Antibacterial therapy improves the effectiveness of prostate

Int Urol Nephrol (2010) 42:13–18
DOI 10.1007/s11255-009-9598-x
UROLOGY - ORIGINAL PAPER
Antibacterial therapy improves the effectiveness of prostate
cancer detection using prostate-specific antigen in patients
with asymptomatic prostatitis
Ping Tang Æ Ke-ji Xie Æ Bin Wang Æ
Xiang-Rong Deng Æ Ru-Biao Ou
Received: 10 December 2008 / Accepted: 25 May 2009 / Published online: 23 June 2009
Ó Springer Science+Business Media, B.V. 2009
Abstract
Objectives To improve prostate cancer (PC) detection accuracy among patients with a prostate-specific
antigen (PSA) above 4.0 ng/ml and asymptomatic
prostate inflammation.
Materials and methods A total of 136 patients with
PSA ranging from 4.0 to 50.0 ng/ml with asymptomatic prostatitis were included in the study cohort. All
these patients underwent antibacterial therapy for
2 weeks followed by repeat PSA determination and
transrectal ultrasound–guided needle prostate biopsy.
The PSA, PSAD (PSA density), and f/t PSA (free/
total PSA) before and after antibacterial therapy were
compared using t-test. The receiver-operating characteristic (ROC) technique was used to evaluate the
effectiveness of PSA, PSAD, f/t PSA, and their
changes after antibacterial therapy (4PSA, 4PSAD,
and 4f/t PSA) on PC detection.
Results Among the 136 patients, 33 had PC and the
other 103 histologically confirmed benign prostatic
disease. After antibacterial therapy for 2 weeks, the
PSA (mean ± standard deviation) decreased from
14.0 ± 7.8 ng/ml to 10.4 ± 7.7 ng/ml (P \ 0.01).
The 4PSA, 4PSAD, and 4f/tPSA were -3.60 ±
4.3 ng/ml, -0.1 ± 0.1 ng/ml/ml, and -0.1 ± 0.1
respectively. The areas under ROC curve were 0.29
P. Tang K. Xie (&) B. Wang X.-R. Deng R.-B. Ou
Guangzhou First Municipal People’s Hospital,
Guangzhou Medical College, 510180 Guangdong, China
e-mail: surgeon666666@yahoo.com.cn
for PSA, 0.64 for PSAD, and 0.50 for f/t PSA. The areas
under ROC curve were 0.91 for 4PSA, 0.96 for
4PSAD, and 0.98 for 4f/t PSA. These values were
increased significantly when compared with those for
the PSA-related parameters before antibacterial therapy (P value, 4PSA, 4PSAD, and 4f/t PSA were
\0.01).
Conclusions Using the changes in PSA-related
parameters after antibacterial therapy 4PSA, 4PSAD,
and 4f/t PSA improve the PC detection rate and
decrease unnecessary prostate biopsies in patients with
asymptomatic prostatitis.
Keywords Antibacterial Prostatitis Prostate-specific antigen Prostate biopsy Prostate cancer
Introduction
Currently, prostate-specific antigen (PSA) is still
considered the most useful parameter in prostate
cancer (PC) detection. A PSA of 4.0 ng/ml is widely
accepted as the cutoff for prostate biopsy around the
world [1]. However, PSA elevation can also be
induced by prostate benign disease. Studies have
identified that clinical symptomatic prostatitis is an
important factor contributing to PSA elevation [2–4].
After antibacterial therapy, PSA can decrease significantly increasing the specificity of PSA upon biopsy
123
14
of prostate [5, 6]. Recently, investigations have
shown that asymptomatic prostatitis can also elevate
PSA values [7, 8]. However, whether antibacterial
treatment can improve the effectiveness of PSA for
PC detection is still unclear. Karazanashvili and
Managadze [6] used the percentage of PSA change
after antibacterial therapy to improve the PC detection accuracy in chronic prostatitis. Little is known
about the impact of PSA and PSA-related parameter
changes after antibacterial therapy on PC detection in
asymptomatic prostatitis patients with an elevated
PSA. In this study, we evaluated the effectiveness of
PSA change (4PSA) for PC detection. We also
assessed the roles of PSA density (PSAD) and free/
total PSA (f/t PSA) changes (4PSAD and 4f/t PSA)
after antibacterial therapy in PC detection.
Materials and methods
From January 2003 to March 2008, 136 patients from
the first municipal people’s hospital of Guangzhou
China were included in the study. To be included,
patients had to be older than 50 years with PSA 4.0–
50.0 ng/ml. They should also have 10 or more white
blood cells per high-power field in their expressed
prostatic secretions and no clinical lower urinary tract
symptoms, demonstrating asymptomatic prostatitis.
Subjects were excluded if they had a suspicious
digital rectal examination, low echo level in the
peripheral zone of prostate, osseous metastasis, PC
suspected using computerized tomography or magnetic resonance imaging, if they were treated by 5-a
reductase inhibitor for more than 3 months, or if they
had a history of transurethral resection of prostate.
The PSA was determined using immunoenzymatic
assay before digital rectal examination and transrectal
ultrasonography to avoid false-positive results. Transrectal ultrasonography was performed by an experienced radiologist using a 5 MHz probe and the
following measures were determined: anteroposterior,
transversal, and longitudinal diameters of the whole
prostate. The prostate volume was calculated according to the ellipsoid formula: prostate volume (ml) =
4/3p 9 anteroposterior (cm)/2 9 transversal (cm)/
2 9 longitudinal (cm)/2. The PSAD was calculated
from total PSA and prostate volume (total PSA/
prostate volume). Prostate fluid was expressed by
digital prostate massage during the digital rectal
123
Int Urol Nephrol (2010) 42:13–18
examination. Expressed prostatic secretion was collected on a glass slide. A cover slip was placed over the
specimen and 5–7 fields were examined under highpower (4009) microscopy. Cases that had 10 or more
white blood cells per high-power field were considered
to have inflammation in the prostate gland [9]. All
included patients were given levofloxacin 0.5 once a
day for 2 weeks. After this, they underwent repeat PSA
determination and then transrectal ultrasound–guided
needle biopsies of the prostate. Biopsy was performed
using an automatic biopsy gun and an 18-gauge needle.
A minimum of six biopsies were performed for each
patient. When transrectal ultrasonography showed that
the prostate volume was greater than 50 ml, additional
biopsies were obtained up to 13.
Data were expressed in mean ± standard deviation. Differences in the PSA-related parameters
before and after antibacterial therapy were analyzed
using the t-test. The effectiveness of PSA, PSAD, f/t
PSA, and their changes (4PSA, 4PSAD, and 4f/t
PSA) for PC detection was assessed by the receiveroperating characteristic (ROC) technique. Data were
analyzed using SPSS11.5. P \ 0.05 was considered
significant.
Results
A total of 136 patients were included in this study.
Among the 136 patients, 33 were shown to have PC
and the remaining 103 histologically confirmed
benign prostatic disease. PSA (mean ± standard
deviation) decreased from 14.0 ± 7.8 ng/ml to
10.4 ± 7.7 ng/ml (P \ 0.01) after 2 weeks of antibacterial therapy. The PSA, f/t PSA, and PSAD
changes after antibacterial therapy are shown in
Table 1. Among the 136 patients, the PSA decreased
in 99 patients (72.8%), reaching values below 4.0 ng/ml
in 56 (41.2%) patients. Among the 33 patients with
PC, the PSA decreased to below 4.0 ng/ml after
antibacterial in only 4.4% (6/136) patients. So, if a
PSA of 4.0 ng/ml after antibacterial therapy was used
for prostate biopsy cutoff, 56 (41.2%) patients would
have been spared from unnecessary biopsies, while 6
(4.4%) patients would have had their PC missed. The
overall PC detection rate would have improved from
24.3% (33/136) to 33.8% (27/80).
ROC curve analysis showed the areas under the
curve for PSA, PSAD, f/t PSA, 4PSA, 4PSAD, and
Int Urol Nephrol (2010) 42:13–18
15
Table 1 PSA and its related parameter changes after 2 weeks of antibacterial therapy in patients with asymptomatic prostatitis
(n = 136)
PSA-related parameters
(mean ± standard deviation)
PSA (ng/ml)
PSAD (ng/ml/ml)
f/t PSA
Before antibacterial therapy
14.0 ± 7.8
0.2 ± 0.1
0.2 ± 0.1
After antibacterial therapy
10.4 ± 7.7
0.2 ± 0.1
0.2 ± 0.1
4value
3.6 ± 4.3
-0.1 ± 0.1
-0.1 ± 0.1
P*
\0.01
\0.01
\0.01
100
100
80
80
Sensitivity
Sensitivity
* After antibacterial therapy versus before antibacterial therapy
60
40
20
60
40
20
PSA
PSAD
PSA
PSAD
0
0
0
20
40
60
80
100
0
100 - Specificity
20
40
60
80
100
100 - Specificity
Fig 1 The specificity and sensitivity of PSA and 4PSA in the
diagnosis of PC. The areas under the curve are 0.29, 0.91
respectively
Fig 2 The specificity and sensitivity of PSAD and 4PSAD in
the diagnosis of PC. The areas under the curve are 0.64, 0.96
respectively
4f/t PSA (Fig. 1, 2, 3). ROC analysis showed that
4f/t PSA was superior compared to the other
parameters listed earlier. Also, 4f/t PSA possessed
the best parameter of diagnostic effectiveness when
using cutoff point -0.40 (Table 2). Accordingly, if
PC was diagnosed when 4f/t PSA equaled -0.40,
then the sensitivity of the diagnostic method would
be 97% and the specificity would be 86% (Table 2).
Of the patients with decreased PSA after antibacterial therapy, 48.5% (48 of 99) were shown to have
either PC with prostatic inflammation or inflammation accompanying benign prostatic hyperplasia
(BPH). It should be emphasized that the PC detection
rate was only 10.7% (6/56) among those patients
whose PSA decreased below the 4.0 ng/ml level
following antibacterial therapy. In patients who had an
unchanged or increased PSA following antibacterial
therapy, PC detection rate was 64.9% (24/37) and
only 8.1% (3/37) of the patients presented with
prostatic inflammation accompanying PC or prostate
inflammation accompanying BPH (Table 3; Fig. 4).
Discussion
PSA is still considered to be the most useful
parameter in PC detection. However, its sensitivity
and specificity are limited. The PSA-related positive
rate of prostate biopsy cancer detection is only 19–
45% [10–12]. Prostate volume and symptomatic
prostatic inflammation are the two most important
factors contributing to the elevated PSA levels in men
without clinically detectable PC [13]. Recently,
123
16
Int Urol Nephrol (2010) 42:13–18
100
Sensitivity
80
60
40
20
f/t PSA
f/t PSA
0
0
20
40
60
80
100
100 - Specificity
Fig 3 The specificity and sensitivity of f/t PSA and 4f/t PSA
in the diagnosis of PC. The areas under the curve are 0.50, 0.98
respectively
Table 2 Diagnostic efficacy of PSA, PSAD, f/t PSA, and their
changes (4PSA, 4PSAD, and 4f/t PSA) after 2 weeks of
antibacterial therapy
Cutoff values
Sensitivity (%)
Specificity (%)
91
30
81
68
91
62
85
85
-0.10
97
55
4f/t PSA
-0.40
97
86
PSA. ng/ml
10.0
PSAD. ng/ml/ml
0.33
f/t PSA
0.21
4PSA. ng/ml
-1.0
4PSAD. ng/ml/ml
studies have shown that asymptomatic prostatitis can
elevate the PSA significantly [14–17]. In this study,
the relationship between asymptomatic prostate
inflammation and PSA elevation was not assessed.
However, after 2 weeks of antibacterial therapy, PSA
decreased significantly indirectly confirming the
result that asymptomatic prostatitis can cause an
elevation of PSA.
Karazanashvili and Managadze [6] demonstrated
the impact of PSA change on prostate biopsy after
123
antibacterial therapy for 15 days in patients with
chronic prostatic inflammation and PSA 4.0–10.0 ng/ml.
In their study, they showed that the PC detection rate
was low (6.0%) among the patients with decreased
PSA after antibacterial therapy, and prostatic inflammation was observed in 100% of cases. Contrary to
this, the PC detection rate was high (83%) among the
patients with an increased or unchanged PSA after
antibacterial therapy while only 17% of these patients
presented with prostate inflammation. The findings in
our study were similar to the previous study. However, the PC detection rate in our study cohort was
higher (9.1 vs. 6.0%) among patients whose PSA
decreased and the PC detection rate was lower (64.9
vs. 83.0%) among patients with an unchanged or
increased PSA after antibacterial therapy when
compared with the previous study. The probable
reasons were the different study cohorts and PSA
ranges in the two studies.
Discriminating between PC and benign prostatic
disease is difficult, especially when a patient is within
the PSA ‘‘gray zone’’ (PSA 4.0–10.0 ng/ml). Recent
studies have shown that discriminating PC from BPH
or other benign prostatic disease was also a challenge
with a baseline of PSA 10.0 ng/ml or greater [8, 18].
Kehinde et al. [18] reported that only 18 (11.0%) of the
161 patients with PSA 10.0 ng/ml or greater were
diagnosed with PC, and 33 (21.0%) of the patients were
diagnosed with of prostatitis. Several PSA-related
factors, including the f/t PSA, PSAD, and PSA
velocity, have been examined in an attempt to improve
the efficiency of prostate biopsies in patients who are
within the PSA ‘‘gray zone’’ [19, 20]. Karazanashvili
and Managadze [6] reported that using the percentage
of PSA change after antibacterial therapy improved the
PC detection accuracy in chronic prostatitis patients
with a baseline PSA of 4.0–10.0 ng/ml. No studies
have evaluated asymptomatic prostatitis patients with
PSA 10.0 ng/ml or greater who frequently are not
diagnosed for PC. In this study, we evaluated the PSA,
PSAD, and f/t PSA changes (4PSA, 4PSAD and 4f/t
PSA) in asymptomatic prostatitis patients with PSA
4.0–50.0 ng/ml. The effectiveness of 4PSA, 4PSAD,
and 4f/t PSA for PC detection after antibacterial
therapy was significantly improved when compared
with PSA, PSAD, and f/t PSA before antibacterial
therapy. To our knowledge, this is the first time using
the changes in PSA-related parameters to diagnose PC.
This method of diagnosis appeared very effective in
Int Urol Nephrol (2010) 42:13–18
Table 3 Final biopsy
results of the 136 patients
who were included in this
study
17
PSA change after
antibacterial therapy
Patients
n
%
Less than
4.0 ng/ml
56
41.2
Decreased
99
Final results
72.8
n
37
27.2
%
BPH
26
19.1
BPH with prostatic
inflammation
24
17.6
PC
0
0.0
PC with prostatic
inflammation
6
4.4
BPH
50
36.7
BPH with prostatic
inflammation
PC
40
29.4
1
0.7
8
5.9
PC with prostatic
inflammation
Unchanged
or increased
Patients
BPH
BPH with prostatic
inflammation
PC
PC with prostatic
inflammation
11
8.1
2
1.5
23
17.0
1
0.7
Fig 4 Pathologic findings
of transrectal needle biopsy
specimens of prostate. a No
inflammation, b distributed
inflammation
distinguishing malignant and nonmalignant conditions, since the specificity and sensitivity were high.
The parameter 4f/t PSA was the best diagnostic
method at a cutoff -0.40. In our study cohort, if a
cutoff point for 4f/t PSA of -0.40 had been used to
diagnose PC, only 5 PC cases would have been missed
while 97 patients would have been spared unnecessary
biopsies.
changes in PSA and PSA-related parameters after
antibacterial therapy (4PSA, 4PSAD, and 4f/t
PSA) can be used to improve the PC detection
accuracy in patients with asymptomatic prostatitis
and PSA 4.0–50.0 ng/ml.
Conclusions
References
After 2 weeks of antibacterial therapy, the PSA and
PSA-related parameters can change significantly. The
Acknowledgments The authors gratefully acknowledge
Benjamin Lack from Duke University Medical Center for his
help with the discussion and proofreading of the manuscript.
1. Schroder FH, Roobol MJ (2009) Defining the optimal
prostate-specific antigen threshold for the diagnosis of
prostate cancer. Curr Opin Urol 19:227–231
123
18
2. Kravchick S, Cytron S, Agulansky L et al (2004) Acute
prostatitis in middle-aged men: a prospective study. BJU
Int 93:93–96. doi:10.1111/j.1464-410X.2004.04642.x
3. Bozeman CB, Carver BS, Eastham JA et al (2002) Treatment
of chronic prostatitis lowers serum prostate specific antigen.
J Urol 167:1723–1726. doi:10.1016/S0022-5347(05)65186-5
4. Battikhi MN, Ismail H, Battikhi Q (2006) Effects of
chronic bacterial prostatitis on prostate specific antigen
levels total and free in patients with benign prostatic
hyperplasia and prostate cancer. Int Urol Nephrol 38:21–
26. doi:10.1007/s11255-005-1662-6
5. Schaeffer AJ, Wu SC, Tennenberg AM et al (2005) Treatment of chronic bacterial prostatitis with levofloxacin and
ciprofloxacin lowers serum prostate specific antigen. J Urol
174:161–164. doi:10.1097/01.ju.0000162017.24965.2b
6. Karazanashvili G, Managadze L (2001) Prostate-specific
antigen (PSA) value change after antibacterial therapy of
prostate inflammation, as a diagnostic method for prostate
cancer screening in cases of PSA value within 4–10 ng/ml
and nonsuspicious results of digital rectal examination. Eur
Urol 39:538–543. doi:10.1159/000052500
7. Stancik I, Luftenegger W, Klimpfinger M et al (2004)
Effect of NIH-IV prostatitis on free and free-to-total PSA.
Eur Urol 46:760–764. doi:10.1016/j.eururo.2004.08.003
8. Kobayashi M, Nukui A, Morita T (2008) Serum PSA and
percent free PSA value changes after antibiotic treatment. A
diagnostic method in prostate cancer suspects with asymptomatic prostatitis. Urol Int 80:186–192. doi:10.1159/000
112612
9. Sindhwani P, Wilson CM (2005) Prostatitis and serum
prostate-specific antigen. Curr Urol Rep 6:307–312. doi:
10.1007/s11934-005-0029-y
10. Terrone C, Poggio M, Bollito E et al (2005) Asymptomatic
prostatitis: a frequent cause of raising PSA. Recenti Prog
Med 96:365–369
11. Koseoglu RD, Erdemir F, Parlaktas BS et al (2007) Effect
of chronic prostatitis on angiogenic activity and serum
prostate specific antigen level in benign prostatic hyperplasia. Kaohsiung J Med Sci 23:387–394. doi:10.1016/
S0257-5655(07)70002-0
12. Ozden C, Ozdal OL, Guzel O et al (2007) The correlation
between serum prostate specific antigen levels and
123
Int Urol Nephrol (2010) 42:13–18
13.
14.
15.
16.
17.
18.
19.
20.
asymptomatic inflammatory prostatitis. Int Urol Nephrol 39:
859–863. doi:10.1007/s11255-006-9125-2
Sheikh M, Al-Saeed O, Kehinde EO et al (2005) Utility of
volume adjusted prostate specific antigen density in the
diagnosis of prostate cancer in Arab men. Int Urol Nephrol
37:721–726. doi:10.1007/s11255-005-4683-2
Yaman O, Gogus C, Tulunay O et al (2003) Increased
prostate-specific antigen in subclinical prostatitis: the role
of aggressiveness and extension of inflammation. Urol Int
71:160–164. doi:10.1159/000071839
Ozden C, Inal G, Adsan O et al (2003) Detection of prostate
cancer and changes in prostate-specific antigen (PSA)
6 months after surgery for benign prostatic hyperplasia in
patients with elevated PSA. Urol Int 71:150–153. doi:
10.1159/000071837
Okada K, Kojima M, Naya Y et al (2000) Correlation of
histological inflammation in needle biopsy specimens with
serum prostate-specific antigen levels in men with negative
biopsy for prostate cancer. Urology 55:892–898. doi:
10.1016/S0090-4295(00)00519-7
Gumus BH, Nese N, Gunduz MI et al (2004) Does
asymptomatic inflammation increase PSA? A histopathological study comparing benign and malignant tissue biopsy
specimens. Int Urol Nephrol 36:549–553. doi:10.1007/
s11255-004-0845-x
Kehinde EO, Sheikh M, Mojimoniyi OA et al (2003) High
serum prostate-specific antigen levels in the absence of
prostate cancer in middle-eastern men: the clinician’s
dilemma. BJU Int 91:618–622. doi:10.1046/j.1464-410X.
2003.04199.x
Catalona WJ, Southwick PC, Slawin KM et al (2000)
Comparison of percent free PSA, PSA density, and agespecific PSA cutoffs for prostate cancer detection and
staging. Urology 56:255–260. doi:10.1016/S0090-4295
(00)00637-3
Brawer MK, Cheli CD, Neaman IE et al (2000) Complexed
prostate specific antigen provides significant enhancement
of specificity compared with total prostate specific antigen
for detecting prostate cancer. J Urol 163:1476–1480. doi:
10.1016/S0022-5347(05)67646-X