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E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 1 0 4 4 – 1 0 4 5
avai lable at www.sciencedirect .com
journal homepage: www.europeanurology.com
Platinum Priority – EditorialReferring to the article published on pp. 1034–1043 of this issue
Postoperative Radiotherapy After Radical Prostatectomy:
Let’s Work Together to Tackle the Known Unknowns
Christopher C. Parker *, Matthew R. Sydes
MRC Clinical Trials Unit at UCL, London, UK; Institute of Cancer Research/Royal Marsden Hospital, London, UK
The debate on the timing of postoperative radiotherapy (RT)
after radical prostatectomy (RP) usually focusses on the
choice between early adjuvant treatment and deferred
salvage treatment. There have been numerous retrospective
studies of postoperative RT. In this month’s issue of
European Urology, Pfister et al. present a pooled analysis
of 10 such studies, having considered no fewer than 115 for
inclusion in their analysis [1].
1. Retrospective studies of postoperative
radiotherapy timing
Retrospective comparisons of outcomes for these two
contrasting approaches are of limited value. A major
problem is the inherent bias between the groups: Those
receiving deferred salvage RT have confirmed recurrent
disease, whereas many of those receiving adjuvant RT
would have been cured by surgery alone. Consequently, the
outcome of adjuvant RT will always appear better than that
of salvage RT.
Pfister et al. have focussed on the outcome of deferred
salvage RT when given ‘‘early,’’ which they define as a
prostate-specific antigen (PSA) level of <0.5 ng/ml. Review-
ing the retrospective studies, they report that even within
this low range of PSA levels, the lower the pre-RT PSA, the
better the subsequent biochemical control. As they
acknowledge, this finding is hard to interpret. It certainly
seems plausible that men with more aggressive recurrent
disease will have more rapidly rising postoperative PSA, and
so, by the time they get salvage RT, their PSA levels will be
higher than those of men with less aggressive recurrent
disease. Retrospective studies cannot avoid this bias.
Having said that, we agree with the authors’ conclusion
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2013.08.013.* Corresponding author. Institute of Cancer Research/Royal Marsden HospitE-mail address: [email protected] (C.C. Parker).
0302-2838/$ – see back matter # 2013 Published by Elsevier B.V. on behahttp://dx.doi.org/10.1016/j.eururo.2013.09.035
that when using salvage RT, it seems prudent to give it early,
as soon as PSA failure is detected [1].
2. Prospective randomised controlled trials
The gold standard of evidence-based medicine is the
randomised controlled trial (RCT) with balanced patient
groups, prospective data collection, and clearly defined
outcome measures. Retrospective studies cannot substitute
for prospective RCTs in this setting, yet there have been
remarkably few completed prospective RCTs of postopera-
tive RT in prostate cancer (PCa)—just three, to be precise.
This parlous situation compares unfavourably with other
common cancers. For example, as long ago as 1995, a meta-
analysis was published of 36 RCTs of postoperative RT in
breast cancer. It is hardly surprising that PCa specialists still
cannot agree on the optimal timing for postoperative RT. For
that matter, they also cannot agree on the most appropriate
target volume, the ideal dose, or the role of adjuvant
hormone therapy whenever postoperative RT is used!
3. Results from randomised trials of postoperative
radiotherapy timing
What can we learn from the three RCTs that have been
completed?
3.1. SWOG 8794
Patients were eligible for the Southwest Oncology Group
trial [2] if they had extracapsular extension, seminal vesicle
involvement, or positive margins at RP. Starting in 1988,
425 men were randomised to immediate RT to the prostate
al, Downs Road, Sutton, Surrey, London, SM2 5PT, UK.
lf of European Association of Urology.
E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 1 0 4 4 – 1 0 4 5 1045
bed versus observation. The primary outcome measure was
metastasis-free survival (MFS): metastases or any death.
Ten-year MFS was 71% for adjuvant RT versus 61% for
observation (hazard ratio [HR]: 0.71; 95% confidence
interval [CI], 0.54–0.94; p = 0.016). Overall survival (OS)
was a secondary outcome measure and also favoured
adjuvant RT (HR: 0.72; 95% CI, 0.55–0.96; p = 0.023). The
trial was small, and only 57 men reported metastatic
disease (20 of 214 in the adjuvant RT arm, 37 of 211 in the
observation arm), so metastases accounted for about a
quarter of MFS events (57 of 207). Treatment for PCa can
only be expected to treat PCa, but around three-quarters of
deaths may be attributed to other causes. Therefore, the OS
benefit should be regarded with caution. It is quite possible
that a chance imbalance in non-PCa deaths could have
contributed to the observed survival benefit.
3.2. EORTC 22911
The European Organisation for Research and Treatment of
Cancer trial had a similar design and recruited 1005
patients, and the latest update had a median follow-up of
10.6 yr [3]. The primary outcome measure was biochemical
progression-free survival, which favoured adjuvant RT
rather than observation (HR: 0.49; 95% CI, 0.41–0.59;
p < 0.0001). This outcome measure shows activity for RT
but, unfortunately, is of little use for clinical decision
making because biochemical progression is the point at
which early salvage RT would be initiated. More important,
there was no statistically significant difference in longer-
term outcome measures, notably, PCa mortality (HR: 0.78;
95% CI, 0.46–1.33; p = 0.34) and OS (HR: 1.18; 95% CI,
0.91–1.53; p = 0.20).
3.3. ARO 96-02
Uniquely, ARO 96-02 was restricted to men with undetect-
able PSA after RP. It is therefore a comparison of truly
adjuvant postoperative RT versus an observation policy.
Starting in 1997, it recruited a modest 307 patients.
Updated results were presented at the American Society
of Clinical Oncology’s Genitourinary Cancers Symposium in
2013, but even at a median follow-up of 9.5 yr, this RCT
remains immature with respect to clinically meaningful end
points, with only 43 deaths and 45 MFS events reported [4].
The number of patients developing metastatic disease was
not given. Based on such small numbers, this RCT
contributes less to the evidence about the relative efficacy
of adjuvant versus salvage RT.
Taken together, the three reported RCTs of postoperative
RT do not provide clear evidence of benefit in long-term
outcome measures for adjuvant treatment with respect to
freedom from metastasis or survival. The optimal timing
of postoperative RT remains an important, unresolved
question.
4. Ongoing trials of postoperative radiotherapy
timing
There is a pressing need for further RCTs to resolve the issue
of early adjuvant RT versus deferred salvage RT. Three such
trials are ongoing: RADICALS-RT (ClinicalTrials.gov identi-
fier NCT00541047) [5], RAVES (ClinicalTrials.gov identifier
NCT00860652), and GETUG-17 (ClinicalTrials.gov identifier
NCT00667069). More information about the trials is
available through trial registries including ClinicalTrials.
gov.
All three trials have similar designs. They are true
adjuvant trials, recruiting men with high-risk disease at RP
with a postoperative PSA <0.2 ng/ml. Men in the control
arm all receive prompt salvage RT in the event of rising PSA.
The combined accrual to these trials has reached >1200
patients, and a pooled analysis is planned to address the
important question of whether or not adjuvant RT improves
OS compared with a salvage RT policy.
Rather than add any further to the extensive literature on
retrospective studies, we urge PCa clinicians to focus their
efforts towards supporting each of these ongoing RCTs. We
have a responsibility to future PCa patients. Indeed, many of
us will be such patients. It is unacceptable that our field lags
more than 20 yr behind that of breast cancer. Together, our
prospective RCTs will define the new standard.
Conflicts of interest: The authors have nothing to disclose.
References
[1] Pfister D, Bolla M, Briganti A, et al. Early salvage radiotherapy
following radical prostatectomy. Eur Urol 2014;65:1034–43.
[2] 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.
[3] Bolla M, van Poppel H, Tombal B, et al. Postoperative radiotherapy
after radical prostatectomy for high-risk prostate cancer: long-term
results of a randomised controlled trial (EORTC trial 22911). Lancet
2012;380:2018–27.
[4] Wiegel T, Bottke D, Bartkowiak D, et al. Phase III results of adjuvant
radiotherapy (RT) versus wait-and-see (WS) in patients with pT3
prostate cancer following radical prostatectomy (RP)(ARO 96-02/
AUO AP 09/95): ten years follow-up. J Clin Oncol 2013;31(Suppl 6).
[5] Parker CC, Clarke NW, Kynaston H, Sydes MR. When should radio-
therapy be used after radical prostatectomy? The RADICALS-RT
Trial. Brit J Med Surg Urol 2010;3:190–3.