fic Antigen Level The Dilemma of a Rising Prostate-Speci Nicholas G. Zaorsky,

The Dilemma of a Rising Prostate-Specific Antigen Level
After Local Therapy: What Are Our Options?
Nicholas G. Zaorsky,a Ganesh V. Raj,b Edouard J. Trabulsi,c Jianqing Lin,d and Robert B. Dena
Prostate cancer is the most common solid tumor diagnosed in men in the United States and
Western Europe. Primary treatment with radiation or surgery is largely successful at controlling
localized disease. However, a significant number (up to one third of men) may develop
biochemical recurrence (BR), defined as a rise in serum prostate-specific antigen (PSA) level. A
general presumption is that BR will lead to overt progression in patients over subsequent years.
There are a number of factors that a physician must consider when counseling and
recommending treatment to a patient with a rising PSA. These include the following (1) various
PSA-based definitions of BR; (2) source of PSA (ie, local or distant disease, residual benign
prostate); (3) available modalities to treat the disease with the least morbidity; and (4) timing of
therapy. In this article we review the current and future factors that clinicians should consider
in the diagnosis and treatment of recurrent prostate cancer.
Semin Oncol 40:322-336 & 2013 Elsevier Inc. All rights reserved.
P
rostate cancer is the second most common
solid tumor diagnosed in men in the United
States and Western Europe, and the second
most common cause of cancer death.1,2 The incidence of prostate cancer rose since the introduction
of prostate-specific antigen (PSA) screening.3 Consequently, more men (80% of diagnoses in the
United States) present with localized (ie, confined
to the prostate capsule)4 disease, and treatment with
radiation or surgery is largely successful at controlling their disease. However with follow-up, approximately one third of these patients may develop
biochemical recurrence (BR). BR is detected by
a
Department of Radiation Oncology, Kimmel Cancer Center, Jefferson
Medical College of Thomas Jefferson University, Philadelphia, PA.
b
Department of Urology, UT Southwestern Medical Center at Dallas,
Dallas, TX.
c
Department of Urology, Kimmel Cancer Center, Thomas Jefferson
University, Philadelphia, PA.
d
Department of Medical Oncology, Thomas Jefferson University
Hospital, Philadelphia, PA.
Conflicts of interest: none.
Funding sources: Prostate Cancer Young Investigator (R.B.D.).
Address correspondence to Robert B. Den, MD, Department of
Radiation Oncology, Jefferson Medical College & Kimmel Cancer
Center, Thomas Jefferson University, 111 S 11th St, Bodine Center
for Cancer Treatment, Philadelphia, PA 19107. E-mail: robert.
[email protected]
0270-9295/ - see front matter
& 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1053/j.seminoncol.2013.04.011
322
rising serum level of PSA.5,6 An estimated 20,000–
35,000 US men per year experience BR after RP.7
A general presumption is that BR will lead to overt
progression in patients over subsequent years. Management of these patients is complex and controversial for a number of reasons. First, the definition
of BR varies. Second, a transient PSA rise after
radiotherapy (ie, a PSA “bounce”) may be difficult
to differentiate from treatment failure. Third, even
after a patient has a confirmed BR, a further dilemma
is the determination of the source of detectable PSA
(ie, local v systemic). Moreover, not all patients with
a rising PSA go on to develop clinical relapse, and it
is difficult to predict which patient will develop
relapse and how quickly.
An additional challenge of a rising PSA is the
plethora of treatment options available for a patient
and the acknowledgment that no single therapy is
the appropriate approach for all patients. Salvage
options include external-beam radiation therapy
(EBRT), brachytherapy (BT), radical prostatectomy
(RP), cryotherapy, combinations of these therapies
with androgen-deprivation therapy (ADT), and
experimental modalities. Finally, the timing of intervention is debated: there is no evidence showing
that early intervention improves survival; conversely,
early treatment may lead to increased morbidity.
In this article we review the dilemma of a rising PSA
post-RP or post-RT. First, we review the use of PSA as a
marker of recurrence. We examine the various definitions of BR, both post-RT and post-RP. Next, we
Seminars in Oncology, Vol 40, No 3, June 2013, pp 322-336
323
Rising PSA after local therapy
evaluate the prospective tests that detect failure.
Finally, we review the current treatment recommendations and guidelines for patients with BR.
PSA AS A MARKER OF TREATMENT SUCCESS
PSA is a soluble protein detected in the peripheral
blood that is a surrogate biomarker used in both the
initial detection and subsequent post-treatment monitoring for prostate cancer. PSA production is
regulated by the androgen receptor, the main proliferative signal for prostate cancer growth. PSA
values are typically measured every 3–6 months after
RP or RT for the initial 1–2 years after completion of
therapy, and then continued yearly.
definition (ie, three consecutive rises in PSA) and
24%–32% using the Phoenix definition (ie, nadir þ
2 ng/mL).23,24 For men with a rising PSA, the 10-year
metastasis-free survival is estimated to be 90%, while
those with stable PSA have a rate of 97%.25 BR has
been used as an outcome measure in multiple
studies; however, because of variable definitions,24
the difficulty with comparing BR across treatments,26 and post-RT BR not directly translating to
mortality, cancer-specific mortality has been the
preferred metric for treatment efficacy. For patients
treated with RP, EBRT, plus ADT, and EBRT alone,
the 10-year cancer-specific survival rates have been
estimated to be 92%, 92%, and 88%, respectively.27
Post-Radical Prostatectomy
PSA AS A MARKER FOR DISEASE RECURRENCE
Serum PSA should reach undetectable levels by
conventional assays in 4–6 weeks in the majority of
men undergoing RP given that the half-life of PSA
is 2.5–3 days.8,9 A detectable PSA after RP may
reflect presence of residual benign prostatic tissue
or cancer.10 Studies have shown that 65%–83% of
men will have PSA levels that remain stable up to 10
years following RP.11–13
Patients post-RP with BR have an 88% 10-year
overall survival (OS) rate in contrast to the 93%
10-year OS rate in men without BR.14 Following RP,
Pound et al15 reported the median time from BR to
clinical progression was found to be 8 years and that
the median time from metastasis to prostate cancerspecific mortality to be 5 years. Thus, they estimated
the median time from BR to death to be 13 years.
Although recent studies have demonstrated even
longer median survival after BR (up to 16 years),
a subset of men with aggressive prostate cancer die
much sooner after BR.16
A rising PSA after RT or RP usually signifies local or
metastatic recurrence, and it is important to differentiate between these possibilities. The definition of
BR varies, and important factors in its definition
include the absolute PSA level,28–34 time to recurrence, PSA kinetics,15,16,35,36 nomograms,15,16,37–39
imaging,40 and biopsy of the prostatic bed.16,41-44
While a number of guidelines for trending PSA posttherapy have been published, future markers of failure will likely use more sensitive and specific PSA
tests and employ other modalities alongside the PSA.
Post-Radiotherapy
It is more difficult to define treatment success
based on PSA values following RT than RP. RT
typically induces a slow and unsteady PSA decrease
to levels that are typically still detectable. Moreover,
10%–30% of patients exhibit a PSA bounce (ie, a
temporary elevation in PSA without disease recurrence) within 3 years after RT, and these bounces
may take up to 18 months to normalize.17–19 The
etiology of PSA bounce remains unclear; radiation
and bacterial prostatitis have been postulated as
possible pathophysiological mechanisms.20,21 Nonetheless, the likelihood of metastases in men with PSA
stabilization at levels ≥1.0 ng/mL is comparable to
outcomes for men with lower or non-rising PSA
values.22 Five-year BR rates post-RT have been
estimated to be 28%–39% using the American Society
for Therapeutic Radiology and Oncology (ASTRO)
The Absolute PSA Level
Often, serial evaluation of PSAs can help evaluate
the clinical significance of a detectable PSA. For
example, a man with a detectable and low PSA level
of 0.05 ng/mL after therapy may have a persistently
detectable PSA (ie, 0.05 ng/mL on every visit) without
significant change for many years. Such a patient is
unlikely to progress and suffer cancer-specific mortality. Thus, a detectable PSA alone may not mandate
salvage intervention. In contrast, a patient with a
detectable and serially rising PSA of 0.5 ng/mL (ie,
from 0.5 ng/mL to 1.0 ng/mL and then to 1.5 ng/mL)
is more indicative of residual prostate cancer and may
benefit from salvage intervention.
Several studies have evaluated specific PSA cutoffs
to define BR after RP.28,29 European Association of
Urology (EAU) guidelines define BR with both a postRP PSA cutoff of 0.2 ng/mL, and two sequential PSA
values ≥0.2 ng/mL.30 These cutoffs are based on
studies showing that only half of men with a
detectable PSA in the 0.2–0.29 ng/mL range had
subsequent PSA progression and could be defined as
having BR. A PSA level ≥0.4 ng/mL correlated with a
79% risk of PSA progression.28 The PSA Working
Group defined BR with a PSA cutoff ≥0.4 ng/mL with
a subsequent elevated level.31 A retrospective
evaluation of BR criteria showed that PSA cutoff
324
≥0.4 ng/mL had the highest correlation with the risk
of clinical progression.29
Similarly, after RT, elevated PSA is associated with
a poorer prognosis. The higher the PSA level, the
greater the burden of disease and higher the risk of
distant metastasis (DM).15,45 A pretreatment serum
PSA level greater than 40 ng/mL is strongly associated with DM.46 Further, a serum PSA level above
1 ng/mL indicates a higher risk of failure of localized
salvage therapy.47 However, the definition of BR
based on an absolute PSA value post-RT is controversial because PSA levels may remain at detectable
levels. A PSA bounce is common in the first 2 years
following RT.18,19,48 Meanwhile, the median time to
PSA nadir is 18 months.46 Moreover, the concomitant use of ADT either prior to or along with RT
complicates the interpretation of the PSA value.
Therefore, using an absolute value for PSA to define
BR is not recommended.
To define BR after definitive radiotherapy, the
ASTRO consensus provided an early common definition for treatment relapse following RT.32 Since
the ASTRO criteria did not specify a PSA cutoff,
a man whose post-RT PSA rose from a nadir of
0.05 ng/mL to 0.06, 0.07, and 0.08 ng/mL on
subsequent evaluations could be classified as having
BR. Moreover, the relationship between ASTROdefined BR and cancer-specific survival or OS has
not been clearly demonstrated.49,50 The ASTRO
definition incorporates backdating, resulting in an
artificial flattening of Kaplan-Meier curves, and therefore falsely provides more favorable estimates of
outcomes when follow-up is short.
The PSA nadir þ 2 ng/mL (PSAn; Phoenix)
definition was introduced in 2005, and it has been
shown to reduce these artifacts. It has been shown
to be a more significant predictor of DM, cancerspecific survival, and OS after controlling for other
significant covariates.33,34 Moreover, it has no apparent length of follow-up bias, provides a BR risk
estimate that remains proportional over time with or
without ADT,34,51 requires a shorter time to diagnosis,34 and is associated with fewer misclassifications when neoadjuvant and adjuvant ADT is
used.17,52 Currently, ASTRO criteria are typically
used in RT-only treated patients and Phoenix criteria
in both patients treated with RT-only and those
treated with RTþADT.
PSA Kinetics
After RP, the time from initial local therapy to BR
and shorter PSA doubling time (PSA-DT) have been
shown to correlate with the site of recurrence.15
A shorter time to BR after initial local therapy is
associated with a higher risk of DM. In contrast, a
longer time to BR after initial local therapy is
N.G. Zaorsky et al
associated with a higher risk of localized recurrence.15,16 While a true cutoff of the time to BR
has not been established, a time to BR r2 years after
RP strongly implicates a distant or metastatic recurrence, while a time period of 42 years suggests a
local recurrence.15 Positive surgical margins also are
associated with an increased likelihood of BR.53
The main purpose of following PSA after treatment is to predict clinically meaningful outcomes.54
However, there is no current standard interpretation
of PSA kinetics after RP or RT. Generally, a shorter
PSA-DT indicates a rapidly growing tumor, a higher
risk of clinical progression to DM, and a higher risk
of cancer-specific mortality.37,55 Trapasso et al55
reported on patients whose PSA-DT was followed
post-RP. Patients with a longer PSA-DT (mean,
11.7 months) had a higher risk of localized prostate
cancer and a lower risk of clinical progression than
patients with a shorter PSA-DT (4.3 months).
Patients with PSA-DT of o3 months represent a
minority (10%–15%) of men with BR but have the
highest risk of systemic recurrence.37
In men post-RT, the use of post-treatment PSAn and
PSA-DT have been proposed. For PSAn, it is not clear
whether a PSAn during a patient’s lifetime,56 at 12
months,57 or at 24 months58 is most prognostic.
Systemic recurrences were associated with higher
PSAn and shorter PSA-DT.59 Patients with a PSADT o3 months had the greatest risk of cancerspecific mortality, with a median survival of 6 years.35
However, patients with a PSA-DT o3 months represent a small high-risk subgroup,60,61 and such a low
DT may be miscalculated.62,63 A novel measurement
of PSA kinetics is the interval to BR (IBR): an IBR
cutoff of 18 months has been shown to predict
cancer-specific mortality following RT without ADT.36
Multivariable Prediction Tools
Multivariable prediction tools such as nomograms
were developed using clinicopathologic and biochemical risk factors such as PSA-DT, time to BR,
and Gleason score (GS) to predict clinical progression after RP15,16,42 and RT.39 Parameters that magnify the risk of systemic relapse in these systems
include a PSA-DT r3 months, time to BR r3 years,
and GS Z7.16
Advanced PSA Detection
PSA levels are typically undetectable after RP,8,64
and between 65%–83% of men have stable PSA levels
after RP.11–13 NADiA ProsVue is an in vitro diagnostic assay approved by the US Food and Drug
Administation that uses a reporter monoclonal antibody against PSA attached to a synthetic doublestranded DNA label. After a serum sample is obtained
from a patient, a biotin-labeled monoclonal antibody
325
Rising PSA after local therapy
Table 1. PSA Trajectory After RT or RP, and Definitions of BR
Post-RP
PSA trajectory
Absolute
Kinetics
Nomograms
Post-RT
PSA should reach undetectable levels in
4 weeks8
65%–83% of men have elevated PSA up
to 10 years post-RP11–13
0.2 ng/mL28,29
2 sequential PSA values Z0.2 ng/mL 30
Z0.4 ng/mL þ subsequent elevated
level31
time to BR r2 years predicts DM15,16
PSA-DT of o3 months have highest risk of
recurrence15,37,56
Post-RP specific15,16,37,38
PSA falls slowly and unevenly
10%–30% of men have PSA bounces in
3 years post-RT17–19,47
Bounces take up to 18 months to
normalize17–19
ADT use confounds the true PSA value
3 consecutive PSA rises (ASTRO)32
PSAn þ 2 ng/mL (Phoenix)33,34
PSA-DT o3 months predicts PCSS35
IBR o18 months predicts PCSS36
Post-RT specific39
Abbreviations: ASTRO, American Society for Radiation Oncology; BR, biochemical recurrence; DM, diabetes mellitus type 2; DT,
doubling time; IBR, interval to biochemical recurrence; PCSS, prostate cancer–specific survival; PSA, prostate-specific antigen;
PSAn, PSA nadir; RP, radical prostatectomy; RT, radiation therapy.
bound to streptavidin-coated paramagnetic microparticles is used to capture and quantify PSA. The
limit of quantitation of the test is 0.65 pg/mL,
significantly lower than the most sensitive commercially available PSA assays. Three samples are collected from patients between 6 weeks and 10
months post-RP, and the three samples are tested
in a single ProsVue run. ProsVue PSA slope results
are calculated using ProsVue software. In a multicenter, retrospective clinical trial of 304 post-RP
patients with stable and recurring disease, ProsVue
linear slope demonstrated significant and independent predictive capability for reduced risk of prostate
cancer recurrence and a low false positive rate (Iris
Molecular Diagnostics, Carlsbad, CA).65
The characteristics of PSA that are commonly
seen and those that define BR are reviewed in
Table 1. PSA values differ in the post-RP and postRT settings; thus, the definitions of BR vary and the
following factors are often considered: the absolute
PSA level, time to recurrence, PSA kinetics, nomograms, imaging, and biopsy of the prostatic bed.
When diagnosing BR, a clinician must discern if the
PSA is produced from local or systemic disease, as
these will drive treatment recommendations.
SALVAGE THERAPY RISK ASSESSMENT
The initial step in management of BR in either the
post-RP or post-RT patient is determination of the
region of recurrence. Recurrence sites include
(1) locoregional, (2) distant, or (3) a combination
of the two.66 Only locoregional recurrence is
expected to benefit from additional local therapy.
Patients with distant recurrence may benefit from
systemic therapy. If recurrence occurs both locoregionally and distantly, then the patient may benefit
from a combination of the two.
In either case, the benefit of any therapy always
comes with a risk, be it cancer-specific mortality or
treatment morbidity. When considering individual
factors to pursue locoregional versus systemic therapy, there is currently no single marker that can
clearly delineate the two. Moreover, for continuous
variables (eg, initial PSA, time of BR after initial
therapy), overlapping timeframes have been published. Nonetheless, the following individual factors
(Table 2) are considered in differentiating local and
systemic recurrence: (1) initial disease risk status41,43,44; (2) pre-primary treatment tumor stage75;
(3) data from imaging at the time of BR (ie, computed
tomography [CT], magnetic resonance imaging [MRI],
choline positron emission tomography [PET])40;
(4) GS at time of BR16,41–44; (5) PSA at time of
BR42,67,68; (6) time of BR after initial therapy16,54; (7)
PSA-DT69,70; and (8) PSA velocity.71,72 With the aid
of computer algorithms, the use of life expectancy
tables73 and clinical progression nomograms15,16,37–39
has been recommended to decide the need for
observation or intervention with salvage therapy.
While a number of factors may influence the
clinician to suspect local versus distant disease at
the time of BR, none is perfect. Advanced imaging
techniques will likely play a large role in determining
the site of BR in the coming decades. In the following
section, we review advances in imaging for BR.
326
N.G. Zaorsky et al
Table 2. Factors in Favor of Locoregional or Distant BR Post-RP or Post-RT
Scenario
Initial disease risk status
Pre-primary treatment T
stage
Imaging at BR (CT, MRI,
choline PET)
Biopsy GS at time of BR
PSA level at time of BR
(ng/mL)
IBR (mo)
PSA-DT (mo)
PSA velocity (ng/mL/yr)
Favoring Locoregional
Recurrence
Favoring Distant
Recurrence
References
Either
Post-RT
Low
T1-2
High
T3-4
41,43,44
Either
Local relapse
40
Post-RT
Post-RP
Post-RP
Post-RT
Post-RT
r6
r6
r7
r8
o10
Metastases,
lymphadenopathy
Z7
Z7
Z8
Z9
Z10
Post-RT
Post-RP
Post-RP
Post-RT
Post-RP
Post-RT
Either
Either
o4
436
424
418
o15
48
43
o2
Z10
r36
r46
r18
Z15
r8
r3
Z2
68
75
41
16
42
43,44
67
16
15
54,60
69
70
16,37
71,72
Abbreviations: BR, biochemical recurrence; CT, computerized tomography; DT, doubling time; GS, Gleason score; IBR, interval to
biochemical recurrence; MRI, magnetic resonance imaging; PSA, prostate-specific antigen; PSAn, PSA nadir; RP, radical
prostatectomy; RT, radiation therapy.
IMAGING
Currently, there is no uniformly accepted imaging
modality that can distinguish local versus systemic
recurrence. Traditional imaging to evaluate BR
involves a radionuclide bone scan, CT scan, or
MRI.74 These techniques best detect macroscopic
disease but have poor sensitivity for microscopic
low volume disease, or when PSA levels are below
10 ng/mL.75–77 A number of imaging modalities are
under investigation (Table 3).
Radiolabeled Imaging
Immunoscintigraphy is a possible future imaging
modality. It uses radiolabeled monoclonal antibodies specific for prostate cancer epitopes. ProstaScint (111In–capromab pendetide, the monoclonal
antibody to the intracellular epitope of prostatespecific membrane antigen [PSMA]) unfortunately
has shown no correlation between response and
salvage RT in a postoperative setting.78 J591 is the
monoclonal antibody targeting the extracellular
domain of PSMA, and it has provided improved
imaging of bony metastasis and the prostatic
fossa.79
Radiolabeled imaging with 18F-DG PET initially
showed promise in detecting recurrent prostate
cancer, but has been unsuccessful in practice.80
Recently, investigational PET tracers have shown
more promising results. 11C-choline PET was
reported to have a sensitivity of 89% and a positive
predictive value of 72% for patients with BR and PSA
levels o2.5 ng/mL.81 Similarly, 18F-choline PET sensitivity and specificity in detecting bone metastases
from prostate cancer were reported to be 79% and
97%, respectively.82 NCT01602783 is an ongoing
study that uses 11C-acetate PET screening to detect
tumor not seen with conventional imaging for men
with post-RP BR. Finally, androgen receptors have
been targeted by 18F-DHT, which also has shown
metastatic disease.83
18
F-NaF was first approved in 1972 but was
eclipsed by 99Tc-labeled phosphate agents. It was
reapproved for PET use in 2000. NaF has advantages
over 99Tc scans, including (1) improved sensitivity
and specificity; (2) increased spatial contrast and
resolution; (3) superior bone-to-background ratio;
(4) faster whole body scanning (up to 60 minutes
after injection); and (5) the ability to fuse information with anatomic information from CT or MRI,
which may boost sensitivity and specificity to
100%.84 These novel imaging modalities are being
explored in advanced prostate cancer patients. They
may help discern which patients will benefit from
salvage therapy.
327
Rising PSA after local therapy
Table 3. Current and Future Imaging Modalities That May Detect the Source of BR
Modality
Immunoscintigraphy
111
In-capromab
pendetide/ProstaScint
J591
MRI subtypes
MRS
DCE
DW
LTNP
PET tracers
18
F-DG
11
C-choline
11
C-acetate
18
F-NaF
18
F-DHT
Comments/References
MAb targeting the intracellular domain of PSMA; no correlation between
response to salvage RT post-RP78
MAb targeting the extracellular domain of PSMA 79
Reported sensitivity of 77% compared to the 68% of MRI alone87
Improved sensitivity and specificity compared to MRI alone89
Detects cancer recurrence, which was later proven by biopsy91
Disturbed nodal architecture visible on MRI 92
Unsuccessful in practice80
Detects BR81 and bony metastases82
NCT01602783, ongoing efficacy study
When combined with CT fusion, sensitivity and specificity approaching
100%84
Detects bony metastases83
Abbreviations: BR, biochemical recurrence; DCE, dynamic contrast enhanced; DW, diffusion weighted; 18F-DG, 18-fluoro deoxy
glucose; 18F-DHT, 18F-dihydrotestosterone; CT, computerized tomography; LTNP, lymphotropic nanoparticle; MAb, monoclonal
antibody; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; PSMA, prostate-specific membrane
antigen; PSA, prostate-specific antigen; RP, radical prostatectomy; RT, radiation therapy.
Multiparametric MRI
The role of endorectal MRI is limited in evaluation
of the patients with BR because of the low signal
intensity of T2-weighted images in radiated tissue.85,86
Magnetic resonance spectroscopy (MRS), which measures elevation in choline or decrease in citrate in
prostate cancer tissue,87 has a reported sensitivity of
77% compared to the 68% of MRI alone after EBRT.
Unfortunately, MRS has poor spatial resolution and a
high sensitivity for field inhomogeneities induced by
sugical clips; thus, its role after RT is unclear.
Dynamic contrast-enhanced (DCE) MRI, which
measures early gadolinium washout in prostate cancer,88 has improved sensitivity and specificity in
detecting local recurrence after RP.89 Diffusionweighted (DW) MRI measures the degree of cellular
crowding.90 In a small Swiss cohort study, DW MRI
has been shown to detect cancer recurrence, which
was later proven by biopsy.91 In lymphotropic nanoparticle (LTNP) MRI, lymph node–avid supraparamagnetic iron oxide nanoparticles are distributed in the
nodal architecture. In 26 men who were candidates
for salvage RT post-RP, LTNP MRI was well tolerated,
and six patients who were previously believed to be
node-negative tested lymph node–positive.92
SALVAGE THERAPY
Once BR is diagnosed and the source of PSA is
confirmed, a clinician must choose the optimal treatment modality. In this section, we review the risk–
benefit assessment and outcomes when using salvage
ADT, RT, RP, and cryotherapy. We then discuss the
investigational therapies for recurrent prostate cancer.
SALVAGE RT POST-RP
Risk–Benefit Assessment
Currently, it remains uncertain whether a rising PSA
after RP indicates isolated local disease, distant metastases, or both.66 The best treatment for recurrent
prostate cancer in patients with a rising PSA without
clinical evidence of disease is controversial, and only
RT has been shown to cure patients with localized
disease post-RP. However, guidelines for the timing of
salvage RT (immediate v delayed) have not yet been
established.93 Moreover, salvage RT includes risks of
bladder irritation, radiation cystitis, and radiation proctitis. If all patients with post-RP BR underwent salvage
RT, 44%–88% of patients would benefit, depending on
the number of adverse features of the cancer.47
Several studies have been published regarding the
predicted success of salvage RT in a post-RP setting.
The presence of perineural invasion at time of RP, an
elevated pre-salvage RT PSA (41 ng/mL),95 and a
short PSA-DT (o3 months)95 are independent factors for decreased biochemical relapse-free survival
after salvage RT. Conversely, when considering
salvage RT, the number of positive surgical margins
after initial RP has been shown to have no associated
link with a secondary BR.96 The extension of the
328
radiation field from prostatic fossa alone to include
the full pelvis including obturator nodes may further
decrease recurrence rates after salvage RT.97,98
Although not all patients will benefit from wholepelvis RT, predictors of which patients would benefit most from this are likely those who have a greater
burden of disease reflected by radiographic imaging
or a higher initial PSA.99 Regarding concomitant ADT
during salvage RT, the subset of patients with seminal vesicle invasion on the RP specimen may have
the greatest benefit of ADT during RT.100
Outcomes of Salvage RT
In general, salvage RT provides effective long-term
biochemical control and freedom from metastasis in
selected patients presenting with detectable PSA after
prostatectomy.99 High-risk patients receiving both
ADT and RT had a 5-year BR-free survival rate of
47% if the whole pelvis was irradiated, compared to
21% for patients with irradiation of the prostate fossa
alone. The benefit from total ADT with post-operative
RT was only observd when given concurrently with
whole-pelvic RT, but not with fossa-alone RT.97 Additionally, the concomitant use of ADT to salvage RT
also may decrease biochemical and clinical recurrence rates.94,101 Intensity-modulated RT, with dose
escalation to 76 Gy, has been shown to be more
effective than three-dimensional conformal RT in a
salvage setting after RP.94,102
N.G. Zaorsky et al
by 2.8 months.106 Treatments targeting bone metabolism, tumor–bone stromal interactions, and bone metastases themselves are becoming a central element of
care in metastatic prostate cancer. Numerous trials of
metastasis-seeking RT agents are underway.107
SALVAGE RP POST-RT
Risk–Benefit Determination
Salvage RP may be offered to patients with biopsyproven prostate-only recurrence after primary RT. Presalvage RP PSA value and prostate biopsy GS are the
strongest prognostic risk factors for progression-free
survival, organ-confined disease, and cancer-specific
survival.108 For patients with initially localized cancer,
clinically significant post-RT recurrence has been
argued to occur at the site of primary tumor.109 Some
studies argue for earlier identification (by pre-RT and
post-RT MRI) of patients with persistent, viable local
cancer post-RT, as these patients will likely benefit
most from salvage RP.109,110
Contrarily, recurrent or radio-resistant prostate
cancer occurs in about 30% of men receiving
primary RT, and they are distributed in regions of
the prostate (apical and periurethral), which are at
risk for undertreatment using current ablative techniques. Thus, in these men, the efficacy of ablative
techniques is adversely affected.111
Outcomes of Salvage RP
Bone-Seeking Radio-isotopes Combined With
Salvage RT
The majority of men dying of prostate cancer have
bone as the only site of metastasis.103 Skeletal
metastases are associated with high morbidity,
including pain, fractures, spinal compression, bone
marrow compression, fatigue, and eventually death.
Clinical trials have evaluated the palliative benefits
of bone-targeted RT in metastatic prostate cancer.
A phase I trial of samarium-153 ethylene-iaminetetramethylenephosponate (153SM-EDTMP) for the
treatment of clinically non-metastatic high-risk prostate cancer as primary or post-RP therapy showed
that 153SM-EDTMP was safe and feasible to use in
men.104 A phase II Radiation Therapy Oncology
Group (RTOG) trial of consolidation docetaxel and
153
SM-EDTMP in 43 men with castration-resistant
prostate cancer showed a plateau in rising PSA and
eventual PSA relapse in all patients, decreased bony
pain in 69% of the cohort, and minimal toxicity.105
Currently, a phase II trial of 153SM-EDTMP followed by
salvage RT for high-risk non-metastatic prostate cancer
post-RP is underway. The ALSYMPCA trial in metastatic castrate-resistant prostate cancer patients with
symptomatic bone metastases showed that the radium223 arm had improved OS when compared to placebo
In patients who have undergone salvage RP in the
post-RT setting, distant metastasis is observed
in o25% of men after 10 years,112 disease-free
survival is reported to be at 61% at 5 years, and
prostate cancer–specific mortality is reported to be
between 17%–36% after 5 years.41,113,114 For experienced surgeons, the rate of postoperative complications is low; moreover, open, laparoscopic, and
robotic techniques are all effective.108,115 The rate
of RP intraoperative morbidity is likely unaffected by
prior pelvic RT; however, the rate of postoperative
morbidity is increased in men previously treated
with RT.116,117 Salvage RP has been shown to be
associated with a high rate of erectile dysfunction
(80%–100%), incontinence (44%–99%), bladder neck
contractures (22%–41%), anastomotic stricture (7%–
41%), and rectal injury (2%–28%).108,113,116,118 The
use of a nerve-sparing approach helps preserve the
erectile function in some patients.119
ADT POST-RP OR POST-RT
The use of ADT for BR when non-metastatic
disease is suspected is controversial because it does
not affect OS. ADT cannot induce cancer apoptosis,
and if it is used alone, it cannot achieve a cure. While
329
Rising PSA after local therapy
men often do not want ADT for primary therapy,
they usually also do not accept delaying ADT in the
setting of BR. Lueprolide acetate, for example, is
only indicated in the palliative treatment of
advanced prostate cancer. Although lueprolide acetate has a number of toxicities, early initiation of
ADT is commonly seen in the community setting
with BR after definitive local treatments. Currently,
the majority of patients with BR are managed by
ADT, including 60% of patients who undergo primary RP and 94% of patients who receive primary
RT.120 ADT has risks of hot flashes, osteoporosis, loss
of muscle mass, sexual dysfunction, decreased
libido, increase fat deposition, dyslipidemias, and
increased risk of cardiovascular events.121,122
Delaying ADT is an option in some men. In a
study of 1,352 men treated with early or delayed
ADT,123 ADT delayed clinical progression only in
those with high-risk features, including GS Z7 or
PSA-DT r10 months. To shorten the time of ADT,
intermittent schedules also have been investigated.
In one phase III study of post-RP BR, patients initially
received leuprorelin as a 3-month depot; when PSA
values dropped to o0.5, they were randomized to
intermittent or continuous leuprorelin and cyproterone. The interim analysis showed progression-free
survival rates of 1,233 and 1,009 days, respectively.124 Intermittent ADT is currently only recommended for men 470 years of age with GS r7.125
Thus, there are a number of uncertainties about
the use of ADT in the setting of BR, and there is no
consensus on who should receive therapy. Medical
practitioners should take into consideration their
suspicion that the rising PSA is related to metastatic
disease, patient comorbidities, the quality of life of the
patient with a known rising PSA (ie, “PSA anxiety”),
and the quality of life of the patient while on ADT
when making recommendations for the therapy.
SALVAGE CRYOSURGERY
Risk-Benefit Determination
Salvage cryosurgery has been an alternative treatment for patients with BR since the 1990s. The
oncologic efficacy of salvage cryotherapy is more
pronounced in low-risk patients (freedom from BR ¼
73%) than in intermediate (45%) or high-risk patients
(11%).126
Outcomes of Salvage Cryosurgery
The 5-year disease-free survival of cryosurgery has
been estimated to be between 23%– 74%.43,44,127–130
Salvage cryotherapy is associated with significant
complications: after about 20 months, the incontinence rate is estimated to be 6%–20%43,129,130;
however, in a study with longer follow-up (72
months) this increased to up to 72%.44 Moreover,
erectile dysfunction may be seen in up to more than
two thirds of men.131
SALVAGE RT WITH REDUCED
FRACTIONATION SCHEDULES
Hypofractionated and stereotactic modalities have
shown promising results as well. Hypofractionated
salvage RT (65 Gy in 2.5-Gy fractions in about
5 weeks) reduces the length of treatment by from
1.5–3 weeks relative to standard salvage RT. It has
been shown to have low rates of BR (33% at 4 years)
and of gastrointestinal and genitourinary toxicity.132
Stereotactic body radiotherapy trials for local control
in BR have not yet been published; NCT00851916 is
a phase II single-group assignment trial of efficacy
that is currently recruiting patients.
Salvage therapy with ADT, RP, RT, or cryosurgery
begins with a risk–benefit determination of a therapy
or the individual patient. A number of factors,
including PSA-DT and surgical margins status at the
time of primary therapy, have been shown to predict
the success of salvage therapy. The clinical trials
currently investigating these modalities are summarized in Table 4. While these established therapies
provide promising results for men with BR, a
number of unconventional investigational salvage
therapies also exist.
INVESTIGATIONAL THERAPIES IN THE
SETTING OF BR
Men with an isolated PSA recurrence after local
treatment represent an ideal population for the evaluation of novel therapies based on minimal disease
state, indolent natural history, and preference to avoid
the adverse effects of hormone therapy. However, the
evaluation of novel agents in this setting is hampered
by the lack of convenient validated end points. Overall
or progression-free survival endpoints are impractical
because of the long interval between an initial PSA
increase and development of metastases. Although
PSA-DT has not been adequately evaluated as a clinical
trial endpoint, changes in PSA-DT may be more
sensitive to detect biologic activity than traditional
PSA response criteria and frequently used in the
recent clinical trial setting to suggest clinical efficacy
of the study drugs.133,134
In the previous placebo-controlled trials for
patients with prostate cancer and a rising PSA (with
baseline PSA-DT between 6–24 months) after definitive local therapy, 20% of placebo-treated participants
had favorable outcomes, defined as post-treatment
PSA-DT of 4200% of baseline PSA-DT.133 In another
randomized controlled trial of men with rising PSA
330
Table 4. Current Trials of Salvage Therapy for Recurrent Prostate Cancer
Trial
Identifier
Type
Salvage Cryotherapy in
Recurrent Prostate Cancer (SCORE)
Salvage HDR BT
Salvage MRI-mapped
dose-escalated RT v standard RT
Early v late RT
Salvage proton RT v photon/proton/
ADT for node negative cancer postRP
Vinflunine in hormone-refractory
prostate cancer
Salvage RT and docetaxel post-RP
NCT00824928
Prospective, multicenter
NCT01583920
NCT01411345
Phase I, pilot
Phase III, randomized, efficacy
study
Phase III, randomized
Phase II, non-randomized, single
group assignment
153
Sm followed by salvage 3D-CRT or
IMRT in high-risk clinically non
metastatic prostate cancer post-RP
Everolimus and RT as salvage therapy
post-RP
Salvage RP post-RT
NCT00480857
MRI-guided HDR BT v RT boost as
salvage in locally recurrent prostate
cancer
Salvage RT (2 schedules) post-RP for
non-metastatic BR
Sm 153 Lexidronam Penta Sodium and
RT in BR post-RP
Docetaxel, prednisone, sunitinib and
RT for BR after RP
Dutasteride v placebo for BR post-RT/
RP/salvage
NCT00860652
NCT00969111
NCT00545766
NCT00480857
Status
n
Biochemical
failure
GI, GU toxicity
Radiographic
Recruiting
800
Not yet open
Recruiting
4
80
BR
Morbidity
Recruiting
Recruiting
470
62
PSA
Completed
41
Progression-free
survival
PSA
Recruiting
44
Recruiting
76
NCT01548807
Phase I
Morbidity
Recruiting
33
NCT00002938
Phase II
survival
49
NCT00913939
Efficacy, non-randomized,
parallel assignment
Technical
measures
Ongoing, not
recruiting
Recruiting
NCT01272050
Phase III, randomized, efficacy
study
Phase II
PSA
Recruiting
350
Disease
response
PSA
Recruiting
76
37
PSA
Ongoing, not
recruiting
Completed
PSA
Recruiting
20
PSA
Recruiting
76
NCT00551525
NCT00734851
NCT00558363
NCT00851916
153
NCT01317043
Phase II, non-randomized, single
group assignment
Phase II, multicenter,
randomized, double-blind,
placebo controlled
Phase II, efficacy, single group
assignment
Phase II, efficacy, single group
assignment
60
294
Abbreviations: 153SM-EDTMP, samarium-153 ethylenediaminetetramethylenephosponate; BR, biochemical recurrence; BT, brachytherapy; CK, CyberKnife; CT, computerized
tomography; HDR, high dose rate; MRI, magnetic resonance imaging; PSA, prostate-specific antigen; RP, radical prostatectomy; RT, radiation therapy; QOL, quality of life.
N.G. Zaorsky et al
CK for local recurrence post-RT
SM-EDTMP followed by salvage RT
post-RP
Phase II, non-randomized, single
group assignment
Phase II, non-randomized
efficacy study
Phase II, non-randomized
efficacy study
Primary
Outcome
331
Rising PSA after local therapy
Table 5. Investigational Therapies in Men With BR Post-RT or Post-RP
Therapy
Troglitazone
Rosiglitazone
GM-CSF
High-dose calcitriol
CV706
Celecoxib
Imatinib mesylate
Marimastat
Lenalidomide
Pomegranate juice
Pomegranate extract
(POMx)
Digoxin
MK2206
Comments/References
Associated with stable disease in phase II study135
No effect on PSA-DT in a prospective study134
Decreased PSA levels by 450% in a phase II study 136
No significant PSA decrease, though 6/22 men had prolonged PSA-DT137
PSA selective oncolytic adenovirus, lowered PSA in a translational study138
Decreased PSA velocity and increased PSA-DT in a prospective, randomized,
placebo-controlled clinical trial with optional cross-over133
Limited PSA response with moderate degree of toxicity139
Decreased PSA velocity but dose-limiting toxicity at active doses is significant140
Dose-dependent PSA velocity decrease with acceptable toxicity141
Significant prolongation of PSA-DT142
Significantly increased PSA-DT 143
NCT01162135, recruiting participants
ECOG 2809/NCT01251861, recruiting participants
Abbreviations: BR, biochemical recurrence; DT, doubling time; ECOG, Eastern Cooperative Oncology Group; HIFU, high-intensity
focused ultrasound; GM-CSF, granulocyte-macrophage colony-stimulating factor; IBR, interval to biochemical recurrence; PSA,
prostate-specific antigen; PSAn, PSA nadir; RP, radical prostatectomy; RT, radiation therapy; SBRT, stereotactic body radiation
therapy.
after RP or RT, 31% of placebo-treated participants
had post-treatment PSA-DT of more than 200% of
baseline PSA-DT.134
Investigational studies (Table 5) have used PSA
kinetics as an outcome measure. Agonists of the
peroxisome proliferator-activated receptor (PPAR) γ
receptor, including troglitazone and rosiglitazone have
been shown to inhibit the proliferation on prostate
carcinoma cells in vitro. In a phase II study,135
troglitazone was associated with stable disease (and
only one case of PSA rise) in men with androgendependent prostate cancer. Rosiglitazone, unfortunately did not increase PSA-DT or prolong time to
disease progression more than placebo in men with a
rising PSA after RP and/or RT.134 In a single-arm phase
II study, granulocyte-macrophage colony-stimulating
factor (GM-CSF, sargramostim) decreased PSA levels
by 450% in three of 29 men with BR post-RP or
-RT.136 In another phase II study, high-dose, weekly
oral calcitriol achieved no PSA decrease 450% in 22
men who had rising PSA levels after definitive RT or
RP, although PSA-DT was increased.137 CV706 is a
replication-competent, PSA-selective oncolytic adenovirus. In a translational study, it was found to decrease
serum PSA values and not be associated with any
irreversible toxicities.138 Finally, celecoxib has been
shown to significantly decrease PSA velocity and
increase PSA-DT.133
These investigational salvage therapies are unconventional in that they do not use surgery or radiation
for the treatment of recurrent disease. These studies
use changes in PSA as an outcome measure, which
may correlate with distant metastasis. While their
results are promising, none has yet been shown to
be effective in a clinical setting, and phase III trials
have not been established.
CONCLUSION
PSA screening has resulted in an increase in the
overall incidence of prostate cancer diagnosis. While
many men can be treated with surgery or radiation, a
number of patients experience a rising PSA after
primary therapy. A general assumption is that BR will
lead to overt progression in patients over subsequent
years. Clinicians face a number of dilemmas when
encountering a rising PSA, including how to define BR,
if the BR comes from localized or systemic disease, the
treatment modality that would work best for an
individual patient, and the timing of therapy. A number
of studies have been published to help guide clinicians
through these problems, and more clinical trials are
currently ongoing. The future of detecting recurrent
prostate cancer will likely use more sensitive PSA
assays and advanced imaging; meanwhile, the future
of treating recurrent disease will likely use a variety of
modalities, including advanced surgical techniques,
bone-seeking radiopharmaceuticals, hypofractionated
radiation schedules, and pharmacotherapy.
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