Prostate Specific Antigen Decrease and Prostate Cancer Diagnosis: Antibiotic Versus Placebo Prospective Randomized Clinical Trial

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Oncology: Prostate/Testis/Penis/Urethra

Prostate Specific Antigen Decrease and Prostate Cancer Diagnosis: Antibiotic Versus Placebo Prospective Randomized Clinical Trial R. M. Stopiglia, U. Ferreira, M. M. Silva, Jr., W. E. Matheus, F. Denardi and L. O. Reis* From the Section of Urologic Oncology, Discipline of Urology, State University of Campinas – UNICAMP, Campinas, Brazil

Abbreviations and Acronyms NIH ⫽ National Institutes of Health PSA ⫽ prostate specific antigen Submitted for publication July 20, 2009. Nothing to disclose. Study received institutional review board approval. Presented at annual meeting of American Urological Association, Chicago, Illinois, April 25–30, 2009. * Correspondence: Rua Votorantim, 51, Ap 43 – Vila Nova, Campinas, São Paulo, Brazil 13073-090 (telephone: ⫹55 19 35217481; e-mail: [email protected]).

Editor’s Note: This article is the third of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1262 and 1263.

Purpose: Prostate inflammation can lead to an increase in serum prostate specific antigen concentration and confound the use of prostate specific antigen kinetics. Repeat prostate specific antigen measurements after a period of observation or a course of empirical antibiotics are controversial in terms of the optimal approach to reduce the confounding impact on prostate cancer screening. This issue was analyzed in patients with a diagnosis of type IV or asymptomatic prostatitis (National Institutes of Health classification) and high prostate specific antigen. Materials and Methods: We studied 200 men between 50 and 75 years old with a high prostate specific antigen (between 2.5 and 10 ng/dl). Of these patients 98 (49%) had a diagnosis of type IV prostatitis. In a prospective, double-blind trial they were randomized to receive placebo (49 patients, group 1) or 500 mg ciprofloxacin (49 patients, group 2) twice a day for 4 weeks. Prostate specific antigen was determined after treatment and all patients underwent transrectal ultrasound guided biopsy of the prostate. Results: In group 1, 29 (59.18%) patients presented with a decrease in prostate specific antigen and 9 (31%) had cancer on biopsy, while in group 2 there were 26 (53.06%) patients with a decrease in prostate specific antigen and 7 (26.9%) with prostate cancer. There was no statistical difference in either group in relation to prostate specific antigen decrease after treatment or the presence of tumor. Conclusions: A considerable number of patients (49%) were diagnosed with type IV prostatitis and high prostate specific antigen in agreement with the current literature. Of the patients 26.9% to 31% presented with a decrease in prostate specific antigen after the use of antibiotic or placebo and harbor cancer as demonstrated on prostate biopsy. Prostate specific antigen decreases do not indicate the absence of prostate cancer. Key Words: prostatitis, prostatic neoplasms, biopsy, prospective studies


THE type IV prostatitis classification of the NIH is a known cause of PSA increase.1 Many patients with this condition are treated with antibiotics to check for PSA decrease, thereby avoiding a considerable number of prostate biopsies. Since 1995, with the classification of prostatitis proposed by the NIH,2 as well as the ini-

tial study to determine the incidence of type IV or asymptomatic prostatitis in men presenting with high PSA by Potts in 2000,3 there has been increasing medical concern about its possible association with benign prostatic hyperplasia and prostate cancer.4,5 In this context we raise 2 questions. 1) Can antibiotics deal adequately with


Vol. 183, 940-945, March 2010 Printed in U.S.A. DOI:10.1016/j.juro.2009.11.044




subclinical or asymptomatic prostatitis in determining the PSA decrease or normalization compared to observation? 2) If PSA decreases can we even waive the biopsy and conclude there is no cancer in these patients? Based on the current literature additional evidence is necessary in which all patients undergo biopsy regardless of the PSA response to antibiotic or placebo.6,7 Such study would help determine the best strategy to safely reduce the number of unnecessary biopsies due to confounding factors such as prostatitis.8,9

PATIENTS AND METHODS Between January 2006 and December 2007, from 230 eligible patients, after institutional review board (ethical committee) approval and written informed consent, 200 asymptomatic men 50 to 75 years old with a high PSA (between 2.5 and 10 ng/dl) and a palpably normal digital rectal examination were examined to search type IV asymptomatic prostatitis (NIH). The laboratory test used to diagnose prostatitis was performed according to modified Mears-Stamey.7 Total PSA was measured with the previously validated Immulite® PSA kit. A positive diagnosis was considered an increase of more than 10 leukocytes per high power field in urine or more than 20 leukocytes per high power field in postprostatic massage urethral secretion compared to premassage or even positive bacterioscopy in this secretion. Exclusion criteria were age less than 50 or greater than 75 years, biopsy refused and PSA greater than 10 ng/dl due to the greater incidence of tumor. Men with evidence of acute urinary tract infection (pyuria and bacteriuria) on urinalysis, those with a prior diagnosis of prostate cancer and acute prostatitis, an indwelling catheter or previous prostatic surgery of any nature, recent instrumentation of the genitourinary tract (less than 6 months), any form of hormonal manipulation or a history of allergy to ciprofloxacin were all excluded from study. Of the original 200 patients 98 (49%) presented with type IV prostatitis according to these criteria and, therefore, were elected to the study. These 98 patients were randomized into 2 groups to receive placebo or antibiotic (500 mg ciprofloxacin) twice daily. A centralized, computer generated randomization was used to which patients and researchers were blinded. Group 1 (placebo) with 49 patients and group 2 (antibiotic) with 49 patients received medication for 28 days, and all underwent a new PSA test and transrectal ultrasound prostate biopsy after treatment. Transrectal ultrasound guided systematic 12-core biopsy of the prostate was performed by a single sonographer using a biplanar technique with a 7.5 MHz probe (Toshiba SSA-250-A, Toshiba, Tokyo, Japan) with patients in the left lateral decubitus position. An automated biopsy gun and an 18 gauge needle were used, and all patients received 500 mg ciprofloxacin twice daily for 5 days starting the day before the biopsy. Pathological biopsy results were classified as benign or showing cancer. In cases of atypical small acinar proliferation re-biopsy


was performed after 3 to 6 months. Prostatic intraepithelial neoplasia was classified as benign. For statistical analysis Fisher’s exact test was used for categorical variables. The Mann-Whitney test was used to compare the numerical variables between the groups due to a lack of normal distribution of variables. To compare each group in each time ANOVA was used for repeated measurements followed by the Tukey multiple comparison test. The significance level was 5% (p ⬍0.05) with a CI of 95%.

RESULTS No statistically significant differences were found in terms of age and pretreatment PSA between patients allocated to receive placebo or antibiotic. There was also no difference between patients with and without prostate cancer on biopsy (p ⬎0.05). Group 1 (placebo) patients had a mean age of 63.9 years and presented with a mean PSA of 5.65 ng/dl. PSA decreased in 29 (59.2%) patients, including 19 (65.5%) who experienced an average 21.2% decrease from baseline with no normalization and 10 (34.4%) in whom PSA decreased an average 69.7% from baseline with normalization (less than 2.5 ng/dl). Of the 19 patients in whom PSA decreased 6 (31.5%) presented with cancer on biopsy with an average decrease of 21.9% from baseline PSA. Of the 10 patients in whom PSA normalized 3 (30%) also presented with tumor with an average decrease of 18.2% from baseline PSA. Thus, there was no statistical difference between the means of decreasing PSA when tumor was present vs not present (21.9% vs 18.2%, respectively, p ⬎0.05). Overall 9 (31%) patients with a decrease in PSA had tumor on subsequent biopsy. Of the 20 patients with an increase in PSA 8 (40%) had tumor. Patients in group 2 (antibiotic) had a mean age of 64.9 years and presented with a mean PSA of 5.01 ng/dl. PSA decreased in 26 (53.1%) patients, including 17 (65.3%) who experienced an average 27.9% decrease from baseline with no normalization and 9 (34.6%) in whom PSA decreased an average 64.2% from baseline with normalization (less than 2.5 ng/ dl). Of the 17 patients in whom PSA decreased with no normalization 2 (11.7%) were diagnosed with cancer on biopsy and of 9 with normalized PSA 5 (55.5%) presented with tumor. Of all patients with a PSA decrease 7 (26.9%) were diagnosed with cancer. Of the other 23 patients who had an increase in PSA 4 (17.4%) had tumor. There was no statistically significant difference between the groups (placebo vs antibiotic) with respect to the decrease in PSA (59.2% vs 53.1%, p ⬎0.05). There was also no difference among patients presenting with a PSA decrease and tumor considering groups 1 and 2 (31% vs 26.9%, p ⬎0.05, see figure). In group 1 (placebo) 7 patients and in group 2 (antibiotic) 9 presented with mild gastrointestinal



Study design and data organogram (red indicates cancer diagnosis)

adverse reactions, and there were no study withdrawals. In terms of prostatitis 6 patients in group 1 and 8 in group 2 presented with histological confirmation. All diagnosed prostate cancers were classified as pT1c, and Gleason score was 3 ⫹ 3 in 6 patients in group 1 and 5 in group 2. Three patients in group 1 and 2 in group 2 presented with Gleason score 3 ⫹ 4 disease.

DISCUSSION The invasive examination, the relatively high cost, and the physical and emotional inconvenience for the patient justify efforts to minimize the unnecessary indication of biopsy. PSA is not a cancer specific tumor marker, and other physiological and benign conditions such as benign prostatic enlargement as well as cancer can increase serum PSA and lead to potentially unnecessary biopsy procedures.10 Furthermore, several studies have shown that the use of antibiotics, regardless of whether they are associated with antiinflammatory action, has produced clinical and biochemical (decrease in PSA) improvement in patients presenting with prostatitis. While antibiotics may influence the course of bacterial prostatitis, 90% of symptomatic prostatitis and virtually all asymptomatic cases are not caused by bacteria.11 Thus, antibiotics have little or no significant effect on nonbacterial prostatitis and cer-

tainly cannot affect PSA in men presenting with type IV prostatitis. Moreover there is no randomized study to our knowledge showing that the use of antibiotics reduces PSA compared to placebo except in the presence of bacterial prostatitis, which is an uncommon condition.7 One must also remember that a significant degree of biological variation can be observed in PSA in normal men.12 A physiological fluctuation in PSA from 10% to 20% was observed in a screening population.13 On the other hand, some studies found a correlation between clinical prostatitis diagnosis and inflammation on prostate biopsies. Nadler et al found 64.3% of demonstrable inflammation on biopsies14 and Stancik et al had 33.9% on 404 sextant biopsies.15 In 2003 Shimomura et al identified only 11.2%.16 Thus, chronic inflammation appears to be associated with benign hyperplasia but does not exclude cases of cancer.5 Gümüs et al described the types of inflammation as glandular, periglandular, stromal and perivascular, and found that only the last type was responsible for significantly increasing PSA.17 Another study showed that if there is more than 20% of inflammation involvement of the gland, this may be responsible for the significant increase in PSA.18 In 2000 Potts was the first to find the incidence of type IV prostatitis in asymptomatic men with high


PSA (greater than 4 ng/ml), reaching 42%.3 This author also concluded in the same work that the identification of patients with type IV prostatitis who had normalization of PSA after the use of antibiotics could reduce unnecessary biopsies by 18%. Another study showed that men with a high PSA have 32% to 42% of evidence of type IV prostatitis, and that PSA decreases to a normal level in 46.3% after antibiotic use for 4 weeks in agreement with the current study (49% of type IV prostatitis and 53.1% of PSA decrease).19 Guercio et al conducted a study showing a decrease of 57.6% in PSA and normalization in 46.7%, thus reducing the biopsy number.20 Serretta et al found a PSA decrease of 59.5% after antibiotic and recommended postponing biopsy if PSA decreased below 4 ng/dl or more than 70% of initial levels.21 Other studies showed an even bigger decrease in PSA (80%) also avoiding biopsy in a considerable number of patients.22 In our study at least a third (30% to 55.5%) of patients with a PSA decrease below 2.5 ng/dl (considered normal) or 70% of initial levels presented with prostate cancer on biopsy. Erol et al showed that the effect of antibiotic use with anti-inflammatory medication may discriminate benign pathology of the malignant prostate provided that PSA decreased considerably.23 Another study of 51 patients with type IV prostatitis found that a PSA decrease of 30% or 20% of baseline could avoid prostate biopsy in patients receiving antibiotics for 4 weeks.24 The main limitation of these studies was not to perform biopsy in all patients. Baltaci et al, biopsying all patients, found prostate cancer in 23 of 100 men (23%) presenting with a PSA between 4 and 10 ng/ml.25 Of these 100 men 17 had a PSA less than 4 ng/ml after antibiotic treatment and 5 of these 17 (29.4%) had prostate cancer. As many as 26.9% of men with a PSA between 2.5 and 4 ng/ml have biopsy detectable prostate cancer.26 Thus, we included patients presenting with a PSA as low as 2.5 ng/ml in this study and unexpect-


edly we found a relatively high rate of cancer in those with a PSA even lower than 2.5 ng/ml during followup receiving placebo (30%) or antibiotic (55.5%). We present the first prospective, double-blind, randomized study comparing the behavior of PSA after treatment with antibiotics vs placebo in patients with type IV prostatitis and high PSA. In these patients a decrease in PSA and normalized levels (below 2.5 ng/ml) do not indicate the absence of prostate cancer, and should not be valued. The valuable pioneering information in the present study is that the PSA behavior (kinetics) does not differ in patients using antibiotics or placebo and, surprisingly, it is not related to the presence or absence of cancer, although it decreases to low and normal levels (less than 2.5 ng/ml). This study presents some limitations, and although all included patients did not present with any symptom, the NIH-Chronic Prostatitis Symptom Index would be useful to assure that they were indeed asymptomatic. Furthermore, treatment with an anti-inflammatory medication would be expected to decrease prostatic inflammation in these patients and it should be addressed in future studies. Another important consideration is that our patients may not be a random sample of male patients because only those with type IV prostatitis were included.

CONCLUSIONS There was no statistical difference in the decrease in PSA in patients with type IV prostatitis after antibiotics or placebo (59.2% vs 53.1%). There was also no significant difference with respect to patients who had a decrease in PSA and diagnosis of prostate cancer after treatment with antibiotic or placebo (31% vs 26.9%). Thus, this study shows that antimicrobial therapy was no more effective than placebo in reducing PSA, and that the proportion of patients with cancer was similar in both groups (at least a third). More studies and larger samples should be conducted to confirm our data.

REFERENCES 1. Krieger JN, Nyberg L Jr and Nickel JC: NIH consensus definition and classification of prostatitis. JAMA 1999; 282: 236. 2. Nickel JC, Nyberg LM and Hennenfent M: Research guidelines for chronic prostatitis: consensus report from the first National Institutes of Health International Prostatitis Collaborative Network. Urology 1999; 54: 229. 3. Potts JM: Prospective identification of National Institutes of Health category IV prostatitis in men

with elevated prostate specific antigen. J Urol 2000; 164: 1550. 4. Terrone C, Poggio M, Bollito E et al: Asymptomatic prostatitis: a frequent cause of raising PSA. Recenti Prog Med 2005; 96: 365. 5. Delongchamps NB, de la Roza G, Chandan V et al: Evaluation of prostatitis in autopsied prostates–is chronic inflammation more associated with benign hyperplasia or cancer? J Urol 2008; 179: 1736.

6. Loeb S, Gashti SN and Catalona WJ: Exclusion of inflammation in the differential diagnosis of an elevated prostate-specific antigen (PSA). Urol Oncol 2009; 27: 64. 7. Mears EM and Stamey TA: Bacteriologic localization patterns in bacterial prostatitis and urethritis. Invest Urol 1968; 5: 492. 8. Scardino PT: The responsible use of antibiotics for an elevated PSA level. Nat Clin Pract Urol 2007; 4: 1.



9. Kaygisiz O, Ugurlu O, Kos¸an M et al: Effects of antibacterial therapy on PSA change in the presence and absence of prostatic inflammation in patients with PSA levels between 4 and 10 ng/ ml. Prostate Cancer Prostatic Dis 2006; 9: 235.

16. Shimomura T, Kiyota H, Takahashi H et al: Prostate histopathology of NIH category IV prostatitis detected by sextant prostate needle biopsy from the patients with high prostatic specific antigen. Kansenshogaku Zasshi 2003; 77: 611.

10. Tchetgen MB and Oesterling JE: The effect of prostatitis, urinary retention, ejaculation, and ambulation on the serum prostate-specific antigen concentration. Urol Clin North Am 1997; 24: 283.

17. Gümüs¸ BH, Nes¸e N, Gündüz MI et al: Does asymptomatic inflammation increase PSA? A histopathological study comparing benign and malignant tissue biopsy specimens. Int Urol Nephrol 2004; 36: 549.

11. Habermacher GM, Chason JT and Schaeffer AJ: Prostatitis/chronic pelvic pain syndrome. Annu Rev Med 2006; 57: 195. 12. Zhang L, Loblaw A and Klotz L: Modeling prostate specific antigen kinetics in patients on active surveillance. J Urol 2006; 176: 1392. 13. Komatsu K, Wehner N, Prestigiacomo AF et al: Physiologic (intraindividual) variation of serum prostate-specific antigen in 814 men from a screening population. Urology 1996; 47: 343. 14. Nadler RB, Humphrey PA, Smith DS et al: Effect of inflammation and benign prostatic hyperplasia on elevated serum prostate specific antigen levels. J Urol 1995; 154: 407. 15. Stancik I, Luftenegger W, Klimpfinger M et al: Effect of NIH-IV prostatitis on free and free-tototal PSA. Eur Urol 2004; 46: 760.

18. Simardi LH, Tobias-Machado M, Kappaz GT et al: Influence of asymptomatic histologic prostatitis on serum prostate-specific antigen: a prospective study. Urology 2004; 64: 1098. 19. Bozeman CB, Carver BS, Eastham JA et al: Treatment of chronic prostatitis lowers serum prostate specific antigen. J Urol 2002; 167: 1723.

22. Karazanashvili G and Managadze L: Prostatespecific 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 2001; 39: 538. 23. Erol H, Beder N, Caliskan T et al: Can the effect of antibiotherapy and anti-inflammatory therapy on serum PSA levels discriminate between benign and malign prostatic pathologies? Urol Int 2006; 76: 20. 24. Kobayashi M, Nukui A and Morita T: Serum PSA and percent free PSA value changes after antibiotic treatment. A diagnostic method in prostate cancer suspects with asymptomatic prostatitis. Urol Int 2008; 80: 186.

20. Guercio S, Terrone C, Tarabuzzi R et al: PSA decrease after levofloxacin therapy in patients with histological prostatitis. Arch Ital Urol Androl 2004; 76: 154.

25. Baltacı S, Süer E, Haliloglu AH et al: Effectiveness of antibiotics given to asymptomatic men for an increased prostate specific antigen. J Urol 2009; 181: 128.

21. Serretta V, Catanese A, Daricello G et al: PSA reduction (after antibiotics) permits to avoid or postpone prostate biopsy in selected patients. Prostate Cancer Prostatic Dis 2008; 11: 148.

26. Thompson IM, Pauler DK, Goodman PJ et al: Prevalence of prostate cancer among men with a prostate-specific antigen level ⬍ 4.0 ng per milliliter. N Engl J Med 2004; 350: 2239.

EDITORIAL COMMENTS Although controversial, antibiotics are often prescribed for men with newly increased PSA on the presumption that the patient has subclinical infectious prostatitis.1 In this randomized, placebo controlled, prospective study the authors evaluated the effect of antibiotics in 98 patients with proven type IV prostatitis and increased PSA. They found that antimicrobial therapy was no more effective than placebo in reducing PSA, and that the proportion of patients with cancer was similar in both groups. There are clearly a number of limitations to this study and the authors address most of them. Considering the power calcula-

tion above 80%, the sample size should be at least 130 patients (65 in each group). Therefore, the results should be read cautiously. As recent studies have revealed percent free PSA to be more helpful in suggesting prostate cancer after antibiotic treatment, future studies should include such PSA parameters (reference 25 in article).1 Sümer Baltacı Department of Urology Ankara University School of Medicine Ankara, Turkey

REFERENCE 1. Dirim A, Tekin MI, Koyluoglu E et al: Do changes in a high serum prostate-specific antigen level and the free/total prostate-specific antigen ratio after antibiotic treatment rule out biopsy and the suspicion of cancer? Urol Int 2009; 82: 266.

Symptomatic prostatitis and urogenital infections acutely increase PSA,1,2 and may increase the longterm risk of prostate cancer and lower urinary tract symptoms.3 Antibiotic treatment of symptomatic infections decreases PSA. However, most patients with prostatitis symptoms do not have active infections. Stopiglia et al ask a critical question. Can antibiotics reduce PSA in patients with asymptomatic

prostatitis to limit unnecessary biopsies? Unfortunately their answer is no. In contrast to the United States where we are lucky to enroll 1 of 3 patients, these investigators enrolled 200 (87%) of 230 patients with PSA 2.5 to 10 ng/dl and normal rectal examinations. After a modified Mears-Stamey test participants were randomized to placebo or ciprofloxacin for 4 weeks. All underwent transrectal ul-


trasound and 12-core prostate biopsy. Overall 98 patients (49%) had asymptomatic prostatitis. The proportion with cancer (27% and 31%) was similar in the 2 groups regardless of PSA decrease. Thus, PSA decrease after antibiotic therapy did not eliminate the need for biopsy. Important questions remain. Could another treatment or a better diagnostic test reduce unnecessary prostate biopsies? How direct is the connection be-


tween prostatitis and prostate cancer or benign prostatic hyperplasia? Can prevention or early treatment of symptomatic or asymptomatic prostatitis decrease the subsequent risk of other prostate diseases? John N. Krieger Department of Urology University of Washington School of Medicine Seattle, Washington

REFERENCES 1. Schaeffer AJ, Wu SC, Tennenberg AM et al: Treatment of chronic bacterial prostatitis with levofloxacin and ciprofloxacin lowers serum prostate specific antigen. J Urol 2005; 174: 161.

2. Sutcliffe S, Zenilman JM, Ghanem KG et al: Sexually transmitted infections and prostatic inflammation/cell damage as measured by serum prostate specific antigen concentration. J Urol 2006; 175: 1937.

3. Nickel JC, Roehrborn CG, O’Leary MP et al: The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol 2008; 54: 1379.

REPLY BY AUTHORS A vital issue in human research that has been receiving increased attention is the cultural scenario. Health research as a global issue concerns all and clearly manifests global inequality. There are some contrasting behavioral differences among people around the world that must be considered.1 While much of a cultural matter, Brazil could be one of the

wealth of countries underexplored by the global pharmaceutical market, where patients agree to participate in trials for diverse reasons. Regarding sample size and power calculations, are they compulsory in the actual research model? How should they be obtained? Important questions remain and there is significant room for improvement.

REFERENCE 1. Oliveira Reis L: Translating questionnaires for use in crosscultural research—are we doing the right thing? Actas Urol Esp 2009; 33: 5.

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