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ORIGINAL ARTICLE
Are post-docetaxel treatments effective in patients with
castration-resistant prostate cancer and performance of 2?
A meta-analysis of published trials
R Iacovelli
1
, A Altavilla
1
, G Procopio
2
, S Bracarda
3
, M Santoni
4
, S Cascinu
4
and E Cortesi
1
BACKGROUND: About 20% of patients with prostate cancer have an ECOG performance status (PS) X2 at diagnosis. We
investigate if current treatment options for castration-resistant prostate cancer (CRPC) may decrease the risk of death even
in patients with ECOG PS of 2.
METHODS: PubMed was reviewed for phase III randomized trials in patients with CRPC progressed after docetaxel
chemotherapy. Characteristics of each study and the relative hazard ratio (HR) for overall survival and 95% confidence interval
(CI) were collected. Summary HR was calculated using random- or fixed-effects models depending on the heterogeneity of
included studies.
RESULTS: A total of 3,149 patients was available for meta-analysis. In the overall population, the experimental treatments decrease
the risk of death by 31% (HR ¼ 0.69; 95% CI: 0.63–0.76; Po0.001). The activity of experimental treatments was similar in 2,859
patients with ECOG-PS ¼ 0 or 1 with a reduced risk of death of 31% (HR ¼ 0.69; 95% CI: 0.62–0.76). A total of 290 patients (9.2%) had
ECOG-PS ¼ 2 and experimental treatments decreased the risk of death by 26% (HR ¼ 0.74; 95% CI: 0.56–0.98; P ¼ 0.035) compared
with the controls even in this sub-group. When patients were stratified by type of treatment, the reduction of the risk of death was
confirmed for hormonal therapies: abiraterone and enzalutamide (HR ¼ 0.72; 95% CI: 0.52–0.99; P ¼ 0.046), but not for
chemotherapy (HR ¼ 0.81; 95% CI: 0.48–1.37; P ¼ 0.43).
CONCLUSIONS: We believe this is the first study reporting a benefit in second-line setting for CRPC patients previously treated with
docetaxel and poor PS.
Prostate Cancer and Prostatic Disease (2013) 16, 323–327; doi:10.1038/pcan.2013.20; published online 30 July 2013
Keywords: castration-resistant prostate cancer; second line; abiraterone acetate; cabazitaxel; enzalutamide; performance status
INTRODUCTION
Prostate cancer is the most frequent cause of cancer in male; in
2012, about 241 740 new cases and 28 170 deaths have been
estimated in the USA.
1
Androgen-deprivation therapy with the
luteinizing hormone-releasing analogue is the gold standard for
advanced disease but despite the initial response, patients will
develop progressive castration-resistant prostate cancer (CRPC).
Treatment of CRPC has completely changed in 2004 with the
approval of docetaxel based on improvement of survival and
control of disease compared with mitoxantrone (Mito).
2,3
In recent
years, several agents have reported to increase survival, delay
disease progression and improve quality of life after docetaxel
progression.
4
About 20% of patients with a new diagnosis of prostate cancer
have an ECOG performance status (PS) X2, and the portion is
probably higher in patients with advanced disease.
5
Furthermore,
PS and other factors such as baseline value of hemoglobin under
the lower normal limit, weight loss and pain have been related to
a short survival in patients with hormone sensitive and CRPC.
6–8
Despite these data, patients with poor PS enrolled in major
clinical trials are less than 10%, and no evidence are currently
available to the benefit of treating this subgroup. Therefore, we
sought to investigate whether current available treatments for
CRPC progressed after first-line docetaxel-based chemotherapy
(CHT) may decrease the risk of death even in patients with poor PS.
MATERIALS AND METHODS
Definition of the outcome
For each trial, the experimental treatment was compared with the control
one. Overall survival (OS) was evaluated in the experimental arms over the
control arms in the entire cohort, and in the patients with poor PS based
on the hazard ratio (HR), and relative 95% confidence interval (CI) was
reported in the study results. Patients with poor PS were defined based on
ECOG scale and have the PS ¼ 2.
9
Selection of the studies
We reviewed PubMed for citations from January 2005 to December 2012.
The search criteria were limited to articles published in English language
and phase III clinical trials. The entry term for the search was ‘CRPC.’ The
search was restricted to randomized controlled trials in which the
experimental treatment was compared with the control one in CRPC
patients. If more than one publication was found for the same trial, the
most recent was considered for analysis. Other characteristics required for
article inclusion were a previous treatment with docetaxel and the
1
Department of Radiology, Oncology and Human Pathology, Oncology Unit B, Sapienza Unive rsity of Rome, Rome, Italy;
2
Fondazione IRCCS Istituto Nazionale dei Tumori, Medical
Oncology Unit 1, Milan, Italy;
3
Azienda Sanitaria USL 8, Medical Oncology Unit, Arezzo, Italy and
4
Department of Medical Oncology, Polytechnic University of the Marche Region,
Ancona, Italy. Correspondence: Dr R Iacovelli, Department of Radiology, Oncology and Human Pathology, Oncology Unit B, Sapienza University of Rome, Viale Regina Elena 324,
Rome 00161, Italy.
E-mail: roberto.iacovelli@uniroma1.it
Received 1 May 2013; revised 24 May 2013; accepted 18 June 2013; published online 30 July 2013
Prostate Cancer and Prostatic Disease (2013) 16, 323–327
&
2013 Macmillan Publishers Limited All rights reserved 1365-7852/13
www.nature.com/pcan
inclusion of patients with PS equal to two other than the availability of
data for OS.
Study quality was assessed by using the Jadad 7-item scale that included
the randomization, double-blinding and withdrawals; the score was
reported between 0 and 5.
10
Data extraction
Data extraction was conducted independently by RI and AA according to
the preferred reporting items for systematic review and meta-analysis
statement,
11
and any type of discrepancies was resolved by consensus.
Data extracted for each trial were: first author’s name, years of publication,
trial phase, the number of patients evaluable, the number of patients with
PS-2, the number of arms, randomization rate, drugs used in the
experimental and in the control arm, dosage, median age, percentage of
bone metastases, median follow-up, median treatment duration, median
progression-free survival and median OS with the relative HR and 95% CI,
in overall, PS-0/1 and PS-2 population.
Statistical method
For the calculation of the incidence of patients with PS ¼ 0–1 and PS ¼ 2,
the number of patients in each group and the total number of patients
enrolled in the study were extracted from the baseline characteristic of
patients of the selected trials.
The HRs and the relative 95% CI for OS in the entire cohort, PS ¼ 0–1 and
in PS ¼ 2 patients were extracted from each study. To calculate the 95%
CIs, the variance of a log-transformed study-specific HR was derived using
the delta method.
12
Statistical heterogeneity between trials included in the
meta-analysis was assessed using Cochrane’s Q statistic, and inconsistency
was quantified with I
2
statistic (100% ([Q df)/Q]).
13
The assumption of
homogeneity was considered invalid for P-values less than 0.1. Summary
HR was calculated using random- or fixed-effects models depending on
the heterogeneity of included studies. When substantial heterogeneity was
not observed, the pooled estimate calculated based on the fixed-effects
model was reported using the inverse variance method.
When substantial heterogeneity was observed, the pooled estimate
calculated based on the random-effects model was reported using the
Der Simonian et al.
14
method, which considers both within- and between-
study variations. Publication bias was evaluated using to funnel plots
(plots of study results against precision) and with the Begg et al.
15
and
Egger et al.
16
tests. A two-tailed p-value of less than 0.05 was considered
statistically significant. All data were collected using Microsoft Office Excel
2007; statistical analyses were performed using PASW statistic software
(version 18) and RevMan software for meta-analysis (v. 5.2.3).
17
RESULTS
The electronic search revealed 18 citations, after screening 13
articles were eliminated because six were sub-analysis of
previously published phase III trials, reviews or letters to the
editor. A total of five articles was eliminated because of patients
Figure 1. Selection of randomized controlled trials (RCTs) included in
the meta-analysis. CRPC, castration-resistant prostate cancer; PS,
performance status.
Table 1. Main characteristics of the included studies
First
author
Year Trials design Type of patients Studies’ results Jadad
score
Phase No. of
patients
No. of
arms
Rand.
rate
Drug Dosage Control
arm
Patients
PS ¼ 2(%)
Bone
mets (%)
Median age,
range (years)
Median follow-
up (months)
Median treat
duration (weeks)
Median PFS
(months)
Median OS
(months)
De Bono
et al.
19
2010 3 755 2 1:1 CBZ 25 mg m
2
,
Q3weeks
Mito 8.1 83.6 68
a
(62–73) 12.8 18 vs 12 2.8 vs 1.4 15.1 vs 12.7 3
Scher
et al.
21
2012 3 1199 2 2:1 ENZ 160 mg per
day
Placebo 8.5 91.7 69
a
(41–95) 14.4 33 vs 12 8.3 vs 2.9 18.4 vs 13.6 4
Fizazi
et al.
20
2012 3 1195 2 2:1 ABI 1 g per day Placebo 10.6 89.2 69
a
(42–95) 20.2 32 vs 16 5.6 vs 3.6 15.8 vs 11.2 5
Abbreviations: ABI, abiraterone; CBZ, cabazitaxel; ENZ, enzalutamide; mets, metastases; Mito, mitoxantrone; NR, not reported; OS, overall survival; PS, performance status; PFS, progression-free survival.
a
Experimental arm.
Second line in CRPC and poor performance status
R Iacovelli et al
324
Prostate Cancer and Prostatic Disease (2013), 323 – 327 & 2013 Macmillan Publishers Limited
were treated in first line of therapy, or they did not receive
docetaxel first; one trial was not in CRPC patients and another
because designed for patients without CRPC and PSA rising only.
Another study (SPARC trial) valuable for the review process was
discarded because of not sufficient parameters were available for
the meta-analysis process.
18
A total of five full-text articles was reviewed for further
assessment; among these, two were excluded because one was
updated and one did not enroll PS-2 patients.
At the end of the reviewed process, only three articles were
included in the meta-analysis because of their adequate quality
and availability of data (Figure 1).
19–21
All were randomized phase
III double blind trials: the experimental treatments were
abiraterone acetate (ABI), cabazitaxel (CBZ) and enzalutamide
(ENZ) while the control arms were placebo for two trials and Mito
in the other. Continuously doses of prednisone were used in both
arms in two studies.
19,20
The characteristics of each study are
presented in Table 1.
Overall population
A total of 3,149 patients was available for meta-analysis. A total of
1975 patients were treated in the experimental arms with:
abiraterone 1000 mg per day p.o. continuously (797 patients), CBZ
25 mg m
2
by IV injection every 3 weeks (378 patients) or ENZ
160 mg per day p.o. continuously (800 patients). A total of the 1174
patients received the control treatments with Mito 12 mg m
2
every 3 weeks (377 patients) or with placebo (797 patients).
In the overall population, each experimental treatment decreased
the risk of death by 26 to 37% compared with the control arm and
the cumulative reduction of the risk of death was 31% (HR ¼ 0.69;
95% CI: 0.63–0.76; Po0.001) (Table 2). No significant heterogeneity
was found (Q ¼ 0.02, P ¼ 0.99; I
2
¼ 0%) (Figure 2a).
Patients with PS 0–1
A total of 2859 patients had a PS-0 or 1: these patients represent
the 90.8% (95% CI: 90.77–90.81) of the entire population included
Table 2. Reduction of the risk of death in overall, PS ¼ 0–1 and PS ¼ 2 population
Author Experimental
arm
Control
arm
OS in overall population OS in PS ¼ 0–1 patients OS in PS ¼ 2 patients
No. of
patients
HR 95% CI P-value No. of
patients
HR 95% CI P-value No. of
patients
HR 95% CI P-value
De Bono
et al.
19
CBZ Mito 755 0.70 0.59–0.83 o0.001 694 0.68 0.57–0.82 o0.001 61 0.81 0.48–1.38 0.43
Scher
et al.
21
ENZ Placebo 1199 0.63 0.53–0.75 o0.001 1097 0.62 0.52–0.75 o0.001 102 0.65 0.39–1.07 0.09
Fizazi
et al.
20
ABI Placebo 1195 0.74 0.64–0.86 o0.001 1068 0.74 0.63–0.87 o0.001 127 0.77 0.50–1.17 0.23
Total 3149 0.69 0.63–0.76 o0.001 2859 0.69 0.62–0.76 o0.001 290 0.74 0.56–0.98 0.035
Abbreviations: ABI, abiraterone; CBZ, cabazitaxel; CI, confidence interval; ENZ, enzalutamide; HR, hazard ratio; Mito, mitoxantrone; OS, overall survival;
PS, performance status.
a
b
c
Figure 2. Forest plots for reduction of the risk of death in overall (a), performance status (PS) ¼ 0–1 (b) and PS ¼ 2(c) population.
Second line in CRPC and poor performance status
R Iacovelli et al
325
& 2013 Macmillan Publishers Limited Prostate Cancer and Prostatic Disease (2013), 323 – 327
in the selected phase III trials. A total of 1795 patients was treated
in the experimental arms: 350 (19.5%) received CBZ, 715 (39.8%)
received ABI and 730 (40.7%) received ENZ, while 1064 patients
were treated in the control arms: 720 (67.7%) patients received
placebo and 344 (32.3%) Mito.
Each study reported a significant reduction of the risk of death
in favor of the experimental treatments ranging from 26 to 38%
compared with the control arms. The cumulative reduction of the
risk of death in the overall group was 31% (HR ¼ 0.69; 95% CI:
0.62–0.76; Po0.001) (Table 2). No significant heterogeneity was
found (Q ¼ 2.02, P ¼ 0.36; I
2
¼ 1.12%) (Figure 2b).
Patients with PS 2
A total of 290 patients had PS-2, and they represent only 9.2% (95%
CI: 9.19–9.23) of patients included in the selected phase III trials. A
total of 185 patients was treated in the experimental arms: 33 (17.8%)
received CBZ, 82 (44.3%) received abiraterone and 70 (37.9%)
received ENZ. A total of 105 patients was treated in the control arms:
77 (73.3%) patients received placebo and 28 (26.7%) Mito.
None of the included studies showed a significant reduction of
the risk of death in patients with PS-2, while in the overall PS-2
population patients in the experimental arms had a significant
reduction of the risk of death by 26% (HR ¼ 0.74; 95% CI: 0.56–
0.98; P ¼ 0.035) compared with controls (Table 2). No significant
heterogeneity was found (Q ¼ 0.4, P ¼ 0.82; I
2
¼ 0.0%) (Figure 2c).
The sub-group analysis based on the type of treatment reported
a reduction of the risk of death by hormonal therapies (HT;
abiraterone or ENZ) (HR ¼ 0.72; 95% CI: 0.52–0.99; P ¼ 0.046) but
not by CHT (CBZ) (HR ¼ 0.81; 95% CI: 0.48–1.37; P ¼ 0.43); no
significant heterogeneity was found in both cases, and no
differences were found between the two groups (Figure 3).
Study quality
Randomized treatment allocation was generated in all trials. The
control arm was the placebo for two trials
20,21
and Mito in the
other.
19
Continuously doses of prednisone were used in both arms
in two studies.
19,20
Follow-up time was reported in all trials
ranging from 12.8 to 20.2 months. Jadad’ scores for each trial are
listed in Table 1. The mean score was 4.0, and all were high-quality
trial (Jadad score 3–5).
Publication bias
No significant publication biases were detected: P-values from
Begg’s and Egger’s test were 0.12 and 0.36 for the overall
population, 0.12 and 0.30 for PS ¼ 0–1 and 0.60 and 0.89 for
PS ¼ 2, respectively.
DISCUSSION
To the best of our knowledge, this is the first meta-analysis to
demonstrate a significant reduction of the risk of death by treating
patients with CRPC and PS-2. We confirm that these patients
represent o10% of entire population enrolled in phase III trials
and probably this low number is the major cause for the lack of
evidence of treatment activity until now.
We report that current available treatments for post docetaxel
treatment of CRPC decrease the risk of death by 31% in the overall
population, and the activity of experimental treatment may be
related to PS even if the difference in the risk of death between
patients PS-0 or 1, and these with PS-2 were only 5% (HR: 0.69 for
PS-0 or 1 and 0.74 for PS-2). These results may improve clinical
practice, encouraging the treatment of patients with PS-2 at the end
of docetaxel therapy even if the expected benefit from treatment
needs to be balanced with possible adverse events due to therapy.
Similarly, recent studies in non-small lung cancer reported as
the combination regimens of CHTwas better in terms of survival
and response rate than a single agent even in patients with
PS-2 and without a substantial increase in toxicity.
22,23
Moreover,
a retrospective analysis showed also as these results are
transposable in clinical practice.
24
All together, this evidence
sustained the idea that patients with PS-2 should be treated with
standard therapy if not general contraindications are present.
About prostate cancer, current guidelines do not report the best
sequence of therapy after docetaxel failure, and several algorithms
have been proposed in medical literature.
4,25
In registration trials, the
incidence of high-grade adverse events was quite similar in the three
drugs (55% for abiraterone, 57% for CBZ and 45% for ENZ),
19–21
but
with a different toxicity profile foreachone.Infact,CBZismainly
characterized by hematologic toxicity (neutropenia G3-4 in 82% and
anemia G3-4 in 11% of cases) and ABI by cardiovascular toxicity (5%
of patien ts for grade 3 or 4).
19,20
A patient-based approach may be
based on the different toxicity profiles of these drugs, residual
toxicity to the docetaxel therapy and patien t’s comorbidity.
In our study, we found that available hormonal treatments
(abiraterone and ENZ) for CRPC decrease the risk of death by
28% compared with controls suggesting a possible role in patients
ineligible for second-line chemotherapy, but no evidence is
available about patients ineligible for first-line docetaxel.
Recently, a large phase III trial confirmed the activity and safety
of ABI in CRPC patients untreated with docetaxel.
4
This study
(COU-AA-302) reports as CHT naı¨ve CRPC patients have a similar
benefit from ABI compared with post-CHT one in terms of
radiographic progression-free survival (HRs: 0.67 vs 0.69,
respectively) and control of disease (16.5 vs 5.6 months), but no
patients with PS-2 were enrolled.
26,27
Figure 3. Forest plots for reduction of the risk of death in performance status (PS) ¼ 2 population based on the type of treatment used in
experimental arms: chemotherapy (CHT) vs hormonal therapies (HT).
Second line in CRPC and poor performance status
R Iacovelli et al
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Prostate Cancer and Prostatic Disease (2013), 323 – 327 & 2013 Macmillan Publishers Limited
Our data may suggest such as the increased survival found in
PS-0/1 patients may be also reached in poor PS patients even in
pre-docetaxel setting, considering that recent analysis reported as
ABI and ENZ are able to reduce pain, fatigue and skeletal related
events in CRPC patients.
21,28,29
The results of our meta-analysis may represent an important
evidence that available therapies for CRPC are active in patients
both with good and poor PS. The quality of this evidence is based
on the high rate of Jadad’ score for included studies. Nevertheless,
some limitations may affect the results of our study. First, this is a
meta-analysis based on studies and not on patients’ data,
therefore confounding variables as patient’s comorbidities, exten-
sion of disease and differences in other possible prognostic factors
could not be incorporated into the analysis. Second, all the
included studies were conducted in patients with adequate organ
function and no severe comorbidity at study entry, so data about
the treatments’ activity might be not directly related to overall
population with PS-2 and affected by CRPC in clinical practice.
Furthermore, PS evaluation is strictly related to the physician’s
sensitivity and experience. Third, considering the number of
patients included with PS-2, the power of this analysis may be low
even if it shows a significant difference. It is also important to
remark that no definitive conclusions may be performed about
the best treatment between hormonal or chemotherapeutic
agents for these patients. Fourth, the control arm was the placebo
in two studies and Mito in the third one, but this heterogeneity
may be mitigated considering that prospective studies on Mito
did not show to prolong OS over prednisone.
30,31
In conclusion, patients affected by CRPC previously treated with
docetaxel and poor PS benefit from current available therapies in
this setting. The different toxicity profiles of these molecules
should be taken into account in the choice of treatment, according
to patients’ comorbidity and drug availability, even if we found a
significant benefit for patients treated with hormonal therapies but
not for chemotherapy. Finally, considering the activity of new
molecules in good PS patients, we sustain that well-designed trials
may elucidate the best strategy for these patients.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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