The role of hormonal treatment in prostate cancer patients with non-metastatic disease
recurrence after local curative treatment: A systematic review
This Systematic Review (and meta-analysis) was performed under the auspices of the:
- European Association of Urology Guidelines Office Board
- European Association of Urology Prostate Cancer Guidelines Panel
Word count
Abstract
Text
Total
302
3827
4290
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
Abstract
Context
The relative benefits and harms of hormonal treatment (HT) versus no or deferred HT in
patients with non-metastatic prostate cancer (PCa) relapse after primary curative therapy
are controversial.
Objective
This systematic review aims to assess the effectiveness of HT for non-metastatic PCa
relapse, prognostic factors for treatment outcome, timing of treatment, and the most
effective treatment strategy, in order to provide guidance for clinical practice.
Evidence acquisition
A systematic literature search was undertaken incorporating MEDLINE, Embase and the
Cochrane Library (latest search March 2015). Studies were critically appraised for risk of
bias. The outcomes included overall and cancer-specific survival, metastasis-free survival,
symptom-free survival, progression to castrate-resistance, adverse events and quality of life.
Evidence synthesis
Out of 9,687 articles identified, 27 studies were eligible for inclusion (2 RCTs, 8 nonrandomized comparative studies, and 17 case series). The results suggest that only a
subgroup of patients, especially those with high-risk disease, may benefit from early HT. The
main predictors for unfavourable outcomes were shorter PSA-doubling time (<6-12 months)
and higher Gleason score (>7). Early HT may be warranted for patients with high-risk
disease. An intermittent HT strategy appears feasible. Most studies had moderate to high
risks of bias.
Conclusion
HT for PCa relapse after primary therapy with curative intent should be reserved for
patients at highest risk of progression and with a long life expectancy. The potential benefits
of starting HT should be judiciously balanced against the associated harms.
Patient summary
This article summarizes the evidence on the benefits and harms of hormonal treatment in
prostate cancer patients in whom the disease has recurred following earlier curative
treatment. We found that only a select group of patients with aggressive prostate cancer
and a fast rising PSA may benefit from early HT, while in others hormonal treatment may be
more harmful than beneficial.
2
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
1. Introduction
Prostate-specific antigen (PSA) monitoring is the cornerstone of follow-up after curative
treatment for prostate cancer (PCa). Elevations in PSA may indicate local or distant disease
recurrence. The most widely used definition of biochemical recurrence (BCR) after radical
prostatectomy (RP) is two consecutive rising PSA values of 0.2 ng/mL or more (ref EAU
guidelines), whilst BCR after radiation therapy (external beam radiation therapy (EBRT) or
brachytherapy) is commonly defined as a confirmed rise in PSA of 2 ng/ml above the posttreatment PSA nadir.(ref Roach) The incidence of BCR at 10 years post-treatment is 21-47%
for RP, and 16-52% for EBRT; for brachytherapy, the figure at 15 years post-treatment is
16%-53% [1, 2].
Although BCR after radical therapy is seen frequently, the natural course of this biochemical
finding is highly variable. It commonly precedes clinical symptoms by years and may not
impact survival outcomes [1, 3]. Nevertheless, up to 34% of men who develop BCR after RP
may eventually develop clinical recurrence, with a median time of 8 years between BCR and
metastatic disease [4]. With the new upcoming imaging modalities metastatic disease might
be discovered more quickly. Hormonal treatment (HT) designed to suppress the androgen
axis is widely used in patients with PCa relapse, but is associated with side effects (including
hot flashes, sexual dysfunction, loss of libido, fatigue, anaemia, depression, cardiovascular
disease, metabolic syndrome and osteoporosis) some of which can be severe and associated
with an increased mortality and/or impair quality of life (QoL) [5]. The relative benefits and
harms of salvage HT in the setting of BCR or local disease recurrence are controversial, and
there is uncertainty regarding how, in whom and when it should be used. It is crucial to
identify those patients with disease recurrence that may benefit most from HT.
This systematic review was undertaken by the EAU Prostate Cancer Guideline Panel as part
of its guidelines update for 2016 and aimed to assess the clinical effectiveness of salvage HT
in patients with BCR or non-metastatic clinical recurrence after curative treatment for PCa,
and to attempt to achieve some clarity regarding prognostic factors which influence
treatment outcomes, the optimum timing of treatment, and the most effective treatment
strategy.
2. Evidence acquisition
2.1 Search strategy
The protocol for the review has been published (http://www.crd.york.ac.uk/PROSPERO/
Registration number: CRD42015016075) and the search strategy is outlined in Appendix 1.
Briefly, databases including MEDLINE, Embase and the Cochrane Central Register of
Controlled Trials were systematically searched in March 2015. All abstracts and full-text
articles were screened by two reviewers independently. Disagreement was resolved by
discussion or with an independent arbiter. There were no language restrictions but only
studies published from 2000 onwards were selected to ensure contemporary data with PSA
measured at PCa recurrence. The search was complemented by additional sources,
3
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
including the reference lists of included studies and a panel of experts (EAU Prostate Cancer
Guideline Panel).
2.2 Types of study designs included
All randomized controlled trials (RCT), quasi-RCTs, non-randomised comparative studies
(NRS) comparing HT to either no HT or deferred HT, and single-arm case series involving HT
in this setting were included. Studies with a minimum follow-up of 1 year (to assess the
primary outcome measure of overall survival (OS) at 1 year) and a minimum of 50
participants were included.
2.3 Types of participants included
Men with PCa who underwent one or more primary or salvage local treatments with
curative intent, and who subsequently developed non-metastatic disease recurrence and
were considered beyond local salvage treatment, were included in the review. The primary
or salvage local treatments included: RP, EBRT, brachytherapy, cryotherapy, and high
intensity focused ultrasound (HIFU). The definition of disease recurrence was as defined by
trialists, including either different definitions of BCR, or local or regional clinical recurrence
(such as radiographical evidence of positive lymph nodes). No restriction on BCR definitions
was imposed due to the expected heterogeneity of the definitions used. Sensitivity analyses
based on standard and non-standard definitions were planned. Patients who had
concurrent, neo- and/or adjuvant HT in the primary or salvage setting were also included,
provided disease recurrence did not occur during this period of HT. Exclusion criteria
comprised men with concomitant salvage local treatment for lymph node recurrence
(radiotherapy or surgery).
2.4 Types of interventions included
The experimental intervention was early HT via surgical castration, LHRH (luteinizing
hormone-releasing hormone) analogues, LHRH antagonists, anti-androgens (non-steroidal
and steroidal), and oestrogens. HT includes monotherapy, combinations of analogues with
anti-androgens and intermittent HT. The control intervention was no HT or deferred HT (i.e.
HT given only at development of metastatic disease or symptom development). Studies with
any participants who received chemotherapy (including estramustine) or 5-alpha-reductase
inhibitor as monotherapy, ketoconazole, abiraterone or enzalutamide were excluded.
2.5 Type of outcome measures included
The primary outcome of clinical effectiveness was OS at one, 1-5 and >5 years. Secondary
outcomes of clinical effectiveness were cancer-specific survival (CSS), freedom from distant
metastasis (DM), symptom-free survival (e.g. need for palliative radiotherapy, lower and
upper urinary tract obstruction, pain, etc.), time to second-line systemic treatment for
recurrence or development of castrate resistance (CRPC) (i.e. chemotherapy, abiraterone,
enzalutamide etc.), adverse events (e.g. cardiovascular events, fractures), QoL (as defined
by each trial), pain (as defined by each trial), and any other outcomes judged important by
the reviewer.
2.6 Assessment of risk of bias
The risk of bias (RoB) in the included RCTs was assessed using the Cochrane risk of bias
assessment tool for RCTs [6, 7]. RoB in NRS was assessed using the modified Cochrane tool
4
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
which included additional items to assess confounding bias. This was a pragmatic approach
informed by the methodological literature pertaining to assessing RoB in NRS [8, 9]. A list of
the three most important prognostic confounders (Gleason score at diagnosis; PSA kinetics
[doubling time (PSA-DT) or velocity] at the moment of recurrence; and proven [radiological]
absence of metastases at the moment of recurrence) was created a priori by the EAU PCa
guideline panel. The overall judgement regarding each confounder was based on whether it
was measured, if it was balanced across groups and whether any statistical adjustments
were made. RoB in case series was assessed using a pragmatic approach based on external
validity (whether study participants were selected consecutively or representative of a
wider patient population; how attrition bias was dealt with; and if outcome measurement
bias was addressed) and whether an a priori protocol was available [10, 11] .
2.7 Data analysis
For time-to-event data (e.g. survival analysis), estimates such as median or the percentage
event free (survival rate) at one year, 1-5 years and >5 years were extracted where
available. Adjusted and unadjusted Hazard ratios (HR), to estimate the size of intervention
differences were extracted where available. For binary/dichotomous/categorical data, risk
ratios (RR), odds ratios (OR) were extracted where available. For continuous outcomes
mean difference (MD) with corresponding 95% confidence intervals (CIs) were extracted
where available. Meta-analyses were planned for data obtained from RCTs only, due to
inherent clinical and methodological heterogeneity and selection bias likely to be present in
non-RCTs. For non-RCTs, a narrative synthesis [12] of the data was planned. Where possible,
dichotomous outcomes comparing the intervention effect were analysed using RRs with
95% CIs. Means and standard deviations were used to summarise the continuous outcome
data and compared using MD and 95% CIs.
To explore the potential impact of clinical heterogeneity on outcomes, subgroup and
sensitivity analyses were planned, including age, clinical nodal stage prior to primary
treatment, metastatic disease status at recurrence, PSA level and kinetics at recurrence,
type, schedule and timing (early vs deferred) of HT (see protocol for the review:
http://www.crd.york.ac.uk/PROSPERO/ Registration number: CRD42015016075).
3. Evidence Synthesis
3.1 Quantity of evidence identified
The study selection process is outlined in the Preferred Reporting Items for Systematic
reviews and Meta-analyses (PRISMA) flow diagram (Figure 1). In total 9,687 abstracts were
screened, of which 307 full texts were retrieved for further screening. Ultimately, 27 studies
met the inclusion criteria, recruiting a total of 11,606 patients (1,679 from RCTs, 5,409 from
NRSs, and 4,518 from case series). This included two RCTs [13, 14], eight retrospective NRSs
[15-22], and 17 case series [23-39]. Out of the 10 comparative studies, two were published
only as abstracts at the American Society of Clinical Oncology annual meeting [14, 15].
3.2 Characteristics of the included studies
Tables 1a and 1b present the baseline study characteristics for the 10 comparative studies
and 17 case series respectively.
5
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
3.2.1 Characteristics of comparative studies
Prior therapy with curative intent was RP in three studies [18, 20, 21], and EBRT with or
without neo-adjuvant or adjuvant HT in four studies [16, 17, 19, 22]. One study [13]
recruited patients following EBRT, of whom a subgroup had received EBRT after RP. Two
studies [14, 15] recruited patients who had undergone either RP or EBRT. Duchesne et al.
[14] also included two patient groups: (group 1) patients with BCR following definitive
therapy; and (group 2) asymptomatic men with either localised or metastatic disease not
suitable for curative therapy at diagnosis.
Information on staging and Gleason scores of the primary tumour was available in most
studies. Data regarding PSA level at the point of starting HT however was only presented in
three studies [16, 19, 20].
Different definitions of early versus delayed HT were used. To stratify patients, studies used
PSA-kinetics (mainly PSA-DT) [17, 19], BCR or absolute PSA values versus clinical recurrence
[16, 18], absolute PSA values [20, 21], or time frame after recurrence [15].
Studies either did not report which specific type or schedule of HT was used [14, 15, 17, 19,
21, 28] or included patients using different forms or combinations of HT [13, 16, 18, 20].
The most frequently reported outcomes included freedom from distant metastases (DM)
[14, 16-21], CSS [13-17, 20], OS [13-16, 28], and development of CRPC [13, 14, 21], or QoL
[13, 14].
3.2.2 Characteristics of case series
Of the 17 case series, four presented outcomes of intermittent HT [26, 27, 36, 39], one of HT
and bisphosphonates [35], one of HT and finasteride [30], and one of observation after
recurrence only [29]. The other 10 studies presented outcomes of continuous HT for disease
recurrence after primary therapy [23-25, 28, 31-34, 37, 38].
Previous primary therapy had been RP with or without adjuvant HT [25, 31, 33, 36], EBRT
with or without adjuvant HT [23, 28, 29, 37, 38], or was not reported [24]. The rest of the
case series combined RP and EBRT patients.
The reported outcomes differed between studies, but mainly included development of
CRPC, DM, CSS, and/or OS. One case series reported QoL measures.
3.3 Risk of bias and confounding assessment of the included studies
Table 2a presents the risk of bias (RoB) summary and confounder assessment for the two
RCTs [13, 14] and eight NRSs [15-22]. The NRSs had a high risk of selection, performance and
detection biases. The risks of attrition bias (incomplete outcome data) and reporting bias
(selective reporting) were low. The confounders Gleason score at diagnosis and PSA kinetics
at relapse were measured and corrected for in most studies. However, metastatic stage at
relapse was not considered in four studies and was unclear in three.
6
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
Table 2b summarises the RoB assessment for the 17 case series. In general, these studies
were at a high risk of bias regarding the selection of consecutive patients, and a generally
low risk of bias regarding loss to follow-up and selective outcome reporting.
3.4 Comparisons of interventions results
3.4.1 Data from comparative studies
Table 3a summarises the outcome results for the two RCTs [13, 14] and eight NRSs [13, 1522].
3.4.1.1 Prognostic factors for outcomes
In the study by Pinover et al. [19], higher age (p=.002) and higher PSA-nadir after HT (p=.04)
were independently significantly associated with less favourable OS. No specific predictors
of CSS were found, though distant metastases were independently predicted by Gleason
score (p=.0039), PSA nadir (p=.0001), PSA-DT (p=.001) at the moment of recurrence, and the
use of HT on PSA failure (p=.0001).
Klayton et al. [17] observed in their retrospective cohort that more patients were treated
with HT when they have a shorter PSA-DT (59% with PSA-DT <6 mo vs 28% with >24
months). Patients with a short PSA-DT had lower freedom of DM, CSS, and OS rates. Other
predictors of distant metastases were Gleason score and the initial use of HT at recurrence.
In this study the six month threshold for PSA-DT held the best discriminative value.
Kim et al. [22] found PSA-velocity to be associated with CSS or OS in patients with
recurrence (defined as PSA >10 ng/ml) with little comorbidity (p=.008), but not in men with
moderate to severe comorbidity (Adult Comorbidity Evaluation-27) (p=0.15). Gleason score
was also related to death.
3.4.1.2 Clinical effectiveness and timing
In a RCT, Duchesne et al. [14] found OS (6-year: 86% and 79%, p=0.047) and overt local (HR
0.51, p=0.001) and distant disease progression (HR 0.54, p=0.018) rates to be significantly
more favourable for patients randomized to early HT versus delayed HT Non-significant
trends towards more favourable outcomes for early HT were also observed for other
endpoints except time to CRPC in which there was no difference. However, the study cohort
(n=293) included two groups of patients (one with BCR following previous definitive
therapy, and one with either localised or metastatic disease not suitable for curative
therapy at the outset) and the relative proportion of these two contrasting groups within
the study cohort is unclear.
Kestin et al. [16] retrospectively analysed the impact of HT on clinical outcomes and the
impact of different definitions of BCR. When defined as a PSA rise ≥3 ng/ml above nadir,
early HT (at moment of BCR versus deferred HT, initiated at the point of clinical progression)
was associated with decreased five-year local failure rate (4% vs 33%), distant metastases
(13% vs 44%), PCa specific death (9% vs 24%), and overall death (32% vs 48%) (all p <0.01).
Early HT was a significant predictor of these endpoints in multivariable analysis. Patients
who received early HT comprised a selected group with worse prognostic factors, for which
was corrected in multivariable analysis.
7
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
Starting HT at the earliest suggestion of BCR (e.g. a single PSA value ≥0.2 ng/ml or with two
consecutive PSA values >0.1 ng/ml and rising) compared with the more conventional
definition (two values ≥0.2 ng/ml and rising), was associated with lower BCR rates (2% vs
17% after 65 months follow-up; p.0279) in one NRS.(ref Taguchi) The low threshold for
defining BCR in the ‘ultra-early’ group may however have led to HT treatment in patients
without true disease recurrence.
Garcia-Albeniz et al. [15] recruited patients with PSA-only recurrence involving different
primary treatments, and found that early HT (<3 months after BCR) did not lead to more
favourable OS or CSS compared with delayed HT (>2 years after relapse, at clinical
progression or in cases with short PSA-DT).
Siddiqui et al. [20] found that patients who received HT at the moment of BCR (different
thresholds analysed; either at PSA >0.4, >1.0, or >2.0 ng/ml) did not have improved systemic
progression-free survival or CSS compared with patients who eventually received HT more
than six months after BCR. In this study, a trend (and including a significant difference for a
threshold PSA of 2.0 ng/ml; p=.021) was observed suggesting worse CSS rates in patients
receiving HT. This counterintuitive finding may be due to a selection bias in which patients
with unfavourable disease characteristics received HT earlier (i.e. indication bias).
Moul et al. [18] found no favourable effect of early HT (defined either as a PSA below 5
ng/ml or 10 ng/ml versus higher PSA levels, or clinical failure) versus no HT on the
development of clinical metastasis for the total cohort. A beneficial effect on distant
metastases (adjusted HR 2.12 [1.20-3.73]; p=0.010) was observed in high-risk patients
(defined as a Gleason score >7 or PSA-DT <12 months). Klayton et al. [17] found a benefit
regarding 7-year CSS for men receiving HT versus observation alone (68% vs 46%; p=.015),
but not in the group with a PSA-DT longer than six months. Irrespective of PSA-DT, HT
resulted in more favourable distant metastases free survival (adjusted HR 0.42; p=.0002).
Pinover et al. [19] found that the use of HT was associated with a significantly longer 5-year
freedom of distant metastases rate in patients with a PSA-DT <6 months (57% vs 78%;
p=.0026), while no difference was observed in the group with a PSA-DT >12 months.
3.4.1.3 HT strategy
In the RCT performed by Crook et al. [13], patients were randomized (median age 74) to
continuous versus intermittent HT in relapsing (PSA >3.0 ng/ml) patients after primary
therapy (mainly EBRT, with previous RP in 11.4%, and adjuvant HT in 39.1%) with curative
intent. The study reported no inferior outcomes between the intermittent versus
continuous HT strategy group (median OS 8.8 vs 9.1 years, respectively; p=.009 for noninferiority; HR 1.02 (0.86-1.21)), independent of Gleason score after a median follow-up of
6.9 years. In terms of QoL, the intermittent therapy arm had slightly better scores for hot
flashes, desire for sexual activity and urinary symptoms which were statistically significant,
but there was no difference in other functional domains and in overall QoL. Men in the
intermittent group were on hormonal therapy for a median of 15.4 months, while the
patients in the continuous group received 43.9 months of hormonal therapy. In the other
8
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
studies patients received continuous HT until the end of follow-up. It was not possible to
determine if one specific type or combination of HT was better than another.
3.4.2 Data from case series
Table 3b summarises the outcome results for the 17 case series [23-39].
3.4.2.1 Prognostic factors for outcomes
Disease-specific factors identified to be associated with unfavourable outcomes included
short PSA-DT [23, 25, 27, 28, 31], higher Gleason score [28, 38], higher PSA [31, 37], seminal
vesicle invasion [23], higher PSA nadir after starting HT [27, 34], early start of HT [28, 33],
longer duration of (neo)adjuvant HT at EBRT [38], and high testosterone values during HT
[24].
3.4.2.2 Clinical effectiveness and timing
Shipley et al. [37] found that in patients without distant metastases at the moment of
starting HT after EBRT, those with a PSA <20 ng/ml had more favourable CSS than those
with higher PSA (p=0.0025).
Another study suggested an overall benefit of HT for risk of death in a recurrence situation
(adjusted HR 0.56, 95% CI, 0.37-0.84) [25].
3.4.2.3 HT strategy
The feasibility of intermittent hormonal therapy in the relapse setting was supported by
different case series [26, 27, 36, 39]. PSA nadir >0.4 ng/ml and off-treatment period <24
weeks were predictors of clinical progression [36].
4. Discussion
4.1 Principal findings
Conflicting results on the clinical effectiveness of HT after previous curative therapy of the
primary tumor were found. Some studies reported a favourable effect of HT, including the
only RCT addressing the research question of this review (86% vs 79% advantage in OS in
early HT group [14]). Other studies did not find any differences between early versus
delayed or no HT. One study found an unfavourable effect of HT [20]. This may be the result
of selecting clinically unfavourable cases for (early) HT and more intensive diagnostic workup and follow-up in these patients.
Men with disease relapse after primary curative treatment comprise a heterogeneous group
of patients. The following factors were found predictive for poor outcomes (CRPC, DM, CSS,
OS): short PSA-DT, high Gleason score, high PSA, increased age and comorbidities. Whilst
the patients are undergoing HT, higher PSA-nadir and higher testosterone levels were also
poor prognostic factors. In a previous review by Boorjian et al. [40], older patient age, higher
Gleason score, higher tumour stage, and short PSA-DT were found to be associated with
systemic progression and death from PCa after RP. High-risk patients, mainly defined by a
high Gleason score and a short PSA-DT (most often <6 months), are suggested in different
studies to benefit most from (early) HT, especially in men with long life expectancy.
9
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
No data were found on the effectiveness of different types of HT, although it is unlikely that
this will have a significant impact on survival outcomes in this setting. Non-steroidal
antiandrogens have been claimed to be inferior compared to castration, but this difference
was not seen for the M0 patients.[NEW REF KUNATH] Also, no conclusions can be drawn on
potential different strategies for patients who received primary RP or EBRT, who did or did
not receive salvage or adjuvant radiotherapy after surgery, or who received (neo)adjuvant
HT. One of the included RCTs suggested that intermittent HT is not inferior to continuous HT
in terms of OS and CSS [13]. A small advantage was found in some QoL domains but not
overall QoL outcomes. An important limitation of this RCT is the lack of any stratifying
criteria such as PSA-DT or initial risk factors.
4.2 Implications for clinical practice
The link between PSA relapse and survival is weak at best, and the management approach
has to be individualized [41, 42]. Based on the lack of definitive efficacy and the
undoubtedly associated significant side effects, not all patients with disease recurrence
after primary curative therapy should receive standard HT at the outset. Only a minority of
patients with disease recurrence will progress to systemic progression or PCa-caused death.
The objective of HT should be to improve OS, postpone DM, and improve QoL. QoL was
reported as an outcome in only one of the included studies. Biochemical response to HT
only holds no clinical benefit for a patient. For older patients and those with comorbidities,
side effects of HT may even decrease life expectancy; in particular, cardiovascular risk
factors need to be considered [43, 44]. However, high-risk patients with long life expectancy
may benefit from HT. Therefore, personalized risk stratification is warranted, taking patient
(age, comorbidity, patient preferences) and disease specific (Gleason score, PSA-DT) factors
into account in clinical decision-making. No strong conclusions can be drawn on the
preferable HT strategy in this setting.
4.3 Further research
The relative benefits and harms of HT in the PCa relapse setting would certainly require
further study, preferably by well-designed prospective studies. Two RCTs were included in
this review [13, 14]. Only Duchesne et al. addressed the specific research question of this
review, that is a study randomizing patients between early and no or deferred HT [14].
However, the study also included asymptomatic men with more advanced disease not
suitable for curative therapy at the outset. The results of the cohorts of men treated initially
with curative intent, and of men with more advanced disease, were not reported separately.
Moreover, the results were available in abstract format only, and hence data are likely to be
incomplete. The trial recruited less patients than the original calculated sample size for
which the trial was powered for. Nevertheless, a significant difference in OS was found. For
all other secondary endpoints, this study may be underpowered to detect any differences.
Further results are awaited.
4.4 Limitations and strengths
Overall, the quality of the evidence obtained from this review was low to moderate, based
on relatively few well-designed prospective studies with low risks of bias. Heterogeneity in
study designs, populations, interventions, definitions of recurrence and types of outcome
measures reported made meta-analysis inappropriate. We could not draw any conclusions
10
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
on the relative benefits or harms of different primary strategies or on different forms of HT.
The review was undertaken by a multi-disciplinary panel of clinical, methodological and
patient experts (EAU Prostate Cancer Guideline Panel) according to PRISMA guidelines, and
the results will be incorporated into the panel’s clinical practice guidelines for 2016.
5. Conclusion
Based on currently available evidence, which has been robustly and systematically assessed
and appraised, the benefit of early systemic HT for non-metastatic PCa relapse remains
unproven. Accordingly, based on the real risk of its associated side effects and its lack of
proven clinical effectiveness, early HT cannot be recommended as the standard of care in
the setting of biochemical or local disease recurrence. Early HT should be reserved for those
at highest risk of disease progression, defined mainly by a short PSA-DT at relapse (<6-12
months) or a high initial Gleason score (>7), and a long life expectancy. In all other
situations, the potential benefits of salvage HT should be judiciously considered and
balanced against its potential harms.
References
NEW REF: Kunath F, Grobe HR, Rücker G, et al. Non-steroidal antiandrogen monotherapy
compared with luteinising hormone-releasing hormone agonists or surgical castration
monotherapy for advanced prostate cancer. Cochrane Database Syst Rev. 2014.
1.
Stephenson AJ, Kattan MW, Eastham JA, et al. Defining biochemical recurrence of
prostate cancer after radical prostatectomy: a proposal for a standardized
definition. J Clin Oncol. 2006;24:3973-8.
2.
Sylvester J, Blasko J, Grimm P, et al. Fifteen year follow up of the first cohort of
localized prostate cancer patients treated with brachytherapy. J Clin Oncol.
2004;22(Suppl.):4567.
3.
Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer.
Part II: Treatment of advanced, relapsing, and castration-resistant prostate
cancer. Eur Urol. 2014;65:467-79.
4.
Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after
PSA elevation following radical prostatectomy. JAMA. 1999;281:1591-7.
5.
D'Amico AV, Denham JW, Crook J, et al. Influence of androgen suppression
therapy for prostate cancer on the frequency and timing of fatal myocardial
infarctions. J Clin Oncol. 2007;25:2420-5.
6.
Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for
assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
11
469
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517
7.
Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of
Interventions version 5.0.2: The Cochrane Collaboration; 2011. Available from:
http://www.cochrane-handbook.org/. [Accessed April 2015]
8.
Deeks JJ, Dinnes J, D'Amico R, et al. Evaluating non-randomised intervention
studies. Health Technol Assess. 2013;7:1-173.
9.
Reeves B, Deeks J, Higgins J, et al. Chapter 13 Including non-randomised studies.
2011. In: Cochrane handbook for systematic reviews of interventions version
502 [Internet]. The Cochrane Collaboration [Accessed February 2014]. Available
from: http://www.cochrane-handbook.org/. .
10.
Dalziel K, Round A, Stein K, et al. Do the findings of case series studies vary
significantly according to methodological characteristics? Health Technol Assess.
2005;9:1-146.
11.
Viswanathan M, Ansari M, Berkman N, et al. Assessing the Risk of Bias of
Individual Studies in Systematic Reviews of Health Care Interventions. Agency
for Healthcare Research and Quality Methods Guide for Comparative
Effectiveness Reviews: Agency for Healthcare Research and Quality Methods
Guide for Comparative Effectiveness Reviews; 2012. Available from:
www.effectivehealthcare.ahrq.gov/. [Accessed July 2015]
12.
Popay J, Roberts H, Sowden A, et al. Guidance on the conduct of narrative
synthesis in systematic reviews: a product from the ESRC Methods Programme.
Lancaster University: Institute for Health Research; 2009. Available from:
http://www.lancaster.ac.uk/shm/research/nssr/research/dissemination/public
ations/NS_Synthesis_Guidance_v1.pdf. [Accessed August 2015]
13.
Crook JM, O'Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for
rising PSA level after radiotherapy. N Engl J Med. 2012;367:895-903.
14.
Duchesne G, Bassett J, D'Este C, et al. The "Timing of androgen deprivation
therapy in prostate cancer patients with a rising PSA (TOAD)" collaborative
randomised phase III trial. J Clin Oncol. 2015;33(Suppl.):5007.
15.
Garcia-Albeniz X, Chan JM, Paciorek A, et al. Immediate versus deferred initiation
of androgen deprivation therapy in prostate cancer patients with PSA-only
relapse. An observational follow-up study. Eur J Cancer. 2015;51:817-24.
16.
Kestin LL, Vicini FA, Martinez AA. Potential survival advantage with early
androgen deprivation for biochemical failure after external beam radiotherapy:
the importance of accurately defining biochemical disease status. Int J Radiat
Oncol Biol Phys. 2004;60:453-62.
17.
Klayton T, Ruth K, Buyyounouski M, et al. PSA Doubling Time Predicts for the
Development of Distant Metastases for patients who fail 3DCRT Or IMRT Using
the Phoenix Definition. Pract Radiat Oncol. 2011;1:235-42.
12
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
562
563
564
565
566
18.
Moul JW, Wu H, Sun L, et al. Early versus delayed hormonal therapy for prostate
specific antigen only recurrence of prostate cancer after radical prostatectomy. J
Urol. 2008;171:1141-7.
19.
Pinover WH, Horwitz EM, Hanlon AL, et al. Validation of a treatment policy for
patients with prostate specific antigen failure after three-dimensional conformal
prostate radiation therapy. Cancer. 2003;97:1127-33.
20.
Siddiqui SA, Boorjian SA, Inman B, et al. Timing of androgen deprivation therapy
and its impact on survival after radical prostatectomy: a matched cohort study. J
Urol. 2008;179:1830-7.
21.
Taguchi S, Fukuhara H, Azuma T, et al. Ultra-early versus early salvage androgen
deprivation therapy for post-prostatectomy biochemical recurrence in pT24N0M0 prostate cancer. BMC Urol. 2014;14:81.
22.
Kim MB, Chen MH, de Castro M, et al. Defining the optimal approach to the
patient with postradiation prostate-specific antigen recurrence using outcome
data from a prospective randomized trial. Cancer. 2013;119:3280-6.
23.
Algarra R, Hevia M, Tienza A, et al. Survival analysis of patients with biochemical
relapse after radical prostatectomy treated with androgen deprivation:
Castration-resistance influential factors. Canadian Urological Association Journal.
2014;8:E333-41.
24.
Bertaglia V, Tucci M, Fiori C, et al. Effects of serum testosterone levels after 6
months of androgen deprivation therapy on the outcome of patients with
prostate cancer. Clin Genitourin Cancer. 2013;11:325-30.e1.
25.
Choueiri TK, Chen MH, D'Amico AV, et al. Impact of postoperative prostatespecific antigen disease recurrence and the use of salvage therapy on the risk of
death. Cancer. 2010;116:1887-92.
26.
de la Taille A, Zerbib M, Conquy S, et al. Study of intermittent endocrine therapy
in patients presenting with biologic recurrence after radical prostatectomy or
radiotherapy. Prog Urol. 2002;12:240-7.
27.
Keizman D, Huang P, Antonarakis ES, et al. The change of PSA doubling time and
its association with disease progression in patients with biochemically relapsed
prostate cancer treated with intermittent androgen deprivation. Prostate.
2011;71:1608-15.
28.
Kim-Sing C, Pickles T, Prostate Cohort Outcomes I. Intervention after PSA failure:
examination of intervention time and subsequent outcomes from a prospective
patient database. Int J Radiat Oncol Biol Phys. 2004;60:463-9.
29.
Martin NE, Chen MH, Beard CJ, et al. Natural history of untreated prostate
specific antigen radiorecurrent prostate cancer in men with favorable prognostic
indicators. Prostate Cancer Print. 2014;2014:912943.
13
567
568
569
570
571
572
573
574
575
576
577
578
579
580
581
582
583
584
585
586
587
588
589
590
591
592
593
594
595
596
597
598
599
600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
30.
Monk JP, Halabi S, Picus J, et al. Efficacy of peripheral androgen blockade in
prostate cancer patients with biochemical failure after definitive local therapy:
results of Cancer and Leukemia Group B (CALGB) 9782. Cancer. 2012;118:413947.
31.
Moreira DM, Cooperberg MR, Howard LE, et al. Predicting bone scan positivity
after biochemical recurrence following radical prostatectomy in both hormonenaive men and patients receiving androgen-deprivation therapy: results from the
SEARCH database. Prostate Cancer Prostatic Dis. 2014;17:91-6.
32.
Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to
definitive radiotherapy in prostate carcinoma--long-term results of phase III
RTOG 85-31. Int J Radiat Oncol Biol Phys. 2005;61:1285-90.
33.
Porter CR, Gallina A, Kodama K, et al. Prostate cancer-specific survival in men
treated with hormonal therapy after failure of radical prostatectomy. Eur Urol.
2007;52:446-52.
34.
Rodrigues NA, Chen MH, Catalona WJ, et al. Predictors of mortality after
androgen-deprivation therapy in patients with rapidly rising prostate-specific
antigen levels after local therapy for prostate cancer. Cancer. 2006;107:514-20.
35.
Rodrigues P, Hering FO, Meller A. Adjuvant Effect of IV Clodronate on the Delay
of Bone Metastasis in High-Risk Prostate Cancer Patients: A Prospective Study.
Cancer Res Treat. 2011;43:231-5.
36.
Sciarra A, Cattarino S, Gentilucci A, et al. Predictors for response to intermittent
androgen deprivation (IAD) in prostate cancer cases with biochemical
progression after surgery. Urol Oncol. 2013;31:607-14.
37.
Shipley WU, Desilvio M, Pilepich MV, et al. Early initiation of salvage hormone
therapy influences survival in patients who failed initial radiation for locally
advanced prostate cancer: A secondary analysis of RTOG protocol 86-10. Int J
Radiat Oncol Biol Phys. 2006;64:1162-7.
38.
Spratt DE, Zumsteg ZS, Pei X, et al. Predictors of castration-resistant prostate
cancer after dose-escalated external beam radiotherapy. Prostate. 2015;75:17582.
39.
Yu EY, Kuo KF, Gulati R, et al. Long-term dynamics of bone mineral density
during intermittent androgen deprivation for men with nonmetastatic, hormonesensitive prostate cancer. J Clin Oncol. 2012;30:1864-70.
40.
Boorjian SA, Thompson RH, Tollefson MK, et al. Long-term risk of clinical
progression after biochemical recurrence following radical prostatectomy: the
impact of time from surgery to recurrence. Eur Urol. 2011;59:893-9.
14
615
616
617
618
619
620
621
622
623
624
625
626
627
628
629
630
631
632
633
634
41.
Trock BJ, Han M, Freedland SJ, et al. Prostate cancer-specific survival following
salvage radiotherapy vs observation in men with biochemical recurrence after
radical prostatectomy. JAMA. 2008;299:2760-9.
42.
Zumsteg ZS, Spratt DE, Romesser PB, et al. The natural history and predictors of
outcome following biochemical relapse in the dose escalation era for prostate
cancer patients undergoing definitive external beam radiotherapy. Eur Urol.
2015;67:1009-16.
43.
Levine GN, D'Amico AV, Berger P, et al. Androgen-deprivation therapy in prostate
cancer and cardiovascular risk: a science advisory from the American Heart
Association, American Cancer Society, and American Urological Association:
endorsed by the American Society for Radiation Oncology. Circulation.
2010;121:833-40.
44.
O'Farrell S, Garmo H, Holmberg L, et al. Risk and timing of cardiovascular disease
after androgen-deprivation therapy in men with prostate cancer. J Clin Oncol.
2015;33:1243-51.
15