La deprivacion androgenica como terapia en cancer de prostata,uso excesivo?

Medscape Medical News

Overused: Androgen-Deprivation Therapy in Prostate Cancer

Nick Mulcahy

June 11, 2009 — Androgen-deprivation therapy (ADT) for prostate cancer is overused, according to experts who have written recent editorials in 2 major journals.

"It's becoming increasingly clear that androgen-deprivation therapy is overused in treating prostate cancer," writes William Dale, MD, PhD, in an editorial accompanying a new American study that indicates that ADT contributes to the development of diabetes. The study and editorial were published online June 8 in the Journal of Clinical Oncology. Dr. Dale is from the geriatrics and palliative medicine and hematology/oncology sections at the University of Chicago in Illinois.

No doubt there is gross overuse of androgen-deprivation therapy in the treatment of prostate cancer.

"No doubt there is gross overuse of androgen-deprivation therapy in the treatment of prostate cancer," said Peter Albertsen, MD, MS, in an interview with Medscape Oncology. Dr. Albertsen is the author of an editorial published in the June 11 issue of the New England Journal of Medicine that accompanies a new European study on the use of ADT in men with locally advanced prostate cancer. He is professor of surgery and chief of the Division of Urology at the University of Connecticut Health Center in Framingham.

Both Dr. Albertsen and Dr. Dale note that ADT has been shown to improve survival in men with metastatic prostate cancer, but that its survival benefits are mostly uncertain or unproven in other stages of the disease.

What's Driving the Overuse?

The overuse of ADT has been driven, in part, by clinicians in the United States overestimating the effectiveness of ADT, suggests Dr. Albertsen. "If it's good for advanced disease, there's a good chance it will work for localized disease — that's probably been the thinking," he explained.

Overuse was probably worse a few years ago.

Money has also been a driver. "Overuse was probably worse a few years ago when clinicians were making a lot of money off of it," Dr. Albertsen said about the administration of ADT and related follow-up care.

The desire to take action is another driver, said Dr. Dale. "There is a propensity to 'do something' about cancer that leads to starting a therapy that is not justified. This is particularly true for older men," he told Medscape Oncology.

Dr. Dale cited 2 "do something" settings in which data don't support the use of ADT. "Starting it early when PSA [prostate-specific antigen] first rises following surgery or radiation — versus waiting until later to start it — has not been shown to extend life. It is also being used increasingly in older men as primary therapy rather than surgery or radiation therapy," he noted.

I was struck by men who had their PSA rising and were going out of their minds with worry.

Dr. Dale, who is trained as a geriatrician and has an appointment in oncology, spent a month in an oncology clinic talking to clinicians and patients about their decisions to start ADT. "I was struck by men who had their PSA rising and were going out of their minds with worry," he noted. In a study coauthored by Dr. Dale (J Clin Oncol 2009; 27:1557-1563), patient anxiety was shown to be the primary reason men with rising PSA counts, or biorecurrence, decided to start ADT .

In their editorials and comments to Medscape Oncology, Drs. Albertsen and Dale encouraged clinicians to limit their use of ADT to appropriate patients.

They also reminded clinicians of the potential deleterious effects of treatment, including osteoporosis, fatigue, weakness, adiposity, worse cholesterol profiles, hot flashes, and now the development of diabetes.

ADT for Some, But Not All, Advanced Localized Disease

In the treatment of prostate cancer, ADT should "primarily be limited to men with advanced localized disease undergoing radiation therapy and to men with clear signs of systemic disease," writes Dr. Albertsen in his editorial.

"These are the patients most likely to benefit from either symptom relief or increased survival that would justify the compromise in quality of life that is associated with androgen-deprivation therapy," he notes.

Dr. Albertsen reached this conclusion based on the available literature, which now includes the European study of men with advanced localized disease published in the New England Journal of Medicine.

In the study, the definition of locally advanced disease was either tumor stages T1c to T2a–b and nodal stage N1 or N2, or tumor stages T2c to T4 and clinical nodal stages N0 to N2. Patients with clinical evidence of metastatic spread were excluded.

The study indicates that, following external-beam radiation for locally advanced prostate cancer, 6 months of ADT does not provide survival superior to 3 years of treatment; the now-published results were originally presented at the ASCO annual meeting in 2007 and reported on by Medscape Oncology at the time.

In short, the study says that 3 years of ADT, which is the standard in this setting, should remain the standard.

The results are not generalizeable to men with other stages of prostate cancer, emphasized Dr. Albertsen. He added that the results might not be very helpful when considering American men with advanced localized disease.

"In Europe, more men have T3 disease," Dr. Albertsen said, referring to roughly 70% of the men in the study. European countries do not screen for prostate cancer as aggressively as the United States, he said. As a consequence, Europe has more cancers detected clinically and thus a different pool of patients with locally advanced prostate cancer.

In the United States, many men with advanced local disease will have T1c disease, which is characteristic of screen-detected cancers, Dr. Albertsen continued. These men typically have prostate cancers of much smaller volume and lower grade than the men in the European study, he explained.

It is "unclear" whether the European findings apply to men who receive radiation and ADT and have smaller volume and lower grade tumors characteristic of so much of screen-detected T1c disease, writes Dr. Albertsen.

Thus, the term locally advanced disease might need some qualification when considering ADT in the United States, suggested Dr. Albertsen.

Balancing the Risks for Therapy and Disease

According to Dr. Dale, the best candidates for early use of ADT are, in addition to patients with overt metastasis, younger patients (under 65) with "high-risk" disease (high-grade prostate cancer, local spread of disease into lymph nodes) receiving external-beam radiation. His comments, in effect, echoed Dr. Albertsen's

Dr. Dale also suggested that otherwise healthy men with very high-risk features (Gleason grade of 8–10, PSA doubling times of less than 3 months, short time between primary therapy and rising PSA) could be started early.

However, older patients with moderate-grade or lower disease and long PSA doubling times should definitely not be started on it right away, he emphasized.

"We have to balance the risk of the prostate cancer with the risks of the therapy when making these decisions," said Dr. Dale, adding that mixed information exists about the role ADT plays in worsening cardiovascular disease or diabetes.

However, the new American study "convincingly supports the conclusion that ADT contributes to the development of [diabetes mellitus]," writes Dr. Dale in his editorial.

In the retrospective study of more than 19,000 patients, the investigators found an adjusted hazard ratio of 1.26 (95% confidence interval, 1.16 - 1.36) for the development of diabetes mellitus among men undergoing ADT, said Dr. Dale. The number needed to harm due to the use of ADT was 91, he added.

Dr. Dale and Dr. Albertsen have disclosed no relevant financial relationships.

J Clin Oncol. 2009. Published online ahead of print June 8, 2009.
N Engl J Med. 2009;360:2516-2525 and 2572-2574.

Authors and Disclosures

Journalist

Nick Mulcahy

Nick Mulcahy is a senior journalist for Medscape Hematology-Oncology. Before joining Medscape, Nick was a freelance medical news writer for 15 years, working for companies such as the International Medical News Group, MedPage Today, HealthDay, McMahon Publishing, and Advanstar. He is also the former managing editor of breastcancer.org. He can be contacted at nmulcahy@medscape.net.

Medscape Medical News © 2009 Medscape, LLC
Send press releases and comments to news@medscape.net.

¡El cáncer de próstata detectado incidentalmente en pacientes a quien se le hace una Cistectomia radical,clinicamente significante?

from American Journal of Clinical Pathology

Is Incidentally Detected Prostate Cancer in Patients Undergoing Radical Cystoprostatectomy Clinically Significant?

Roberta Mazzucchelli, MD, PhD; Francesca Barbisan, MD; Marina Scarpelli, MD; Antonio Lopez-Beltran, MD, PhD; Theodorus H. van der Kwast, MD, PhD; Liang Cheng, MD; Rodolfo Montironi, MD, FRCPath

Published: 08/21/2009

Abstract and Introduction

Abstract

Cystoprostatectomy specimens obtained from patients with bladder cancer provide a unique opportunity to assess the features of silent prostate adenocarcinoma (PCa). The whole-mount prostate sections of 248 totally embedded and consecutively examined radical cystoprostatectomy (RCP) specimens were reviewed to determine the incidence and features of incidentally detected PCa. PCa was considered clinically significant if any of the following criteria were present: total tumor volume, 0.5 cc or more; Gleason grade, 4 or more; extraprostatic extension; seminal vesicle invasion; lymph node metastasis (of PCa); or positive surgical margins. PCa was present in 123 (49.6%) of 248 specimens. Features were as follows: acinar adenocarcinoma, 123 (100.0%); peripheral zone location, 98 (79.7%); pT2a, 96 (78.0%); pT2b, 11 (8.9%); pT2c, 9 (7.3%); pT3a, 5 (4.1%); pT3b, 2 (1.6%); pT4, 0 (0.0%); Gleason score 6 or less, 107 (87.0%); negative margins, 119 (96.7%); pN0 for PCa, 123 (100.0%); and tumor volume less than 0.5 cc, 116 (94.3%). Of the 123 incidentally detected cases of PCa, 100 (81.3%) were considered clinically insignificant. Incidentally detected PCa is frequently observed in RCP. The majority are clinically insignificant.

Introduction

Prostate cancer (PCa) can be found incidentally when the prostate is removed during cystoprostatectomy for bladder cancer (incidentally detected cancer), found latently at autopsy without ever having caused symptoms during the person’s lifetime, or clinically diagnosed by physical examination, laboratory tests, and/or symptoms. The incidence of prostate cancer in each of these settings is different.[1-4]

It is widely known that PCa has great discrepancy between its high incidence and its comparatively low morbidity and mortality rates.[5,6] For example, the lifetime probability of being diagnosed with PCa is 16% and the probability of dying of PCa is 3%.[5] Early diagnosis of lethal prostate cancer is a laudable goal, as is avoidance of unnecessary treatment, but current methods are inaccurate for making this determination. In no other malignancy is there such a vast reservoir of undetected cases that may never become clinically significant or cause death,[7] yet we are unable to stratify significant and insignificant cancers.

The aim of this study was to determine the incidence and features of incidental PCa in radical cystoprostatectomy (RCP) specimens for bladder cancer.

Materials and Methods

The study was done on specimens from 248 consecutive men with muscle-invasive bladder urothelial carcinoma and no history or clinical evidence of PCa before surgery and whose RCP specimen was examined from 1995 to 2007 at the 5 pathology services associated with the United Hospitals-Polytechnic University of the Marche Region, Ancona, Italy. The mean patient age was 68 years (range, 43–95 years). All patients were white men from the Marche Region, located in eastern central Italy, where a relatively homogeneous population lives. The procedure for this research project conformed to the provisions of the Declaration of Helsinki.

A routine pathologic examination was used for all RCP specimens. Soon after the operation, the prostate was severed from the bladder and then covered with India ink. After fixation for 24 hours in 4% neutral buffered formalin, the prostate specimens were step sectioned at 3-mm intervals perpendicular to the long axis (apical-basal) of the gland (in the years 1995 and 1998, some of the prostate specimens were sliced at an interval of 5 mm).[1] The apex, base, and seminal vesicles were removed from each specimen and submitted in total for routine histologic examination. The cut specimens were postfixed for an additional 24 hours and then dehydrated in graded alcohols, cleared in xylene, embedded in paraffin, and examined histologically as 5-µm-thick, whole-mount, H&E-stained sections.[8,9]

All of the prostate H&E-stained slides and pathology reports were reviewed by 2 genitourinary pathologists (R. Mazzucchelli and R. Montironi). Data on the features listed in Table 1 were obtained. The stage of prostate cancers was based on the 2002 revision of the TNM.[10] The Gleason grading used in this study was the modified system according to the International Society of Urological Pathology/World Health Organization.[11,12]

Table 1. Incidentally Detected Prostate Cancer

PCa volume was determined by using the point-counting method as previously described.[13] Briefly, the number of grid points falling within the area with cancer were counted, multiplied by the area associated with each point (2.25 mm2), then multiplied by the thickness of the slice to yield the volume of cancer in the corresponding prostate tissue slice. The volume obtained in all slices was then summed and multiplied by a shrinking factor of 1.3.

For the present study, PCa was considered clinically significant if any of the following criteria were present: total tumor volume, 0.5 cc or less; Gleason grade, 4 or more; extraprostatic extension; seminal vesicle invasion; lymph node metastasis (of PCa); or positive surgical margins.[14]

Results

PCa was present in 123 (49.6%) of 248 specimens (Table 1). The mean patient age was 67 years (range, 53–95 years). All were acinar adenocarcinomas, and 98 (79.7%) were located in the peripheral zone (Figure 1). Of the 123 adenocarcinomas, 96 (78.0%) were pT2a, whereas 11 (8.9%) and 9 (7.3%) were pT2b and pT2c, respectively, with lower frequency in other pT categories ( Table 1 ). In 107 specimens (87.0%), the Gleason score was 6 or less. Negative margins were present in 96.7% of cases. All cases were pN0 for PCa. In 116 specimens (94.3%), the volume was less than 0.5 cc. Of the 123 cases of incidentally detected prostate cancer, 100 (81.3%) were considered clinically insignificant. Follow-up data were available for 60 patients (length of follow-up, mean, 60 months; range, 1–120 months). The cause of death was not related to the PCa in any of the patients.

Table 1. Incidentally Detected Prostate Cancer

Table 1. Incidentally Detected Prostate Cancer

Figure 1. Whole Mount Section With Monofocal Cancer (Dotted Area) Located in the Peripheral Zone (H&E, ×1).

Discussion

The frequency of PCa incidentally detected in RCP specimens is extremely variable, ranging from less than 10% to nearly 60%.[15,16] This variability can be explained by several factors, including pathologic sampling techniques. In this respect, the slice thickness of the prostate and whether the prostate is totally embedded represent 2 important issues. In our study, with slices taken every 3 mm from the base to the apex of the gland, as is usually performed for radical prostatectomy specimens, incidentally detected PCa was present in 49.6% of specimens. Others observed similar rates of PCa using the same technique.[17-21] Ruffion et al[22] found a 51.0% rate of incidentally detected PCa, advocating the use of even finer slices (2.5 mm). Similar results were seen in the study by Abbas et al,[23] who examined prostatic tissue from 40 RCP specimens with serial step slices taken at 2- to 3-mm intervals. The frequency of autopsy-detected cancer is similar.[1] On the other hand, a lower incidence was seen in studies using a different pathologic examination protocol. For example, Moutzouris et al[24] identified PCa in 27% of the examined specimens when using 5-mm thick slices, while the percentage was low (4.0%) in a report from a Taiwanese group.[25] The latter result could be due to the influence of the study population in addition to the pathologic technique, as it is well known that the incidence of PCa is higher in the West than in Asian countries.[26]

In 81.3% of the incidentally detected carcinomas in the present study, the total tumor volume was less than 0.5 cc, and, in this group, there were no tumors with a Gleason pattern of 4 or greater, extraprostatic extension, seminal vesicle invasion, lymph node metastasis (of PCa), or a positive prostatic surgical margin. This means that the majority of incidentally detected cancers can be considered clinically insignificant, ie, only 18.7% of incidentally detected cancers in our series were clinically significant.

The proportion of clinically significant cancers in the series published previously varies from 10% to 70%[8,17-25,27-39] Table 2 . Also such wide variability could be related to the pathologic examination protocol, criteria adopted to define clinically significant cancer, and the population under investigation. Prange et al[33] found PCa incidentally in 48% of their cases, and only 10% of the tumors were clinically significant, whereas the presence of clinically significant PCa in the study by Abdelhady et al[27] was 31%. Revelo et al[20] found a 41.3% rate of unsuspected PCa; 48% of these were considered clinically significant. In a series of 141 RCPs reported by Delongchamps et al,[29] 20 (14.2%) PCas were identified, 14 of which (70%) were considered significant.

Table 2. Prostate Cancer in Radical Cystoprostatectomy Specimens: Data From the Literature*

Androulakakis et al[40] suggested that the simultaneous finding of PCa and bladder cancer did not affect the prognosis of either disease. The patient’s prognosis seemed to be related to the characteristics of each tumor, separately.[40] Pritchett et al[34] reported no worse survival in patients with both cancers compared with patients with bladder cancer alone. In our study, in none of the patients whose follow-up data were available to us was the cause of death related to the PCa. Other authors have found results similar to ours.[23,24,29,32,41]

In the series reported by Delongchamps et al,[29] 10 patients died of bladder cancer after a median interval of 13 months. Eight patients remained free of disease after a median follow-up of 64.5 months. The poor survival rate was due to the advanced stage of the bladder tumors seen in the majority of patients, compared with that of the incidentally detected PCa.[29] In the study by Abbas et al,[23] 16 of 18 patients with incidentally detected PCa were alive with no apparent disease progression at a mean follow-up of 15.2 months. The cause of death in the 2 patients who died was not related to the PCa.[23] Moutzouris et al,[24] in analyzing patient outcomes for 16 patients with unsuspected PCa, found only 1 recurrent prostatic disease. Concomitant PCa was localized to the apex and recurred on a urethral-ileal anastomosis. At a mean follow-up of 39 months, 7 patients died of metastatic bladder cancer, whereas the patient with recurrent PCa was still alive.[24]

Compared with the aforementioned studies, in the present investigation, precise information on clinically insignificant cancer was obtained from a relatively homogeneous population in eastern central Italy and from a population larger than in the other series, by meticulous pathologic grading and staging after review, and by volume measurement with sectioning at an interval of 3 mm. A detailed examination of prostatic tissue specimens was of paramount importance in the detection of small cancers.

Previous studies from our group indicated that incidentally detected PCa is less aggressive than PCa clinically detected with regard to stage, Gleason score, and surgical margin status.[1] The expression of some markers of aggressiveness (ie, nuclear and nucleolar size, proliferation activity, HER2 gene amplification, HER2 protein expression, endothelin-1 and its receptors, and racemase) was investigated by our group in incidentally detected pT2 Gleason score 6 PCa and compared with clinical cancer with matched stage and score. It was found that incidentally detected cancers are different from clinically detected cancers in terms of marker expression, having cell features of less aggressiveness.[1-4] To the best of our knowledge, studies comparing insignificant with significant incidentally detected cancer are lacking.

Incidentally detected PCa is frequently observed in RCP specimens. The majority are considered clinically insignificant. The results of the current investigation could be of paramount importance when trying to understand the type of cancers found in screening programs. To this end, it would be of great interest to conduct a study in which the features of incidentally detected PCa are compared with those of PCa found in a screening program. Such a study could be of help in further defining the criteria for clinically insignificant prostate cancer.

References

Montironi R, Mazzucchelli R, Santinelli A, et al. Incidentally detected prostate cancer in cystoprostatectomies: pathological and morphometric comparison with clinically detected cancer in totally embedded specimens. Hum Pathol. 2005;36:646-654.

Montironi R, Mazzucchelli R, Barbisan F, et al. HER2 expression and gene amplification in pT2a Gleason score 6 prostate cancer incidentally detected in cystoprostatectomies: comparison with clinically detected androgen-dependent and androgen-independent Cancer. Hum Pathol. 2006;37:1137-1144.

Santinelli A, Mazzucchelli R, Barbisan F, et al. á-Methylacyl coenzyme A racemase, Ki-67, and topoisomerase IIá in cystoprostatectomies with incidental prostate Cancer. Am J Clin Pathol. 2007;128:657-666.

Barbisan F, Mazzucchelli R, Santinelli A, et al. Overexpression of ELAV-like protein HuR is associated with increased COX-2 expression in atrophy, high-grade prostatic intraepithelial neoplasia, and incidental prostate cancer in cystoprostatectomies [published online ahead of print April 30, 2008]. Eur Urol.

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Breslow N, Chan CW, Dhom G, et al. Latent carcinoma of prostate at autopsy in seven areas. The International Agency for Research on Cancer, Lyon, France. Int Cancer. 1977;20:680-688.

Stamey TA, Freiha FS, McNeal JE, et al. Localized prostate cancer: relationship of tumor volume to clinical significance for treatment of prostate Cancer. Cancer. 1993;71:933-938.

Esgueva R, Lorente JA, Mojal S, et al. Incidental prostatic adenocarcinoma in radical cystoprostatectomy specimens: the impact of embedding protocols [abstract]. Mod Pathol. 2008; 21(suppl 1):155A.

Montironi R, Mazzucchelli R, van der Kwast T. Morphological assessment of radical prostatectomy specimens: a protocol with clinical relevance. Virchows Arch. 2003;442:211-217.

Sobin LH, Wittekind C. Urologic tumours: prostate. In: Sobin LH, Wittekind C; for the International Union Against Cancer (UICC), eds. TNM Classification of Malignant Tumours. 6th ed. New York, NY: Wiley-Liss; 2002:184-187.

Epstein JI, Allsbrook WC Jr, Amin MB, et al; ISUP Grading Committee. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005;29:1228-1242.

Lopez-Beltran A, Mikuz G, Luque RJ, et al. Current practice of Gleason grading of prostate carcinoma. Virchows Arch. 2006;448:111-118.

Scattoni V, Montironi R, Mazzucchelli R, et al. Pathological changes of high-grade prostatic intraepithelial neoplasia and prostate cancer after monotherapy with bicalutamide 150 mg. BJU Int. 2006;98:54-58.

Epstein JI, Walsh PC, Carmichael M, et al. Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate Cancer. JAMA. 1994;271:368-374.

Autorino R, Di Lorenzo G, Damiano R, et al. Pathology of the prostate in radical cystectomy specimens: a critical review [published online ahead of print August 28, 2008]. Surg Oncol. In press.

Damiano R, Di Lorenzo G, Cantiello F, et al. Clinicopathologic features of prostate adenocarcinoma incidentally discovered at the time of radical cystectomy: an evidence-based analysis. Eur Urol. 2007;52:648-657.

Cindolo L, Benincasa G, Autorino R, et al. Prevalence of silent prostatic adenocarcinoma in 165 patients undergone cystoprostatectomy: a retrospective study. Oncol Rep. 2001;8:269-271.

Conrad S, Hautmann SH, Henke RP, et al. Detection and characterization of early prostate cancer by six systematic biopsies and fine needle aspiration cytology in prostates from bladder cancer patients. Eur Urol. 2001;39(suppl 4):25-29.

Montie JE, Wood DP Jr, Pontes JE, et al. Adenocarcinoma of the prostate in cystoprostatectomy specimens removed for bladder Cancer. Cancer. 1989;63:381-385.

Revelo MP, Cookson MS, Chang SS, et al. Incidence and location of prostate and urothelial carcinoma in prostates from cystoprostatectomies: implications for possible apical sparing surgery. J Urol. 2004;171:646-651.

Yang CR, Ou YC, Ho HC, et al. Unsuspected prostate carcinoma and prostatic intraepithelial neoplasm in Taiwanese patients undergoing cystoprostatectomy. Mol Urol. 1999;3:33-39.

Ruffion A, Manel A, Massoud W, et al. Preservation of prostate during radical cystectomy: evaluation of prevalence of prostate cancer associated with bladder Cancer. Urology. 2005;65:703-707.

Abbas F, Hochberg D, Civantos F, et al. Incidental prostatic adenocarcinoma in patients undergoing radical cystoprostatectomy for bladder Cancer. Eur Urol. 1996;30:322-326.

Moutzouris G, Barbatis C, Plastiras D, et al. Incidence and histological findings of unsuspected prostatic adenocarcinoma in radical cystoprostatectomy for transitional cell carcinoma of the bladder. Scand J Urol Nephrol. 1999;33:27-30.

Lee SH, Chang PL, Chen SM, et al. Synchronous primary carcinomas of the bladder and prostate. Asian J Androl. 2006;8:357-359.

Hsing AW, Tsao L, Devesa SS. International trends and patterns of prostate cancer incidence and mortality. Int J Cancer. 2000;85:60-67.

Abdelhady M, Abusamra A, Pautler SE, et al. Clinically significant prostate cancer found incidentally in radical cystoprostatectomy specimens. BJU Int. 2007;99:326-329.

Aydin O, Cosar EF, Varinli S, et al. Prostatic intraepithelial neoplasia in prostate specimens: frequency, significance and relationship to the sampling of the specimen (a retrospective study of 121 cases). Int Urol Nephrol. 1999;31:687-697.

Delongchamps NB, Mao K, Theng H, et al. Outcome of patients with fortuitous prostate cancer after radical cystoprostatectomy for bladder Cancer. Eur Urol. 2005;48:946-950.

Hosseini SY, Danesh AK, Parvin M, et al. Incidental prostatic adenocarcinoma in patients with PSA less than 4 ng/mL undergoing radical cystoprostatectomy for bladder cancer in Iranian men. Int Braz J Urol. 2007;33:167-173.

Kabalin JN, McNeal JE, Price HM, et al. Unsuspected adenocarcinoma of the prostate in patients undergoing cystoprostatectomy for other causes: incidence, histology and morphometric observations. J Urol. 1989;141:1091-1094.

Kouriefs C, Fazili T, Masood S, et al. Incidentally detected prostate cancer in cystoprostatectomy specimens. Urol Int. 2005;75:213-216.

Prange W, Erbersdobler A, Hammerer P, et al. High-grade prostatic intraepithelial neoplasia in cystoprostatectomy specimens. Eur Urol. 2001;39(suppl 4):30-31.

Pritchett TR, Moreno J, Warner NE, et al. Unsuspected prostatic adenocarcinoma in patients who have undergone radical cystoprostatectomy for transitional cell carcinoma of the bladder. J Urol. 1988;139:1214-1216.

Rocco B, de Cobelli O, Leon ME, et al. Sensitivity and detection rate of a 12-core trans-perineal prostate biopsy: preliminary report. Eur Urol. 2006;49:827-833.

Ward JF, Bartsch G, Sebo TJ, et al. Pathologic characterization of prostate cancers with a very low serum prostate specific antigen (0-2 ng/mL) incidental to cystoprostatectomy: is PSA a useful indicator of clinical significance? Urol Oncol. 2004;22:40-47.

Weizer AZ, Shah RB, Lee CT, et al. Evaluation of the prostate peripheral zone/capsule in patients undergoing radical cystoprostatectomy: defining risk with prostate capsule sparing cystectomy. Urol Oncol. 2007;25:460-464.

Winfield HN, Reddy PK, Lange PH. Coexisting adenocarcinoma of prostate in patients undergoing cystoprostatectomy for bladder cancer. Urology. 1987;30:100-101.

Winkler MH, Livni N, Mannion EM, et al. Characteristics of incidental prostatic adenocarcinoma in contemporary radical cystoprostatectomy specimens. BJU Int. 2007;99:554-558.

Androulakakis PA, Schneider HM, Jacobi GH, et al. Coincident vesical transitional cell carcinoma and prostatic carcinoma: clinical features and treatment. Br J Urol. 1986;58:153-156.

Konski A, Rubin P, DiSantangnese PA, et al. Simultaneous presentation of adenocarcinoma of prostate and transitional cell carcinoma of bladder. Urology. 1991;37:202-206.

Authors and Disclosures

Roberta Mazzucchelli, MD, PhD;1 Francesca Barbisan, MD;1 Marina Scarpelli, MD;1 Antonio Lopez-Beltran, MD,PhD;2 Theodorus H. van der Kwast, MD, PhD;3 Liang Cheng, MD;4 Rodolfo Montironi, MD, FRCPath 1

1 Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy

2 Department of Pathology, Reina Sofia University Hospital and Faculty of Medicine, Cordoba, Spain

3 Department of Pathology and Laboratory Medicine, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Canada

4 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis

Reprint Address

Address reprint requests to Dr Montironi: Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Via Conca 71, I−60126 Torrette, Ancona, Italy.

American Journal of Clinical Pathology. 2009;131(2):279-283. © 2009 American Society for Clinical Pathology

multiples factores ligados a la NOCTURIA

rom Reuters Health Information

Multiple Factors Tied to Nocturia

NEW YORK (Reuters Health) (Updated Aug 24) - Although a number of conditions can be correlated with nocturia, none in particular seems to account for more than half of cases, Finnish researchers say.

"Nocturia," lead investigator Dr. Kari A. O. Tikkinen, of Helsinki University Central Hospital, told Reuters Health, "is a common but largely misunderstood urological condition in adults." He added that among men who have undergone prostatectomy or trans-urethral resection of the prostate, nocturia is the most persistent lower urinary tract symptom, and "many pharmacological approaches...can be ineffective or involve side-effects."

"Moreover," he said, "bedtime fluid intake patterns likely have little to do with the frequency of nocturia in most individuals."

Noting that nocturia can be associated "with impaired mental and somatic health, impaired quality of life, and even increased mortality," the research team reports in the August issue of the American Journal of Epidemiology on responses from more than 3300 men and women, ages 18 to 79, to questions about nocturia that were included on mailed questionnaires.

Younger age groups were "oversampled" to improve estimates in populations with lower frequencies of nocturia.

"Numerous risk factors for nocturia were identified," Dr. Tikkinen said. "For instance, overactive bladder, obesity, snoring and restless legs syndrome (were found) in both sexes, benign prostatic hyperplasia in men and overweight in women."

"However," he pointed out, "none of the identified risk factors was associated with nocturia in more than half of the affected subjects of both sexes, highlighting the multifactorial etiology."

"Health care providers," Dr. Tikkinen concluded, "should consider the lower urinary tract, but also beyond it, when treating bothersome nocturia."

Am J Epidemiol 2009;170:361-368.

Reuters Health Information © 2009

El hombre maduro(aging)

rom Geriatrics & Aging

Sexuality in the Aging Couple, Part II: The Aging Male

Irwin W. Kuzmarov, MD, FRCSC; Jerald Bain, BScPhm, MD, MSc, FRCPC

Published: 07/30/2009

Abstract

Sexual desire and activity continue well into later life, and advanced age alone is not a deterrent to a happy and healthy sex life; however, clinicians should be aware that the normal sexual response of men and women may change with aging. When sexual dysfunction occurs, studies show that men and women tend to view sexual dysfunction differently. Part I (which appeared in the November-December 2008 issue of Geriatrics & Aging) addressed sexual function and dysfunction with age in females. Part II of this two-part article series addresses sexuality and sexual dysfunction in aging men. For the emotional well-being of their patients, it is crucial that family doctors be aware of sexuality in the aging couple, and be able to evaluate and manage problems that may arise.

Introduction: Sexual Function and Dysfunction in Men

Evaluation of sexual responsiveness in older men and women has shown that sexuality and sexual activity continue well into later life, and that age-related changes do not necessarily prohibit sexual activity. While research has shown that sexual activity decreases with age, particularly among women, sexual activity in both men and women continues well into the senior years.^[1-4] For example, Marsiglio et al., showed that 24% of people over age 75 were having sexual relations more than twice per month.^[5]

Normal Sexual Response in Older Men

The normal male sexual response cycle is shown in Figure 1. There is a period of excitement followed by a plateau period, an orgasmic phase, a resolution, and a refractory period.^[6] As men age, there are many changes that occur in their sexual response. This is shown in Table 1 .

Table 1. Sexual Function Changes with Age

Figure 1. Sexual Response and Sexual Dysfunction in Males

In the previous article in this series, we discussed an emerging paradigm of women's sexual responsiveness that replaced a cycle of libido (desire)-arousal-orgasm-resolution with a model of intimate experience emphasizing that, while libido is maintained until quite late in the aging process, sexual arousal and response involve a sense of intimacy, bonding, commitment, love, affection, acceptance, etc., all of which may enter the sexual response equation, and result in pleasurable resolution, in which orgasm may or may not play a part. Similarly, with advancing age, some men may experience sexual response that is less orgasmically driven and more attached to a broader experience of intimacy.

While sexual desire and response continue into late life, there are numerous physical alterations that can affect sexual activity. With age, men experience a decrease in the number of spontaneous and morning erections. The rigidity of the erection diminishes, the force and volume of the ejaculate diminishes, and there is faster detumescence. The preejaculatory sensation also diminishes. These changes often lead to distress in men unless they can be made aware of the fact that they are the normal changes of aging.

Many of these changes can be related to or exacerbated by several causes other than normal aging. These include lifestyle factors as well as cardiovascular, psychosocial, and psychiatric causes such as depression, all of which are prevalent in the aging population. These changes can lead to erectile problems and the development of erectile dysfunction. Antihypertensive drugs represent the single largest medication group implicated in the development of sexual side effects, including difficulties in attaining orgasm for both women and men.^[7] Counselling of men as they age by their family physicians on the physiologic changes in their sexual performance, on the side effects that medications and other interventions may induce, and other intervening psychosocial factors may be helpful. This should be part of the annual visit, as well as part of the explanation given to men as medication or interventions are recommended and instituted.

Such counselling can start with simple information. Many men do not know what to expect as they age. Men may have less anxiety about the changes they are experiencing if they are made aware that they are normal and expected.

Sexual Dysfunction

Sexual dysfunction occurs when the normal pattern of sexual interaction between partners becomes interrupted and creates discontent in one or other of the partners or in the couple. In the female it is defined as any disorder related to sexual desire, arousal, orgasm, and/or sexual pain that results in significant personal distress and may impair the quality of life. Figure 2 shows the prevalence for male sexual dysfunction.^[8] Loss of libido, erectile dysfunction, and rapid ejaculation are the three most significant and prevalent sexual complaints in this population.

Figure 2. National Health and Social Life Survey: Prevalence of Male Sexual Dysfunction

Decrease in libido with age can be associated with various factors. These factors can relate to the psychosocial aspects of aging, which include the mental and physical status of both parties; the nature of their interpersonal relationship; marital conflicts and unresolved issues; and their overall lifestyles quality, including financial, social and, most important, communication issues.^[9]

Other psychosocial stresses seen in older men that correlate with sexual dysfunction include the "Widower's Syndrome," which men may experience with the resumption of sexual activities after a period of celibacy. When a man has had the same sexual partner for many years, particularly a partner with whom he has enjoyed a satisfying marital life in general, and the partner dies, he may enter a new relationship with some trepidation. The trepidation may be amplified by erectile dysfunction, which he might not have experienced with his late wife. This may, of course, be due to newly manifested organic factors but it may also be due to the powerful impact of his psyche related to unconscious guilt that he is betraying the fidelity and happiness he enjoyed with his wife. These and other factors require more intense sexual and/or psychological counselling.

Note that alcohol consumption, poor physical fitness, diet, and lifestyle as well as concomitant comorbidities can also exert a negative pressure on libido. The loss of libido can also be related to low testosterone levels, which may be remediable through supplementation with exogenous testosterone.

Testosterone Therapies

Studies have shown that total testosterone does not correlate with levels of sexuality but that there are correlations between bioavailable testosterone and sexual desire and arousal, and erectile dysfunction occurs when the testosterone level falls below certain thresholds.^[10-12]

It has been shown that testosterone levels decline with age; this progressive decline may begin as early as age 30.^[13]Testosterone deficiency symptoms can include a loss of libido, fatigue, progressive decrease in muscle mass, erectile dysfunction, depression, and lack of concentration, as well as an increased risk of osteoporosis.^[14] There is also evidence that testosterone can induce a response to phosphodiesterase type 5 inhibitors (PDE-5i's) in hypogonadal patients who have not responded to PDE-5 inhibitors prior to initiation of testosterone therapy. If there is evidence of hypogonadism, the addition of testosterone is indicated and may improve sexual interest. Recent evidence suggests that testosterone replacement among men with hypogonadism can provide significant sexual, physical, and psychological benefits.

Testosterone therapy is supplied in a variety of dosage forms, including oral, transdermal (gel or patch), and intramuscular preparations. With appropriate pretreatment investigations and regular assessments of efficacy, safety and treatment adherence, testosterone therapy can safely be used to improve the well-being of aging men experiencing symptoms of testosterone deficiency. It should be noted that there is emerging evidence for no increased risk of prostate cancer in men treated with testosterone therapy.^[15]

Erectile Dysfunction and PDE-5 Inhibitors

The incidence of erectile dysfunction (defined as the inability to develop and sustain an erection sufficient for satisfactory sexual intercourse in 50% or more attempts at intercourse) is well documented particularly in the Massachusetts Male Aging study, where greater than 50% of men had some degree of symptom.^[12] The relationship with diseases such as diabetes mellitus, cardiovascular disease, hypertension, neurological disorders, and psychiatric conditions such as depression, as well as medication, has been well described.

The introduction of PDE-5i's for erectile dysfunction has changed the profile of sexual functioning in aging men. The increasing use of PDE-5i's, the emerging understanding of the role of testosterone decline in men as they age, and the availability and use of adjunctive testosterone therapies have played a role in restoring men's sexual potency and libido.

The use of PDE-5 inhibitors has proven very effective in alleviating the physical effects of reduced erectile function in many men. This has generally been a constructive addition to the management of sexual dysfunction and relationship issues concerned with sexuality. It has, however, created consternation in some female partners who have interpreted the use of these agents as a sign of diminished interest in sex in general or with them specifically. The addition of a foreign agent, namely a drug to produce an erection, has been perceived as a sign that the partner is no longer attractive and is not desirable. The misperception is that the drug is preventing rather than promoting a healthy sexual relationship. For the first time, women who have never required their partners to be artificially stimulated to become erect are placed in this situation. The lack of understanding about the erectile response of their partner, and the role that medication or other devices play fuels this negative response. There are many couples who face this catch-22 situation in which the male partner's libido remains at a level satisfactory to him but who for largely organic reasons has erectile dysfunction remediable by a PDE-5i. In such a circumstance it would be useful to invite your male patient to return with his partner for a brief discussion about the causes of erectile dysfunction. In only a small minority of instances is the male's loss of libidinous interest in his wife the major cause of his ED. If this is the case he is usually aroused to erection by other stimuli.

The family physician, the urologist, the sex therapist, or the psychologist who deals with erectile problems in couples must explain the role and function of the erectile aids. The provision of PDE-5i's to aging patients necessitates a discussion of these factors.

Specific PDE-5 Inhibitors

Sildenafil (Viagra®), vardenafil (Levitra®), and tadalafil (Cialis®) are the three oral PDE-5i's currently approved for clinical use and have become the preferred first-line ED therapy for most men due to their efficacy, safety, and ease-of-use. Published clinical trial data suggest an efficacy of ~70% for all three PDE-5i's across a wide range of causes of ED and patient subgroups.^[16]

The arrival of PDE-5 inhibitors and the increased awareness of the need to evaluate potential hypogonadal states in this cohort of men has greatly improved the management of this problem, and has also increased awareness of the need by primary care physicians to evaluate both partners, individually and as an interactive unit. It is important that the primary care physician take initiative and discuss these matters with patients: patients themselves may avoid addressing issues of sexual dysfunction in a forthright matter, either asking about it at the end of a visit in passing, in connection with a separate matter, or not at all. If the physician fails to inquire, these concerns may go ignored.

Conclusion

Although the aging process is associated with many changes--both physiologic and psychosocial--in men and women, it in no way precludes continued sexual activity. Sexual relations in aging couples are an important source of gratification within the relationship. It is important for primary care physicians to discuss sexual issues in their annual visits. Be aware of the changes and the etiology and management of sexual dysfunction, and be aware of the resources available to patients.

The impact of publicity surrounding the PDE-5 inhibitors has brought sex into the public domain. It has allowed couples to seek help and begin to express their concerns. Many studies have shown the high incidence of sexual dysfunction in patients visiting their family physicians. It is essential that physicians be aware of the potential problems in couples of a sexual nature, and be prepared to allocate the time to approach the subject, and deal with the issues.^[17]

Sidebar: Key Points

Sidebar: Clinical Pearls

References

1. Pfeiffer E, Davis GC. Determinants of sexual behavior in middle age and old age. J Amer Geriatric Soc 1972;20:151-8.
2. AARP/Modern Maturity Sexuality Study. Washington, DC: National Family Opinion Research, 1999. Online at http://assets.aarp.org/rgcenter/health/mmsexsurvey.pdf.
3. Laumann EO, Nicolosi A, Glasser DB, et al. Sexual problems among women and men aged 40 to 80: prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors. Int J Impot Res 2005;17:39-57.
4. Bancroft JH. Sex and aging. New Engl J Med 2007;357:820-22.
5. Marsiglio W, Donnelly D. Sexual relations in later life: a national study of married persons. J Gerontol 1991;46:S344-8.
6. Masters WH, Johnson VE. Human Sexual Inadequacy. New York: Boston Little Brown, 1970.
7. Masters WH, Johnson VE, Kolodny R. Heterosexuality. New York: Harper Collins, 1994.
8. Laumann EO, Paik A, Rosen RD. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999;281:537-44.
9. Meston CM. Aging and sexuality. West J Med 1997;167:285-90.
10. Schiavi RC, Schreiner-Engel P, White D, et al. The relationship between pituitary-gonadal function and sexual behaviour in healthy aging men. Psychosom Med 1991 53:363-74.
11. Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Met 2006;91:4335-43.
12. Johannes CB, Araujo AB, Feldman HA, et al. Incidence of erectile dysfunction in men 40-69 years old: longitudinal results from the Massachusetts Male Aging Study. J Urol 2000;163:460-3.
13. Lunenfeld B, Gooren L, Editors. Textbook of Men's Health. Parthenon Publishing Group, 2002:148-50.
14. Ostatnikovà D, Celec P. Testosterone: an overview; insights into its physiology and clinical implications. Int J Endocrinol Metab 2003;2:84-96.
15. Morgentaler A. Testosterone and prostate cancer: an historical perspective on a modern myth. Eur Urol 2006;50:935-9.
16. Lue TF, Giuliano F, Montorsi F, et al. Summary of the recommendations on sexual dysfunctions in men. J Sex Med 2004;1:6-23.
17. Nazareth I, Boynton P, King M. Problems with sexual function in people attending London general practitioners: cross sectional study. BMJ 2003;327:423.

Authors and Disclosures

Irwin W. Kuzmarov, MD, FRCSC,¹ Jerald Bain, BScPhm, MD, MSc, FRCPC <sup>2

1</sup>Department of Surgery (Urology), McGill University; Director of Professional and Hospital Services, Santa Cabrini Hospital, Montreal, QC; Past President, Canadian Society for the Study of the Aging Male
²Department of Medicine, Division of Endocrinology and Metabolism, Mount Sinai Hospital; University of Toronto, Toronto, ON; Past President, Canadian Society for the Study of the Aging Male

Disclosure: Dr. Kuzmarov has been a speaker for many companies that manufacture and/or market testosterone products, medication for erectile dysfunction, and for benign and malignant prostatic disease. Dr. Bain has given lectures at CME events sponsored by Organon Canada and Solvay Pharma,and has served on Solvay Pharma Advisory Board.

Geriatrics and Aging. 2009;12(1):53-57. © 2009 1453987 Ontario, Ltd.

testosterona,pde5,

La terapia hormonal,puede aumentar el riego de morir en los hombres con Cáncer de prostata y Enfermedad cardiaca

From Medscape Medical News

Hormone Therapy May Increase Risk for Death in Men With Prostate Cancer and Heart Disease

Nick Mulcahy

Authors and Disclosures

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August 26, 2009 – In localized or locally advanced prostate cancer, the use of neoadjuvant hormone therapy was associated with a nearly 2-fold risk for death in men who also had a history of coronary artery disease.

This finding comes from a retrospective study of 5077 men who were treated with brachytherapy for their cancer, 30% of whom received neoadjuvant hormone therapy for a median treatment duration of 4 months.

The hormone therapy consisted of both a luteinizing hormone-releasing hormone agonist (leuprolide or goserelin) and a nonsteroidal antiandrogen (bicalutamide or flutamide).

On the bright side of the data, there was no increase in all-cause mortality among men treated with hormone therapy who had either no cardiovascular comorbidity or a single coronary artery disease risk factor, such as diabetes mellitus, hypercholesteremia, or hypertension. Smoking and a family history of heart disease were not evaluated as risk factors.

The study was published in the August 26 issue of the Journal of the American Medical Association.

In an interview with Medscape Oncology, the study's lead author stressed that only 5% of the men in the study — a "small subgroup" — had coronary artery disease (congestive heart failure or past heart attack).

"Our results suggest that for these men, either hormonal therapy not be used in the treatment of their prostate cancer or their underlying heart disease be addressed by a primary-care physician and/or a cardiologist before they are considered for hormonal therapy," said Akash Nanda, MD, PhD, from Brigham and Women's Hospital and the Dana-Farber Cancer Institute in Boston, Massachusetts.

This study should heighten awareness about the potential for harm with neoadjuvant hormone therapy in select men.

Dr. Nanda acknowledged that it is not known if treatment for heart disease would improve outcome. "The study does not address whether or not treatment for coronary artery disease potentially changes the risk for these patients," he said.

Dr. Nanda and his coauthors concluded that "this study should heighten awareness about the potential for harm with neoadjuvant hormone therapy in select men."

Study Details

Several clinical trials have shown that adding hormonal therapy to radiation therapy in the treatment of aggressive prostate cancer leads to an increase in survival, observed Dr. Nanda. However, a recent analysis (JAMA. 2008:299:289-295) indicated that "this may not be the case for men with coexisting illnesses," according to Dr. Nanda. The purpose of the new study was to identify comorbidities that might affect survival.

To that end, the investigators looked at 5077 men with clinical stage T1 to T3 N0 M0 prostate cancer treated between 1997 and 2006 at the Chicago Prostate Cancer Center, a community practice in Westmont, Illinois. Men were referred to this center on the basis of their interest in or candidacy for brachytherapy.

Among the men, 2653 (52.3%) had no history of a cardiovascular comorbidity, 2168 (42.7%) had a coronary artery disease risk factor, and 256 (5%) had coronary artery disease. The median age of the men was 69.5 years, and 557 (10.9%) had received supplemental external-beam radiation.

Most of the men in the study (70%) did not receive neoadjuvant hormone therapy and served as comparators for the men who did.

Neoadjuvant hormone therapy use was not significantly associated with an increased risk for all-cause mortality in men with no comorbidity (9.6% vs 6.7%; adjusted hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.72 - 1.32; P = .86) or a single coronary artery disease risk factor (10.7% vs 7.0%; adjusted HR, 1.04; 95% CI, 0.75 - 1.43; P = .82) after median follow-ups of 5.0 and 4.4 years, respectively.

However, for men with coronary artery disease, the therapy was significantly associated with an increased risk for all-cause mortality (26.3% vs 11.2%; adjusted HR, 1.96; 95% CI, 1.04 - 3.71; P = .04). These men had a median follow-up of 5.1 years.

In arriving at these findings, the investigators adjusted for age, treatment year, supplemental external-beam radiation therapy, treatment propensity score, and known prostate cancer prognostic factors (such as Gleason score).

The authors also noted that, in other research in different settings, hormone therapy has been associated with a variety of adverse effects, including increased risk for cardiovascular death.

More on Clinical Significance

Dr. Nanda and his colleagues recommend that, in men with favorable-risk prostate cancer and a history of coronary artery disease, alternative strategies to brachytherapy and hormone therapy be considered. These include active surveillance, treatment with external-beam radiation alone, and prostatectomy. In such men, hormone therapy is not really needed to "maximize outcome" anyway, explained Dr. Nanda. Instead, hormone therapy is used to reduce the size of the gland, ensuring that brachytherapy is not obstructed by the arch of the pubic bone.

Hormone therapy is needed to maximize outcome.

However, in men with unfavorable-risk prostate cancer, hormone therapy offers a survival benefit. "This is a tougher decision because hormone therapy is needed to maximize outcome," said Dr. Nanda. The risks and benefits of hormone therapy must be balanced; as noted above, appropriate medical evaluation or treatment is needed before hormone therapy is used in this setting, Dr. Nanda said.

Dr. Nanda also pointed out that the findings were limited to brachytherapy and, as a result, not necessarily generalizable to men with prostate cancer who are treated with external-beam radiation. "Other investigators will want to validate these findings in other settings," he said.

The authors also note that the duration and extent of hormone therapy are variables in need of study. "Men with locally advanced prostate cancer are frequently treated with 2 to 3 years of hormone therapy in combination with external-beam radiation therapy," they write.

The researchers have disclosed no relevant financial relationships.

JAMA. 2009;302:866-873.