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SPECIAL FOCUS y Prostate Cancer

Special Report

Adjuvant versus salvage

radiotherapy following
radical prostatectomy: do the
AUA/ASTRO guidelines have
all the answers?
Expert Rev. Anticancer Ther. 14(11), 12651270 (2014)

Michael Z Su1,
Andrew B Kneebone1,2
and Henry H Woo*3
1
Northern Clinical School, Sydney
Medical School, University of Sydney,
St Leonards, Australia
2
Department of Radiation Oncology,
Royal North Shore Hospital,
St Leonards, Australia
3
Sydney Adventist Hospital Clinical
School, Sydney Medical School,
University of Sydney, Wahroonga,
Australia
*Author for correspondence:
hwoo@urologist.net.au

Debate continues surrounding the indications for adjuvant and salvage radiotherapy as the
published randomized trials have only addressed adjuvant treatment. Salvage radiotherapy has
been advocated to limit significant toxicity to patients that would not have benefited from
immediate adjuvant radiotherapy. The American Urological Association and American Society
for Radiation Oncology guideline released in 2013 has since recommended offering adjuvant
therapy to all patients with any adverse features and salvage to those with prostate-specific
antigen or local recurrence. The suggested criteria is limited in its application as it potentially
subjects patients with few adverse features to adjuvant therapy despite not qualifying as high
risk according to established postoperative predictive tools such as the Kattan nomogram. This
article reviews the indications for postoperative radiotherapy, limitations of the guideline
and alternative prognostication tools for clinicians faced with biochemical or locally recurrent
post-prostatectomy prostate cancer.
KEYWORDS: adjuvant radiotherapy oncological outcomes postoperative radiotherapy prostate cancer radical
prostatectomy salvage radiotherapy

The efficacy of adjuvant postoperative radiotherapy (ART) after radical prostatectomy for
patients with high risk features has been demonstrated in three randomized controlled
trials [13]. This has led the American Urological
Association (AUA) and American Society for
Radiation Oncology (ASTRO) to release in
2013 a joint guideline on post-prostatectomy
radiotherapy to address the expanding body of
evidence on this approach [4]. One of their recommendations was that physicians should offer
adjuvant radiotherapy to patients with adverse
pathologic findings at prostatectomy, including
seminal vesicle invasion, positive surgical margins or extraprostatic extension because of demonstrated reductions in biochemical recurrence
(BCR), local recurrence and clinical progression. Salvage radiotherapy (SRT) was also
recommended for patients with prostate-specific
antigen (PSA) or local recurrence after radical
prostatectomy in whom there is no evidence of
informahealthcare.com

10.1586/14737140.2014.972381

distant metastatic disease with biochemical

relapse defined as 0.2 ng/ml or higher.
However, despite these recommendations,
debate continues over the timing and role of
post-prostatectomy radiotherapy leading to the
relatively low rate of utilization of adjuvant
radiotherapy around the world [510]. Many
argue that SRT should be regarded as the standard of care for high-risk patients due to the
toxicity related to ART and the potential overtreatment of patients that may not develop
biochemical disease recurrence [4]. The purpose
of this article is to explore some of these controversies that have led to the poor adoption
of guideline recommendations.
Is the consensus definition of biochemical
failure (PSA > 0.2) clinically relevant?

The guidelines state that clinicians should

define BCR as a detectable or rising PSA value
after surgery that is 0.2 ng/ml with a second

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ISSN 1473-7140

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Special Report

Su, Kneebone & Woo

confirmatory level 0.2 ng/ml. They also recommend that

patients should be informed that the development of a PSA
recurrence after surgery is associated with a higher risk of development of metastatic prostate cancer or death from the disease.
The three randomized trials of adjuvant RT have essentially
shown a halving in the risk of biochemical failure with adjuvant
radiotherapy but only one has shown a benefit in reducing the
rate of distant metastases and survival (Southwest Oncology
Group study) [11]. Ten-year follow-up of the European Organization for Research and Treatment of Cancer and arbeitsgemeinschaft radiologische onkologie trials, however, have both failed
to show a difference in progression-free survival (PFS) or overall
survival leading some to question the validity of biochemical
failure-free survival as an endpoint influencing treatment recommendations [3,12]. It is possible that due to the very long natural
history of prostate cancer that more than 10-year median followup is necessary. In both studies, death due to prostate cancer is
relatively uncommon (<5% of cohort) though there is the suggestion that in the subgroup of positive margins patients (aged
<70 in the Bolla trial), there may indeed be a PFS benefit from
adjuvant radiotherapy treatment [3]. Alternatively, some argue
that perhaps adjuvant radiotherapy is eradicating harmless
BCRs which is why no clinical PFS benefit is shown.
The natural history of PSA progression after radical prostatectomy has been well documented in multiple studies [1315]. While
it is true that almost all patients developing metastatic disease
will have exhibited a biochemical failure, PSA level after BCR
was not shown to be predictive of metastatic disease progression
in many of these studies. Instead pathological Gleason score 8 or
greater, time from surgery to BCR, rapid PSA doubling time,
advanced tumor stage and elderly age were found to be predictive
of progression to distant metastases and prostate cancer-related
death [1315]. Therefore, these factors need to be considered when
making decisions about the significance of any BCR.
Are all patients with extraprostatic extension, surgical
margin involvement or seminal vesicle involvement at
high risk of recurrence?

Based on the adjuvant therapy trials, the AUA/ASTRO guidelines state that patients with pathologic T3 disease including
seminal vesicle invasion or positive margins are at high risk of
recurrence with the randomized trials demonstrating a 5-year
biochemical progression rate of between 40 and 56% in the
surgery control arms. However, both the Southwest Oncology
Group and European Organization for Research and Treatment
of Cancer trial did not necessitate an undetectable postoperative
PSA as an eligibility criteria and indeed, in the Southwest
Oncology Group trial, a third of patients had a postoperative
PSA of >0.2 indicating that many of these patients were receiving early SRT rather than true adjuvant treatment. In the era
of ultrasensitive assays, is it fair to say that a patient with
extraprostatic extension but clear margins and a postoperative
PSA <0.01 is at high risk?
A much better approach is to use the Kattan nomogram
which is the most widely utilized tool to risk stratify patients
1266

for disease recurrence post-prostatectomy [16]. It incorporates

variables including surgical margin status, extracapsular extension, seminal vesicle invasion, lymph node invasion, primary
and secondary Gleason score and preoperative PSA level to predict the 10-year biochemical-free progression rate [17]. The
nomogram was validated in 5020 patients from three large
high-volume referral centers with high concordance-index values up to 0.88. It has since been validated against other population groups in subsequent studies [18,19].
This nomogram is a reminder that high-risk prostate cancer
is a complex, heterogeneous condition. A 64-year-old patient
with a preoperative PSA of 5 and a pathologic T3a, Gleason
7 cancer with clear margins has a 10% risk of BCR. This can
be compared to an 89% risk of recurrence in a 62-year-old
patient with a preoperative PSA of 14 and found to have a
Gleason 8 disease, a positive surgical margin and seminal vesicle invasion [20]. Therefore, some patients who fit the AUA/
ASTRO guideline criteria for ART may receive relatively small
benefit from radiation treatment and be unnecessarily exposed
to potential side-effects from this modality. The guidelines provide clinicians with an overly simplistic approach to selecting
patients for ART. We recommend referring to the validated
nomograms that provide more comprehensive modeling to
guide our risk stratification and patient selection, especially in
those patients with an undetectable postoperative PSA.
Firas Abdollah and colleagues have highlighted that certain
subgroups benefit more than others from adjuvant radiotherapy
in two recent studies. The first was a single center study of
1049 patients receiving surgery alone or in combination with
adjuvant therapy. A cancer-specific mortality benefit was seen
only in patients with Gleason score 8, pT3b/4 disease or positive lymph node disease. A follow-up Surveillance Epidemiology and End-Results Medicare-linked database review of
7616 patients with adverse pathological features confirmed the
findings from the earlier study [21]. These findings suggest that
we reconsider the indications suggested by the AUA/ASTRO
guidelines and reassess how we select patients who will receive
the most benefit from postoperative radiotherapy.
Who & when to offer early SRT?

The guidelines state that patients should be informed that the

effectiveness of radiotherapy for PSA recurrence is greatest when
given at lower levels of PSA. What the guideline recommendations do not specify is what threshold of PSA should trigger the
initiation of SRT; though in the body of the text they state that
radiotherapy should ideally be started before the PSA exceeds
1 ng/ml. The guideline recommendation stems from research
including the Christopher King systematic review of 41 papers
looking at the timing of SRT after radical prostatectomy [22]. His
recommendation is similar to the AUA guidelines stating that
SRT should be given at the lowest possible PSA and made the
observation that there was an average 2.6% loss in biochemical
relapse free survival seen for a 0.1 ng/ml increment of PSA level
at the time of SRT. However, in his review, the average median
pre-SRT PSA across all series was 1.1 0.67 ng/ml with a range
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Adjuvant versus SRT following radical prostatectomy

of 0.253.7 ng/ml. As Dr King states in the discussion, the conclusion that SRT should be initiated at the lowest PSA level raises
the practical question of what that PSA level is. Dr King conceded that this question was well beyond the scope of this study.
Recommendations that SRT be given at the lowest possible
level can generate significant anxiety in patients exhibiting
small rises in PSA using ultrasensitive assays following surgery
(e.g., from 0.01 to 0.04 ng/ml). Patients should be counseled
that at these very low levels, there is no proven benefit for
starting SRT immediately and indeed there can be a strong
rationale to wait to confirm a BCR and also to get a better
feeling of the doubling time and hence aggressiveness of the
disease. Obviously, each case needs to be individualized according to the original histopathological features, timing of any
rise, individual function and patient wishes/anxiety. However,
it is recognized that the AUA/ASTRO guideline recommended
1 ng/ml threshold is now routinely <0.5 ng/ml [2325].
The past 2 years have seen the emergence of multiple predictive tools that aid the clinician in counseling patients on the
likelihood of success with SRT following a BCR. Stephenson
et al. published the first nomogram addressing SRT post-radical
prostatectomy (RP) in an internally validated 1540 patient
multi-institutional cohort [26]. SRT was initiated at a PSA level
0.2 ng/ml or higher at least 6 weeks postoperatively followed
by a subsequent higher PSA level or a single PSA level 0.5 ng/
ml or higher resulting in a median PSA level of 1.1 ng/ml
(IQR: 0.62.2). A proportion of patients included in the validation model received pre-radiotherapy (pre-RT) androgen
deprivation therapy (14%). They included multiple variables
including pre-surgery PSA, pathological Gleason score, seminal
vesicle invasion, extracapsular extension, surgical margin status,
lymph node status, neoadjuvant androgen deprivation therapy,
a persistently elevated postoperative PSA, PSA doubling time,
pre-RT PSA level and radiation dose (cGy) to predict the
6-year biochemical progression-free probability. This model
had a high concordance index of 0.69 and provided a longawaited systematically developed tool to guide clinicians on
selecting patients for SRT. However, the high median PSA
level for this population meant that these findings were not
necessarily applicable to patients receiving early SRT.
Briganti et al. released the first nomogram predicting the
5-year BCR probability in node negative patients receiving
early SRT (defined as SRT commenced prior to pre-RT PSA
levels rising above 0.5 ng/ml) that incorporated variables
including surgical margins, pathological Gleason score, pathological T23 stage and pre-RT PSA level [20,27]. Validated in a
multi-center 472 men cohort over a median follow-up of
48 months, they found that all these variables were significantly
associated with BCR on multivariate analysis. This nomogram
emphasized more weight on pathological T3b stage, Gleason
810 score and positive margin status. Pre-RT PSA level was
included as a range from 0.05 to 0.5 ng/ml with a 0.4 ng/ml
equivalent to pT3a status.
It is important that nomograms such as these are incorporated into patient discussions so that patients are counseled
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Special Report

about the likelihood of being rendered biochemically disease

free with SRT. This obviously needs to be balanced against the
potential toxicity of the radiotherapy treatment. However,
many patients exhibiting a biochemical failure following surgery
are never offered SRT which was the case for nearly half of
patients in the surgery arm of the European Organization for
Research and Treatment of Cancer trial. According to the postprostatectomy nomograms, it is rare to find a subgroup of
patients receiving early SRT that do not have at least a 20%
chance of being rendered biochemically disease free. Hence, we
agree with the guideline recommendations that all patients
exhibiting a biochemical failure should be offered SRT.
What is the evidence addressing adjuvant versus early
salvage treatment?

Although there are currently no randomized trials to address

this issue, several retrospective observational studies have provided evidence showing that salvage techniques can achieve a
durable oncological response. Trock et al. at Johns Hopkins
performed a retrospective analysis of 635 men with clinically
localized T12 after radical prostatectomy and staging pelvic
lymphadenectomy including 160 that received SRT alone and
78 with SRT and hormonal therapy with a median follow-up
from diagnosis of recurrence of 6 years [28]. SRT was offered to
patients found to have a single post-operative PSA measurement of 0.2 ng/ml or higher. They found a clinically significant reduction in cancer-specific mortality compared to those
who did not receive salvage therapy (hazard ratio [HR]: 0.34;
95% CI: 0.170.69; p = 0.03) regardless of hormonal therapy.
Duke University published a 519 men study with a median
follow-up of 11.3 years after PSA recurrence similar findings [29]. SRT, also initiated for post-RP PSA level of 0.2 ng/
ml or higher, was found to improve all-cause mortality among
patients with rapid PSA doubling time less than 6 months
(adjusted HR: 0.35; 95% CI: 0.170.72; p = 0.004) or protracted PSA doubling time of 6 months or longer (adjusted
HR: 0.60; 95% CI: 0.370.98; p = 0.04).
The Mayo Clinic presented findings from their larger
2:1 matched cohort study in a group of 2657 men post-RP
that developed PSA failure [30]. SRT was defined as treatment
initiated greater than 90 days post-RP. PSA recurrence was
defined as 0.4 ng/ml and higher post-RP. SRT was delivered
to 865 men and on multivariate analysis was found to lower
the risk of local recurrence, defined as biopsy proven disease in
the prostatic bed (HR: 0.13; 95% CI: 0.060.28; p < 0.0001)
and metastatic progression (HR: 0.24; 95% CI: 0.130.45;
p < 0.0001). All-cause mortality was not affected by SRT in
this study (p = 0.48).
Several large matched-group analysis studies presented findings that questioned the oncological efficacy of SRT compared
to ART. Ost et al. retrospectively compared adjuvant intensitymodulated radiotherapy to salvage intensity-modulated radiotherapy (offered after a PSA recurrence >0.2 g/ml) in matching
89 patients in each group according to preoperative PSA level,
Gleason score and pathological T stage [31]. The ART group
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Su, Kneebone & Woo

had significantly better biochemical PFS (bPFS) compared to

SRT (3-year biochemical relapse free survival: 91 vs 79%;
p < 0.05). Trabulsi et al. had similar results in their retrospective multi-center study of 192 patients with 6.1 years follow-up
after radiotherapy for pathological T34 patients. They found
a 5-year bPFS of 73% for ART and 50% for SRT
(p = 0.0007) with both SRT and Gleason score of 8 or greater
significant predictors of BCR on multivariate analysis [32].
Optimizing timing of ART has also provided further stimulus for the adjuvant and salvage debate. A SEER database analysis by Kowalczyk et al. of 963 pT3N0 patients receiving ART
compared groups according to early (less than 4 months postRP) to delayed (412 months post-RP) across outcomes of
overall mortality, prostate cancer-specific mortality, bone-related
morbidity, salvage hormonal therapy and intervention for urethral stricture [33]. Although delaying ART beyond 9 months
reduced urethral stricture burden, therapy started less than
5 months postoperatively improved prostate cancer-specific
mortality, while even earlier ART improved bone-related morbidity and salvage hormonal therapy rates. However, the lack of
postoperative PSA levels for this study is a significant limitation
given the possibility of that many of the delayed patients may
indeed have been having salvage treatment.
Timing has been similarly investigated in SRT studies, with
other groups reporting findings from SRT studies suggesting
that survival outcomes may be improved by selecting patients
at earlier points of recurrence. Maurizi et al. found in a retrospective unmatched study of 302 ART and 126 SRT patients
who were treated for rising PSA after undetectable levels or
persistently elevated levels post-prostatectomy that SRT patients
had poorer bPFS than the ART group (5-year bPFS: 71 vs
49%; p < 0.0001) [34]. Importantly, pre-RT PSA level was the
only predictor with a significant effect on BCR for the SRT
group. Patients with a pre-RT PSA level of 1 ng/ml or less had
significantly better bPFS than those with higher PSA levels
(5-year bPFS: 61.8 vs 38.2%; p = 0.02).
Briganti et al. reported a large multi-centre retrospective
cohort study of pathological T3 patients and/or positive surgical margins comparing adjuvant to early SRT for a detectable
PSA less than or equal to 0.5 ng/ml (n = 890) [25]. The 5-year
bPFS for ART (78.4%) and SRT (81.8%) did not reach statistical significance between the two groups on post-propensity
matching (p = 0.9). Pazona et al. reported further compelling
evidence that lower pre-RT PSA levels was associated with
improved oncological outcomes with non-responders having a
significantly higher pre-RT PSA level compared with responders (1.2 ng/ml vs 0.7 ng/ml) [35]. These results highlight the
conflicting data around combined ART and SRT studies.
Comparisons in these studies may have reflected patient selection with many men in the ART arm unlikely to have progressed to BCR given the large proportions that did not have a
detectable PSA pre-RT.
Several recent systematic reviews have refocused attention on
the importance of pre-RT PSA levels on oncological control in
this group of patients. Dr King in a review article concluded
1268

on adjuvant and salvage RT techniques from 2013 that early

SRT was a favorable alternative strategy to ART. Pfister et al.
reported findings from a systematic review of 10 retrospective
studies assessing early SRT defined as pre-RT PSA levels
0.5 ng/ml or less among patients with lymph node negative
disease [36]. A pooled analysis of 886 patients yielded a mean
5-year bPFS of 71% (range: 4881.8%) which is comparable
to results from ART therapy studies. Another systematic review
of 41 SRT studies found that pre-RT PSA (p < 0.001) and RT
dose (p = 0.0052) were significant independent predictors of
BCR after RT [22]. SRT patients with a PSA level of 0.2 ng/ml
or less prior to treatment had a 5-year bPFS of 64% with an
average loss of 2.6% bPFS for each 0.1 ng/ml PSA at the time
of SRT (95% CI: 2.23.1). Several studies published after this
systematic review also noted improvements in bPFS with preRT PSA levels below 0.280.3 ng/ml [24,37]. These findings
have highlighted that the optimal timing for early SRT may in
fact be lower than the 0.2 ng/ml cut-off recommended by the
AUA/ASTRO guideline. This has been recognized and already
included in the new nomogram proposed by Briganti et al. [27].
A notable concern of retrospective studies attempting this
address this controversy is that men were often irradiated to
the prostatic bed only and at low-moderate RT doses. A wider
adoption of whole-pelvis radiotherapy to prophylactically treat
the pelvic lymph-nodal area and/or a moderate dose-escalation
may significantly modify the scenario in the near future.
Expert commentary & five-year view

Early SRT has emerged as an attractive alternative to adjuvant

therapy, but we continue to rely on retrospective and level
2 cohort or casecontrol studies to guide our decision making.
This is an exciting period in prostate cancer care and the
opportunity is now open to further fine tuning the balance
between cancer control and toxicity reduction. The greatest
controversy is now improving individualization of patient care
in those men who may need to consider post-operative radiation therapy, an issue which is inherently reliant on timing,
careful monitoring of PSA levels in combination with the other
recognized pathological risk factors. The current guidelines do
not adequately support individualized care for postprostatectomy men.
In response to the contradictory data on ART and SRT survival outcomes and lack of randomized trial data on the efficacy of early SRT, three randomized trials are aiming to
provide improved guidance on the choice between ART and
early SRT. The Trans-Tasman Radiation Oncology Groups
Radiotherapy Adjuvant Versus Early Salvage is aiming to
recruit 470 patients randomized to either ART (commenced
less than 4 months post-prostatectomy) or early SRT (triggered
by a PSA level of 0.2 ng/ml or greater) with at least one feature
of positive surgical margins, extraprostatic extension or seminal
vesicle involvement with an endpoint of BCR [38]. Postoperative PSA levels also need to be 0.1 ng/ml or less at
recruitment. The UK Medical Research Council/National Cancer Institute of Canada Trials Group Radiotherapy and
Expert Rev. Anticancer Ther. 14(11), (2014)

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Adjuvant versus SRT following radical prostatectomy

Androgen Deprivation in Combination with Local Surgery trial

is expanding on the focus to adjuvant hormonal therapy [39]. It
is aiming to recruit 2600 patients to either immediate ART or
early SRT after two consecutive rises in PSA level to a level
above 0.1 ng/ml and then randomize to 6 or 2 months of hormone therapy or radiotherapy alone with an endpoint of
cancer-specific survival. The third trial is GETUG-17, a multiinstitutional European study investigating 718 patients randomizing patients with pT34, node negative disease with positive
margins and undetectable PSA to ART with ADT or SRT
with ADT. The end-point is a composite of clinical recurrence,
BCR and death at 5 years. A promising meta-analysis is
planned between the three trials upon completing follow-up

Special Report

that will hopefully provide the necessary insights to decide

between these two therapies [40]. These randomized trials comparing adjuvant to early salvage radiation therapy will hopefully
provide much awaited answers to this issue.
Financial & competing interests disclosure

The authors have no other relevant affiliations or financial involvement

with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents
received or pending or royalties.
No writing assistance was utilized in the production of this manuscript.

Key issues
Current guidelines define biochemical recurrence (BCR) as detectable or rising prostate-specific antigen value after surgery >0.2 ng/ml
with a second confirmatory level >0.2ng/ml.
Long follow-up (median 10 or more years) is required to characterize metastatic and cancer-specific survival for prostate cancer
recurrence.
PSA level after BCR needs to be considered with Gleason score, time from surgery to BCR, rapid PSA doubling time, advanced tumor
stage and elderly age when considering prognosis and postoperative radiotherapy.
Risk factors including extraprostatic extension, positive surgical margin or seminal vesicle involvement need to be interpreted in
combination with other variables, ideally using a validated predictive tool such as the Kattan nomogram.
Studies comparing adjuvant to salvage radiotherapy (SRT) have shown biochemical survival benefit in commencing early SRT at lower
pre-radiotherapy PSA levels, often lower than the figure recommended by the AUA/ASTRO guideline.
Early SRT has been increasingly recommended at lowest possible PSA levels despite no proven benefit for starting SRT immediately on
first PSA recurrence.
New nomograms predicting survival after post-prostatectomy radiotherapy provided more tools to characterize patient prognosis and
highlight the importance of offering SRT to all patients with biochemical failure.
Shared-care decision making with the patient must include a discussion balancing the benefits of BCR control and potential
treatment toxicity.
Upcoming adjuvant versus early SRT randomized trials will provide new data to address the shortcomings of current evidence comparing
these two modalities.

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