearly that men with lower-risk cancers
do not benefit from RP, a finding that is largely consistent
with active surveillance trials [4]. Although this result is not
surprising, several important findings are worth noting.
Men with higher-risk PCa benefited from RP. Bone metastases were lower in the RP group than in the observation
group, and patients with PSA >10ng/ml had improved
Re: Postoperative Radiotherapy After Radical Prostatectomy for High-risk Prostate Cancer: Long-term
Results of a Randomised Controlled Trial (EORTC Trial
22911)
Bolla M, van Poppel H, Tombal B, et al.
Lancet 2012;380:2018–27
Experts’ summary:
This paper reports on the third large randomized trial exploring the value of adjuvant radiotherapy following radical prostatectomy for prostate cancer [1,2]. A total of 1005 patients
from 37 European institutions were randomized. Eligible
patients had pT2N0M0 or pT3N0M0 disease after surgery
and at least one of the following additional risk factors:
extracapsular extension, positive surgical margins, or seminal
vesicle invasion.
In total, 502 patients were assigned to immediate
irradiation (60 Gy). For the 503 patients in the wait-andsee group, irradiation was deferred until biochemical
progression had occurred. After 10 yr, 227 patients (45.1%)
remained biochemically and clinically recurrence-free. Only
[1] Holmberg L, Bill-Axelson A, Helgesen F, et al. A randomized trial
comparing radical prostatectomy with watchful waiting in early
prostate cancer. N Engl J Med 2002;347:781–9.
[2] Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy
versus watchful waiting in early prostate cancer. N Engl J Med
2011;364:1708–17.
[3] Vickers AJ, Bianco FJ, Serio AM, et al. The surgical learning curve for
prostate cancer control after radical prostatectomy. J Natl Cancer
Inst 2007;99:1171–7.
[4] Klotz L, Zhang L, Lam A, Nam R, Mamedov A, Loblaw A. Clinical
results of long-term follow-up of a large, active surveillance cohort
with localized prostate cancer. J Clin Oncol 2010;28:126–31.
Jonathan L. Silberstein*, James A. Eastham
Urology Service, Department of Surgery,
Memorial Sloan-Kettering Cancer Center, New York, NY, USA
*Corresponding author. Memorial Sloan-Kettering Cancer Center,
Urology Service, Department of Surgery, 1275 York Ave.,
New York, NY 10021, USA.
E-mail address: [email protected] (J.L. Silberstein).
http://dx.doi.org/10.1016/j.eururo.2013.03.020
155 patients (30.8%) received salvage irradiation. Biochemical progression was more common in the wait-and-see group
than the immediate irradiation group (61.8% compared with
39.4%), but this reduced risk did not translate into a survival
benefit, as the two treatment groups did not differ with
respect to progression-free survival (PFS), distant metastasis–free survival, or overall survival.
Experts’ comments:
It is already apparent that this important paper will be interpreted in two quite opposite ways. Radiation oncologists will
highlight the improved biochemical-free survival in the immediate irradiation group and argue in favor of adjuvant
therapy for patients with high-risk features after radical
prostatectomy. Urologists will point to the lack of improvement in overall survival, clinical PFS, or distant metastasis, as
well as the higher rate of late adverse effects in the patients
randomized to immediate irradiation.
What are we to conclude? Clearly, there is a population
of patients who will benefit from early administration of
radiotherapy after radical prostatectomy, that is, patients
with extracapsular disease and positive margins. However,
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EUROPEAN UROLOGY 63 (2013) 1128–1133
if the prostate-specific antigen (PSA) remains undetectable, then a period of surveillance in this cohort may
also be reasonable, especially as patients continue their
functional recovery after surgery. In the era of ultrasensitive PSA testing, there may be a considerable period during
which early salvage radiotherapy (eg, PSA 0.3 ng/ml)
will provide the same survival outcome as adjuvant
radiotherapy.
Most important, Bolla et al. have shown us that many
patients with these high-risk features do perfectly well
with observation and do not require further intervention. At
10-yr follow-up, more than half of the patients (272 patients,
54% in the wait-and-see group) had no additional treatment.
This is a population of patients who would have been
overtreated had they undergone immediate irradiation, and
therefore they avoided the inconvenience, expense, and
morbidity of this intervention [3].
For now, many urologists (the gatekeepers for referral to
radiation oncology) will interpret this study as showing
no survival advantage for immediate irradiation and will
observe high-risk patients after radical prostatectomy with
a view to early salvage radiotherapy instead. That will
certainly be our practice.
References
Conflicts of interest: The authors have nothing to disclose.
http://dx.doi.org/10.1016/j.eururo.2013.03.021
Re: Effect of Abiraterone Acetate and Prednisone
Compared with Placebo and Prednisone on Pain Control
and Skeletal-related Events in Patients with Metastatic
Castration-resistant Prostate Cancer: Exploratory Analysis of Data from the COU-AA-301 Randomised Trial
Logothetis CJ, Basch E, Molina A, et al.
events leading to discontinuation: 10% compared with 13%).
The end points of the secondary analysis, on which the Lancet
Oncology article is based, were occurrence of skeletal-related
events and pain care.
With a median follow-up of 20.2 mo, the combination
of abiraterone acetate and prednisone favorably affected
disease-related symptoms (ie, pain palliation, delay in pain
progression, and delay to skeletal-related events) compared
with placebo and prednisone. Abiraterone acetate and
prednisone resulted in significantly more pain palliation
(45% compared with 28.8%; p = 0.0005) and faster pain
palliation (median time to palliation: 5.6 mo compared with
13.7 mo; p = 0.0018) than placebo and prednisone. Median
time to occurrence of the first skeletal-related event was
significantly longer with abiraterone acetate and prednisone compared with placebo and prednisone (25 mo
compared with 20.3 mo; delay: 4.7 mo; p = 0.0001).
Lancet Oncol 2012;13:1210–7
Experts’ summary:
Logothetis et al. performed a secondary analysis of the landmark placebo-controlled phase 3 trial that led the US Food and
Drug Administration to approve abiraterone acetate for use
in the postchemotherapy setting (COU-AA-301). The study
was designed as an international, multicenter, prospective,
randomized trial comparing the survival effect of abiraterone
acetate and prednisone with that of placebo and prednisone
in patients with metastatic castration-resistant prostate
cancer (mCRPC) previously treated with one or two lines
of chemotherapy (one of which was docetaxel-based) [1,2].
Eligible patients were randomly assigned (2:1) to receive
either abiraterone acetate and prednisone (n = 797) or placebo and prednisone (n = 398) with an intention-to-treat
purpose. Overall survival was the primary end point of this
trial. Patients were encouraged to continue treatment until
disease progression (on the basis of radiographic findings,
clinical findings, or change in serum prostate-specific antigen
[PSA] levels).
Compared with placebo, abiraterone acetate significantly
improved overall survival (14.8 mo compared with 10.9 mo;
hazard ratio: 0.65), had a better PSA response (38% compared
with 10%), and was better tolerated (grade 3–4 adverse
[1] Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy
for pathological T3N0M0 prostate cancer significantly reduces risk
of metastases and improves survival: long-term followup of a
randomized clinical trial. J Urol 2009;181:956–62.
[2] Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant
radiotherapy after radical prostatectomy compared with radical
prostatectomy alone in pT3 prostate cancer with postoperative
undetectable prostate-specific antigen: ARO 96–02/AUO AP 09/95.
J Clin Oncol 2009;27:2924–30.
[3] Abdollah F, Suardi N, Cozzarini C, et al. Selecting the optimal
candidate for adjuvant radiotherapy after radical prostatectomy
for prostate cancer: a long-term survival analysis. Eur Urol 2013;
63:998–1008.
James B. Duthiea, Declan G. Murphya,b,*
a
Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne,
Australia
b
Australian Prostate Cancer Research Centre, Epworth Healthcare,
Richmond, Australia
*Corresponding author. Division of Cancer Surgery, Peter MacCallum
Cancer Centre, St Andrews Place, East Melbourne,
Victoria 3002, Australia.
E-mail address: [email protected] (D.G. Murphy).
Experts’ comments:
Prostate cancer (PCa) is the most commonly diagnosed cancer
among men in the industrialized world. Metastatic bone
disease is the most common cause of PCa pain and of
serious skeletal-related events, defined as pathologic fractures, spinal cord compression, bone pain requiring palliative
radiotherapy, and orthopedic surgery. Both bone metastases
and skeletal-related events are associated with unfavorable
prognosis and greatly affect quality of life. Numerous new
drugs have been approved for patients with mCRPC, with
variable efficacy on overall survival and secondary end
points such as bone pain and skeletal-related events. This
study provides convincing evidence that abiraterone acetate