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E U R O P E A N U R O L O G Y 5 6 ( 2 0 0 9 ) 4 7 9 – 4 8 5
Prostate Cancer
Platelet Microparticles: A Potential Predictive Factor of Survival
in Hormone-Refractory Prostate Cancer Patients Treated with
Docetaxel-Based Chemotherapy
Dominique Helley a,b,c,*, Eugeniu Banu d, Abdelkader Bouziane a, Adela Banu d,Florian Scotte d, Anne-Marie Fischer a,b,c, Stephane Oudard b,c,d
a AP-HP (Assistance Publique–Hopitaux de Paris), Service d’Hematologie Biologique, Hopital Europeen Georges Pompidou, Paris, F-75015, Franceb Universite Paris Descartes, Faculte de Medecine, Paris, F-75014, Francec INSERM Unite 765, Paris, F-75006, Franced AP-HP (Assistance Publique–Hopitaux de Paris), Service d’Oncologie Medicale, Hopital Europeen Georges Pompidou, Paris, F-75015, France
ava i lable at www.sciencedirect .com
journal homepage: www.europeanurology.com
Article info
Article history:
Accepted June 11, 2008Published online ahead ofprint on June 20, 2008
Keywords:
Hormone-refractory prostate
cancer
Platelet microparticles
Predictive factor
Abstract
Background: Several studies suggest a causal relationship between platelet activation and
cancer metastasis. Activated platelet microparticles (PMPs) release vascular endothelial
growth factor (VEGF) and basic fibroblast growth factor (bFGF), which play a major role in
angiogenesis.
Objective: We conducted a prospective, nonrandomised, single-centre study in hormone-
refractory prostate cancer (HRPC) patients to determine the impact of PMPs on the outcome.
Design, setting, and participants: Eligible chemonaive and metastatic HRPC patients
received docetaxel-based chemotherapy and a low dose of prednisone.
Intervention: PMPs in whole blood were quantified before the start of chemotherapy through
flow cytometry using an anti-CD41a monoclonal antibody, and plasma VEGF and bFGF were
determined with an enzyme-linked immunosorbent assay.
Measurements: The primary end point was to evaluate the impact of the PMPs on overall
survival (OS). We also studied the statistical interaction between PMPs and platelets and their
relationship with OS. The median PMP value was used to sort patients into two groups.
Results and limitations: Data of 43 consecutive HRPC patients treated in a single French
centre were analysed. Significant correlations were observed between Eastern Cooperative
Oncology Group performance status (ECOG PS), platelets, and PMP level. The median OS was
significantly shorter for patients with >6867 PMPs per ml of whole blood than for those with
lower values (16.7 vs 26.4 mo, p = 0.013). A significant relationship was found between OS and
PMPs, whereas a statistical interaction term between PMPs and platelets was significantly
associated with OS ( p = 0.019). No association was found between OS and plasma VEGF and
bFGF. In the multivariate analysis, only baseline prostate-specific antigen (PSA) and ECOG PS
remained significantly predictive of risk of death.
Conclusions: In HRPC patients, PMPs and their interaction with platelets were predictive of
outcome. A biologic association between PMPs and the OS of HRPC patients, independent of
chemotherapy regimen, should be demonstrated by confirmatory prospective studies.
# 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Hopital Europeen Georges Pompidou, Service d’Hematologie Biologique, 20,rue Leblanc, 75908 Paris Cedex 15, France. Tel. +33 1 56 09 39 05; Fax: +33 1 56 09 33 93.E-mail address: dominique.helley@egp.aphp.fr (D. Helley).
0302-2838/$ – see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2008.06.038
E U R O P E A N U R O L O G Y 5 6 ( 2 0 0 9 ) 4 7 9 – 4 8 5480
1. Introduction
Prostate cancer is currently the most frequent malignancy
in men and represents the second leading cause of cancer-
related deaths [1]. About 186 320 new cases of prostate
cancer will be diagnosed in the United States in 2008 and
almost 28 660 deaths are expected [1]. More than 90% of
these new cases are expected to be diagnosed at local or
regional stages [1]. Around 306 369 cases are diagnosed
each year in Europe [2]. Androgen deprivation therapy
allows a primary response rate of 80% to 90% [3]. Those
remissions last 2 or 3 yr, but almost all metastatic prostate
cancer patients evolve towards an androgen-refractory
state resulting in death due to widespread metastases [4].
Docetaxel-based chemotherapy is the standard of care for
hormone-refractory prostate cancer (HRPC) patients [5–7].
Platelets have been reported to contribute to the
metastatic process and to tumour growth [8]. They may
participate in metastatic spread by accumulating on
embolic tumour cells, thus protecting them from the
clearance exerted by the immune system [4]. A two-way
interaction has been shown between cancer spread and
platelet activation, with a hypercoagulable state found in
most cancer patients [9]. Platelets can act as bridges
between endothelial cells and lymphocytes or monocytes,
and thrombin-based platelets activation can enhance this
function [10]. In the same way, by facilitating tumour cell
arrest and adhesion to the endothelium, platelets may
promote micrometastases [11]. Moreover, cancer procoa-
gulant and tissue factor generated by the tumour itself
induce platelet activation and thrombin generation [12].
The authors demonstrated that metastatic patients with
breast or pancreatic cancer had increased levels of
microparticles associated with tissue factor compared to
nonmetastatic patients. Formation of metastatic deposits in
target organs depends on the balance between positive and
negative growth factors (eg, vascular endothelial growth
factor [VEGF] and basic fibroblast growth factor [bFGF]),
many of which are released by platelets. Thrombin-
activated platelets may promote proliferation of tumour
cells by secreting growth factors such as VEGF. Platelets
adhering to circulating tumour cells may release VEGF at
the adhesion points to endothelium, enhancing vascular
permeability and extravasation. VEGF-induced platelet
adhesion to endothelial cells depends on tissue factor
activation [13]. Platelet activation results in the shedding of
PMPs which promote proliferation, survival, and migration
of human umbilical vein endothelial cells as well as the
ability to form vascular tubes in vitro [14]. Furthermore,
PMPs induced angiogenesis in vivo according to a model of
chronic myocardial ischemia in rats. Additionally, ischemia
induces a decrease in the number of functional capillaries,
but their amount increased after injection of PMPs into the
myocardium [15]. Thus, PMPs shed from the circulating
platelets may reach adequate concentrations and their
elevated levels could contribute to florid formation of new
blood vessels and enhance tumour growth and metastases.
Angiogenesis appears to be essential to the growth and
spread of prostate cancer cells [16]. Microvessel density, a
quantitative measure of tumour angiogenesis, is signifi-
cantly greater in tumours from men with metastatic
prostate cancer than in those with localised disease [17].
Similarly, plasma levels of VEGF increase incrementally and
significantly from healthy men to men with localised
prostate cancer and then to those with metastatic disease
[18]. Moreover, plasma VEGF level at the initial diagnosis
predicts prostate-specific antigen (PSA) biochemical relapse
and clinical progression [18], and the VEGF level at
diagnosis of HRPC correlates with survival [19].
The aim of the present study was to isolate and estimate
the absolute number of PMPs in plasma of HRPC patients
and to investigate the predictive value of baseline PMPs on
overall survival (OS).
2. Methods
2.1. Study population
Eligible patients had histologically proven prostate adenocarcinoma
with distant metastases. The hormone-refractory status was defined as a
progressive increase in PSA level (three consecutive determinations)
after hormonal treatment (surgical castration or androgen blockade).
Patients had to fail both androgen blockade and antiandrogen with-
drawal. Hormonal castration had to be confirmed biologically (serum
testosterone <0.5 ng/ml). Patients had not previously undergone
chemotherapy, and time elapsed between blood sample collection
and start of chemotherapy might not exceed 90 days. Docetaxel-based
chemotherapy (docetaxel single drug or associated with estramustine or
capecitabine) was combined with a low dose of orally administered
prednisone. Main eligibility criteria were Eastern Cooperative Oncology
Group (ECOG) performance status (PS) �2, adequate haematologic
(granulocyte count >1.5 � 109/l, platelets count >100 � 109/l, haemo-
globin>8.5 g/dl), hepatic (transaminases�2.0 the upper limit of normal
[ULN], alkaline phosphatases �4 ULN or 8 ULN in case of bone
metastases), and renal (creatinine <150 mmol/l) levels. Only HRPC
patients with >4 ng/ml of PSA at baseline were included. Whole-blood
PMPs have to be measured 2 h after sampling; thus, only those patients
consulting in the morning were eligible. Written informed consent was
obtained before inclusion.
2.2. Blood sample collection and laboratory tests
Before the start of chemotherapy, a venous blood sample was collected
into trisodium citrate 0.105M Vacutainer tubes (Becton Dickinson, San
Jose, CA, USA). The whole blood sample was centrifuged for 15 min at
2800 g, and then plasma was recentrifuged for 15 min at 2800 g. Platelet-
poor plasma was aliquoted and kept frozen at �80 8C until assay. The
VEGF and bFGF plasma levels were quantified using a commercial
enzyme-linked immunosorbent assay (ELISA) kit (Quantikine human
VEGF and Quantikine high-sensitivity human fibroblast growth factor
[FGF] basic immunoassays, R&D Systems, Minneapolis, Minnesota, USA)
according to the manufacturer’s protocol. Duplicate assays were
performed to control the internal validity.
PMPs were determined in whole blood through flow cytometry
using an anti-CD41a, PE-coupled antibody, purchased from Becton
Dickinson (BD BioScience). A 1:10 dilution of whole blood drawn on
citrate Vacutainer tubes was analysed within 2 h of blood collection.
Fifty ml of these blood dilutions were incubated during 20 min with
10 ml of platelet-specific antibody (CD41a-PE) or isotype control (BD
BioScience). Calibrated polypropylene beads in Tru-count tube (BD
BioScience) were used for quantification. The reaction was stopped by
E U R O P E A N U R O L O G Y 5 6 ( 2 0 0 9 ) 4 7 9 – 4 8 5 481
1 ml of phosphate-buffered saline solution. The sample was immedi-
ately analysed by using a FACSCalibur flow cytometer with CellQuest
software (BD BioScience).
PMP gate was defined using 1-mm diameter beads on a log forward (FS)
and log side (SS) scatter cytogram. Among events within this gate (size
<1 mm), PMPs were discriminated from microparticles of other cellular
origin and background noise, according to their positive fluorescence
intensity on a log fluorescence–log FS dot plot. Events with size of>1 mm
that were positive for CD41a were defined as platelets. Results were
expressed as total number of PMPs and platelets per ml of whole blood. This
concomitant platelets count allows an internal control of PMP quantifica-
tion. The platelet count, performed through flow cytometry, was
compared to the standard platelets numeration on the whole blood
obtained with GEN’s counter (Beckman Coulter).
2.3. Statistical analysis
We selected a homogenous cohort of patients with a long follow-up and
treated consecutively. The primary end point was OS defined as the time
from start of chemotherapy until death from any cause or last follow-up
for censored patients. Categorical and quantitative data were presented
as percentages (with 95% confidence interval [CI]) and median with
range, respectively. Observed cumulative OS probabilities were com-
puted according to the Kaplan-Meier method, and curves were
Table 1 – Baseline characteristics of patients according to platelet mic
Characteristic �6867 per ml (n = 20)
n %
Age (yr)
Median 68
Range 52–82
ECOG performance status
0 16 8
1 4 2
2 0
Gleason score
2–6 3 1
7 6 3
8–10 11 5
UK 0
Hormone-sensitivity duration (mo)
Median 38.3
Range 6.3–148.5
Serum PSA (ng/ml)
Median 80.1
Range 4–3014
Haemoglobin (g/dl)
Median 12.3
Range 8–17
PSA-DT (days)
Median 43.4
Range 5.1–358.9
Number of metastatic sites
1 12 6
2 8 4
�3 0
Sites of metastases
Bone 18 9
Lymph nodes 9 4
Visceral 0
n = number of patients; PSA-DT = prostate-specific antigen doubling time; ECOG P
compared using Breaslow-Gehan (generalized Wilcoxon test) as a
nonparametric method. The following covariates were selected for the
univariate analyses: Gleason score, PSA and PSA doubling time (PSA-DT),
platelets, haemoglobin, PMPs, VEGF, bFGF level at baseline, age, ECOG PS,
number of metastatic sites, and hormone-sensitivity duration. A
multivariate Cox proportional hazards regression analysis using
significant variables for the univariate analyses ( p < 0.05) was
performed by forward stepwise selection. Hazard ratios (HR) were
presented with 95% CI. All p values were two-sided. A relational database
containing all data was constructed using FileMaker Pro 8.5v2 (File-
Maker Inc, Santa Clara, CA, USA) software. Both SPSS 16.0 (SPSS Inc,
Chicago, IL, USA) and Epi Info 3.3.4 (Centers for Disease Control and
Prevention, Atlanta, GA, USA) were used for the statistical analysis.
3. Results
3.1. Patients characteristics
Between July 2001 and November 2006, 43 consecutive
HRPC patients were treated in a single French institution
(Georges Pompidou European Hospital, Medical Oncology
Department, Paris, France). The main characteristics of
eligible patients are described in Table 1. Patients received a
roparticle (PMP) level
>6867 per ml (n = 23)
n %
72
53–85
0 7 30
0 13 57
0 3 13
5 4 17
0 8 35
5 10 44
0 1 4
38.6
3–215.6
63.9
4.2–2416
12.5
7.8–15.7
53.6
8.1–220.1
0 15 65
0 5 22
0 3 13
0 20 87
5 9 39
0 4 17
S = Eastern Cooperative Oncology Group performance status; UK = unknown.
Fig. 1 – Kaplan-Meier analysis of overall survival: Probabilities of overall survival among 43 patients split into two groups according to the median plateletmicroparticle (PMP) level.
E U R O P E A N U R O L O G Y 5 6 ( 2 0 0 9 ) 4 7 9 – 4 8 5482
chemotherapy-based regimen combined with a low dose of
prednisone in all cases. Docetaxel was administered as
single chemotherapy in 28 patients (65%); it was combined
with estramustine phosphate or capecitabine orally in 9
(21%) and 5 (12%) patients, respectively. The median age,
haemoglobin, and PSA at baseline were 69 yr (range: 52–
85), 12.5 g/dl (range: 8.6–14.6), and 53.9 ng/ml (range:
4.24–3720), respectively. PMP data were normally dis-
tributed; the median value was 6867 per ml (range: 3319–
16 270). Only 7% of patients had a poor ECOG PS of 2, and
only one involved metastatic site was found in 63% of HRPC
patients. Bone metastases were found in more than 90% of
cases. Half of patients had an aggressive disease expressed
by an elevated Gleason score between 8 and 10. No major
imbalances were found between two groups of HRPC
patients (according to baseline PMP level), including PSA-
DT and excepting ECOG PS ( p = 0.004). Patients with poor
clinical status (ECOG PS = 2) were found to have >6867
PMPs per ml of whole blood. Highly significant positive
correlations were found among ECOG PS, platelets, and PMP
level at Spearman test (correlation coefficients of 0.46 and
0.40, respectively, p < 0.009); however, younger patients
had significantly more platelets. No significant correlations
were found among VEGF, bFGF, and PMP level.
3.2. Survival analysis
At the moment of the analysis, 32 patients (74%) had died.
Overall, the median survival time for the entire cohort was
22.1 mo (95% CI: 20.4–23.7 mo), and observed cumulative
survival probabilities at years 1, 2, and 3 were 72% (95% CI:
Table 2 – Overall survival distribution according to platelet micropart
PMP category Median OS, months (95% CI) 1-yr OS, % (9
�6867 per ml (n = 20) 26.4 (16.7–36) 85 (69–1
>6867 per ml (n = 23) 16.7 (5.6–27.8) 60 (39–8
n = number of patients; OS = overall survival; CI = confidence interval.
58–85%), 43% (95% CI: 27–59%), and 25% (95% CI: 10–39%),
respectively. At a cut-off level of 6867 per ml of PMPs
(defined according to the baseline median value), the
median OS was significantly shorter for patients with higher
PMP values than for those with lower levels: 16.7 mo (95%
CI: 5.6–27.8 mo) versus 26.4 mo (95% CI: 16.7–36 mo),
respectively (Fig. 1; p = 0.034 [Breaslow-Gehan test]).
Cumulative survival probabilities with 95% CI for both
PMP categories are shown in Table 2. The univariate Cox
regression analysis demonstrated that the absolute PMP
level as a continuous variable was significantly associated
with OS ( p = 0.013). When the categorical variable was used
(>6876 versus �6876 per ml), the associated HR was 1.97
(95% CI: 0.94–4.15, p = 0.074), and the OS impact was
considered to be borderline. Other prognostic factors
significantly related with OS were baseline PSA and ECOG
PS. Moreover, a significant impact on OS was found for
statistical interaction between PMPs and platelet level
( p = 0.019). No association was found between plasma
VEGF and bFGF with OS; however, in the multivariate
analysis, PMPs were not predictive of survival ( p = 0.19),
whereas baseline PSA ( p = 0.013) and ECOG PS ( p = 0.014)
remained significantly predictive of risk of death.
4. Discussion
Prognostic and predictive factors were described in HRPC
patients and some recently published guidelines focused on
the role of chemotherapy as an evolving tool in the
management of these patients [20–22]. Platelets and PMPs
were extensively studied in thrombotic and vascular
icle (PMP) level
5% CI) 2-yr OS, % (95% CI) 3-yr OS, % (95% CI) p value
00) 58 (35–80) 29 (8–50) 0.034
0) 28 (6–50) 21 (1–41)
E U R O P E A N U R O L O G Y 5 6 ( 2 0 0 9 ) 4 7 9 – 4 8 5 483
diseases [23] and only recently studied in cancer patients. In
haematological cancers, elevated levels of PMPs were found
in 11% to 12% of patients with chronic myeloproliferative
syndromes such as chronic myelogenous leukaemia, poly-
cythemia vera, chronic myelofibrosis, and essential throm-
bocythemia [24]. More recently, in gastric cancer, Kim et al
[25] showed that PMPs levels are better predictors of
metastasis than VEGF, IL-6, and RANTES. Platelet level was
also claimed as a prognostic factor in cancer; thrombocy-
tosis was associated with a poor outcome in patients with
localized pancreatic cancer, operated with curative intent,
as demonstrated by a recent study on 105 patients [26]. Our
findings were based on a mature analysis: more than 80% of
HRPC patients are dead at the moment of the analysis. We
found that baseline PMP level was significantly related with
survival of HRPC patients treated with docetaxel-based
chemotherapy. Other important variables such as baseline
PSA and ECOG PS were associated with the outcome of HRPC
patients, as recently shown by Bamias et al [27]. Our cohort
of patients was homogeneous, with no potential source of
bias; however, the sample size and the short follow-up
restricted the statistical power of this exploratory analysis,
which possibly explains why the multivariate model did not
highlight a significant impact of PMPs on OS. Indeed, the
analysis was underpowered for some of other prognostic
covariates that are already known to significantly affect the
outcome, such as haemoglobin level or number of meta-
static sites at baseline [28]. Some expected statistical
associations were not found in the present analysis.
The role of PMPs on AKT cascade activation was explored
by recent research [29]. Several transmembrane-span
receptors could be transferred by PMPs to the membranes
of normal cells as well as to malignant ones. Observations
showed that PMPs chemo-attracted these cells; increased
their adhesion, proliferation, and survival; and activated in
these cells various intracellular signalling cascades, includ-
ing MAPK p42/44, PI-3K-AKT, and STAT proteins [18]. This
effect could explain one of multiple pathways enhancing
proliferation, angiogenesis, and metastasis. Our results
highlighted a potential statistical interaction between
platelets and PMPs. This possibility may be the expression
of a biological and physical interaction between two major
players implicated in the metastatic cascade. PMP levels
were significantly correlated with Gleason score, platelets,
and ECOG PS, meaning that a high PMP level was highly
correlated with aggressive tumours, elevated number of
platelets, and a poor clinical status. It is a potential
biological marker of tumour burden. Today, PMPs could
be considered as an actor in the intricate metastatic process,
adding a potential new target for specific, directed therapies
such as antiplatelet agents (antibodies against glycoprotein
IIb-IIIa, direct thrombin inhibitors, protease activated
receptor-1 inhibitors, cyclo-oxygenase inhibitors) [30].
Moreover, if PMPs are also thought to reflect a proangio-
genic effect of platelet release, they could be proposed as a
sign to suggest that antiangiogenic therapy is needed.
Plasma PMPs are increased in some patients with localised
prostate cancer, and a significant correlation with tissue-
factor (TF) antigen level was demonstrated, potentially
linking positive TF tumour cells with in vivo platelet
activation [31]. Moreover, a recent study shows that PMP
membranes have specific procoagulant activity that is 50-
to 100-fold higher than that of activated platelets [32].
5. Conclusion
In spite of a limited sample size, we have demonstrated a
significant impact of PMPs on survival. Our results warrant
confirmation in larger cohorts as well as in nonmetastatic
prostate cancer patients with a rising PSA after prostatect-
omy or external radiotherapy. Such studies would also test
the correlation between PMP levels and responsiveness to
hormonal treatment. In this group of patients, the role of
PMPs could be even more important; a high level of PMPs
could be predictive of poor prognosis and of shorter,
relapse-free, or overall survivals. These results raise
questions for therapeutic strategies: Could a treatment
modality have a goal of decreasing the absolute PMP level?
Is there a place for antiplatelet agents? Is PMP level a new
goal for targeted therapies? What is the effect of conven-
tional chemotherapy on PMPs? Serial PMPs assessments
during the course of chemotherapy and follow-up period
should be the best way to isolate potential effects on the
outcome. An extended Cox regression integrating PMPs as a
time-dependent variable could be the optimal modality to
identify possible relationships.
Author contributions: Dominique Helley had full access to all the data in the
study and takes responsibility for the integrity of the data and the accuracy
of the data analysis.
Study concept and design: Oudard, Helley, Fischer.
Acquisition of data: Banu E, Banu A, Helley, Bouziane.
Analysis and interpretation of data: Banu E, Banu A, Helley, Oudard.
Drafting of the manuscript: Banu E, Helley, Oudard.
Critical revision of the manuscript for important intellectual content:
Oudard, Fischer, Banu E, Scotte.
Statistical analysis: Banu E, Banu A.
Obtaining funding: Oudard, Helley, Fischer.
Administrative, technical, or material support: Oudard, Banu A, Scotte,
Fischer.
Supervision: Banu E, Oudard, Fischer, Banu A.
Other (specify): None.
Financial disclosures: I certify that all conflicts of interest, including
specific financial interests and relationships and affiliations relevant to
the subject matter or materials discussed in the manuscript (eg,
employment/ affiliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents filed,
received, or pending), are the following: None.
Funding/Support and role of the sponsor: ARTIC Association supported
collection of the data, management of the data, analysis, and
preparation.
Acknowledgment statement: The authors acknowledge Isabelle Cha-
pelle-Marcillac for providing editorial assistance in the preparation of
the initial drafts of the manuscript. We thank the technicians of the
haematology laboratory of Georges Pompidou European Hospital for
performing PMPs measurements.
E U R O P E A N U R O L O G Y 5 6 ( 2 0 0 9 ) 4 7 9 – 4 8 5484
References
[1] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J
Clin 2008;58:71–96.
[2] Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P.
Estimates of the cancer incidence and mortality in Europe in
2006. Ann Oncol 2007;18:581–92.
[3] Prostate Cancer Trialists’ Collaborative Group. Maximum androgen
blockade in advanced prostate cancer: an overview of the rand-
omised trials. Lancet 2000;355:1491–8.
[4] Pienta K, Smith D. Advances in prostate cancer chemotherapy: a
new era begins. CA Cancer J Clin 2005;55:300–18, quiz 323-5.
[5] Di Lorenzo G, Autorino R, Perdona S, et al. Docetaxel, vinorelbine,
and zoledronic acid as first-line treatment in patients with hor-
mone refractory prostate cancer: a phase II study. Eur Urol 2007;
52:1020–7.
[6] Fossa SD, Jacobsen A-B, Ginman C, et al. Weekly docetaxel and pre-
dnisolone versus prednisolone alone in androgen-independent pros-
tate cancer: a randomized phase II study. Eur Urol 2007;52:1691–9.
[7] Kikuno N, Urakami S, Nakamura S, et al. Phase-II study of docetaxel,
estramustine phosphate, and carboplatin in patients with hor-
mone-refractory prostate cancer. Eur Urol 2007;51:1252–8.
[8] Borsig L, Wong R, Feramisco J, Nadeau DR, Varki NM, Varki A.
Heparin and cancer revisited: mechanistic connections involving
platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc
Natl Acad Sci U S A 2001;98:3352–7.
[9] Nash GF, Turner LF, Scully MF, Kakkar AK. Platelets and cancer.
Lancet Oncol 2002;3:425–30.
[10] Huo Y, Schober A, Forlow SB, et al. Circulating activated platelets
exacerbate atherosclerosis in mice deficient in apolipoprotein E.
Nat Med 2003;9:61–7.
[11] Nierodzik M, Karpatkin S. Thrombin induces tumor growth, metas-
tasis, and angiogenesis: Evidence for a thrombin-regulated dor-
mant tumor phenotype. Cancer Cell 2006;10:355–62.
[12] Tesselaar M, Romijn F, Van Der Linden I, Prins F, Bertina R, Osanto S.
Microparticle-associated tissue factor activity: a link between can-
cer and thrombosis? J Thromb Haemost 2007;5:520–7.
[13] Verheul HM, Jorna AS, Hoekman K, Broxterman HJ, Gebbink MF,
Pinedo HM. Vascular endothelial growth factor-stimulated
endothelial cells promote adhesion and activation of platelets.
Blood 2000;96:4216–21.
[14] Kim HK, Song KS, Chung JH, Lee KR, Lee SN. Platelet microparticles
induce angiogenesis in vitro. Br J Haematol 2004;124:376–84.
[15] Brill A, Dashevsky O, Rivo J, Gozal Y, Varon D. Platelet-derived
microparticles induce angiogenesis and stimulate post-ischemic
revascularization. Cardiovasc Res 2005;67:30–8.
[16] Dahut W, Gulley J, Arlen P, et al. Randomized phase II trial of
docetaxel plus thalidomide in androgen-independent prostate can-
cer. J Clin Oncol 2004;22:2532–9.
[17] Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J. Tumor
angiogenesis correlates with metastasis in invasive prostate carci-
noma. Am J Pathol 1993;143:401–9.
Editorial Comment on: Platelet Microparticles:
A Potential Predictive Factor of Survival in Hormone-
Refractory Prostate Cancer Patients Treated with
Docetaxel-Based Chemotherapy
Antonio Lopez-Beltran
Faculty of Medicine, Cordoba, Spain
em1lobea@uco.es
[18] Shariat S, Anwuri V, Lamb D, Shah N, Wheeler T, Slawin K. Associa-
tion of preoperative plasma levels of vascular endothelial growth
factor and soluble vascular cell adhesion molecule-1 with lymph
node status and biochemical progression after radical prostatec-
tomy. J Clin Oncol 2004;22:1655–63.
[19] George DJ, Halabi S, Shepard TF, et al. Prognostic significance of
plasma vascular endothelial growth factor levels in patients with
hormone-refractory prostate cancer treated on Cancer and Leuke-
mia Group B 9480. Clin Cancer Res 2001;7:1932–6.
[20] Calabro F, Sternberg CN. Current indications for chemotherapy in
prostate cancer patients. Eur Urol 2007;51:17–26.
[21] Heidenreich A, Aus G, Bolla M, et al. EAU guidelines on prostate
cancer. Eur Urol 2008;53:68–80.
[22] Sciarra A, Salciccia S. New treatment strategies in the management
of hormone refractory prostate cancer (HRPC): only chemother-
apy? Eur Urol 2007;52:945–7.
[23] VanWijk MJ, VanBavel E, Sturk A, Nieuwland R. Microparticles in
cardiovascular diseases. Cardiovasc Res 2003;59:277–87.
[24] Villmow T, Kemkes-Matthes B, Matzdorff AC. Markers of platelet
activation and platelet-leukocyte interaction in patients with mye-
loproliferative syndromes. Thromb Res 2002;108:139–45.
[25] Kim HK, Song KS, Park YS, et al. Elevated levels of circulating
platelet microparticles, VEGF, IL-6 and RANTES in patients with
gastric cancer: possible role of a metastasis predictor. Eur J Cancer
2003;39:184–91.
[26] Suzuki K, Aiura K, Kitagou M, et al. Platelets counts closely correlate
with the disease-free survival interval of pancreatic cancer
patients. Hepatogastroenterology 2004;51:847–53.
[27] Bamias A, Bozas G, Antoniou N, et al. Prognostic and predictive
factors in patients with androgen-independent prostate cancer
treated with docetaxel and estramustine: a single institution
experience. Eur Urol 2008;53:323–32.
[28] Oudard S, Banu E, Beuzeboc P, et al. Multicenter randomized phase
II study of two schedules of docetaxel, estramustine, and predni-
sone versus mitoxantrone plus prednisone in patients with meta-
static hormone-refractory prostate cancer. J Clin Oncol 2005;23:
3343–51.
[29] Baj-Krzyworzeka M, Majka M, Pratico D, et al. Platelet-derived
microparticles stimulate proliferation, survival, adhesion, and
chemotaxis of hematopoietic cells. Exp Hematol 2002;30:
450–9.
[30] Sierko E, Wojtukiewicz M. Inhibition of platelet function: does it
offer a chance of better cancer progression control? Semin Thromb
Hemost 2007;33:712–21.
[31] Langer F, Kyoung-Hwan Chun F, Amirkhosravi A, et al. Plasma tissue
factor antigen in localized prostate cancer: Distribution, clinical
significance and correlation with haemostatic activation markers.
Thromb Haemost 2007;97:464–70.
[32] Sinauridze E, Kireev D, Popenko N, et al. Platelet microparticle
membranes have 50- to 100-fold higher specific procoagulant
activity than activated platelets. Thromb Haemost 2007;97:
425–34.
Rodolfo Montironi
Polytechnic University of the Marche Region,
Ancona, Italy
r.montironi@univpm.it
Platelet activation results in the production of platelet
microparticles (PMPs) and has been found to be increased
in several types of cancer. PMPs are suggested to be useful
in a number of basic and preclinical papers. The study by
Helley et al [1] found that hormone refractory prostate
cancer patients treated with docetaxel showing PMP levels
above the median had a significantly lower overall
survival. PMPs presumably reflect microthrombosis, a
finding that seems to be commonly seen in prostate
cancer. Although the topic of this report [1] is of interest to
urologists and scientists who work in the field of prostate
cancer research, there is no ‘‘major impact on treatment’’
[2–4], and the study shows a biologic association resulting
in a negative study since PMPs were not independently
associated with overall survival in multivariate analysis. In
addition, the study series is of value because it is
prospective, but limited in size because it includes only
43 cases recruited over a period of 5 years. This represents
a major limitation, and the paper should be considered as a
preliminary data report. Adding more cases to the
reported series would thus add strength to the paper in
terms of clinical value. Finally, although the authors
suggest that therapies targeting PMPs may be useful, it is
not clear whether they contribute to disease progression
or are only a marker of disease extension and ongoing
thrombosis [2–4]. In summary, this study represents a
limited advance that is consistent with previous data [2–4]
and suggests that PMPs or other markers of ongoing
thrombosis might be indicators of disease burden; none-
theless, the potential value of PMP as an independent
marker remains unclear. The data reported by Helley et al
[1] underscore the need for more studies with appropriate
sample size confirming the suggested clinical potential of
PMP formation in hormone refractory prostate cancer
patients.
References
[1] Helley D, Banu E, Bouziane A, et al. Platelet microparticles: a
potential predictive factor of survival in hormone-refractory
prostate cancer patients treated with docetaxel-based che-
motherapy. Eur Urol 2009;56:479–85.
[2] Calabro F, Sternberg CN. Current indications for chemotherapy in
prostate cancer patients. Eur Urol 2007;51: 17–26.
[3] Heidenreich A, Aus G, Bolla M, et al. EAU guidelines on prostate
cancer. Eur Urol 2008;53:68–80.
[4] Bamias A, Bozas G, Antoniou N, et al. Prognostic and predictive
factors in patients with androgen-independent prostate cancer
treated with docetaxel and estramustine: a single institution
experience. Eur Urol 2008;53:323–32.
DOI: 10.1016/j.eururo.2008.06.039
DOI of original article: 10.1016/j.eururo.2008.06.038
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