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Platinum Priority – Editorial Referring 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 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 EUROPEAN UROLOGY 65 (2014) 1044–1045 available at www.sciencedirect.com journal homepage: www.europeanurology.com DOI of original article: http://dx.doi.org/10.1016/j.eururo.2013.08.013. * Corresponding author. Institute of Cancer Research/Royal Marsden Hospital, Downs Road, Sutton, Surrey, London, SM2 5PT, UK. E-mail address: [email protected] (C.C. Parker). 0302-2838/$ – see back matter # 2013 Published by Elsevier B.V. on behalf of European Association of Urology. http://dx.doi.org/10.1016/j.eururo.2013.09.035

Postoperative Radiotherapy After Radical Prostatectomy: Let's Work Together to Tackle the Known Unknowns

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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.