PSA Screening for Men in their 40's: Message from the Brady

PSA screening for prostate cancer has been one of the most controversial issues in medicine, medical literature and the lay press over the past few years.  Arguably the most controversial aspects of the recent AUA (American Urological Association) Guideline on "Early Detection of Prostate Cancer" is

Guideline Statement 2:  The Panel does not recommend routine screening in men between ages 40 to 54 years at average risk. (Recommendation; Evidence Strength Grade C).

Here we review review the data regarding PSA screening in men aged 40-54.  Drs. H. Ballentine Carter, Bruce Trock, and Ashley E. Ross provide their expert interpretation of these data and comment on the AUA Guidelines.

Data Regarding PSA Screening in Men Aged 40-55

• There are no randomized, controlled studies (Level 1 Evidence) of PSA screening of men in their 40's.
• Baseline testing at 40-years of age can identify men at increased risk of developing prostate cancer.[1]   
• 44% of prostate cancer deaths occur in men age 45-55 years with a PSA in the top 10th percentile.[2]
• In the Malmo study, a single baseline PSA level in 21,277 men (age 27-52 between 1974-1984) was correlated to metastatic disease and prostate-cancer death over 25 year follow-up.[2]
• In over 4,500 men followed for 20 years at Duke Medical Center, 0.6% of men with a PSA <4ng/mL died of prostate cancer whereas 5.9% of men with a PSA >4ng/mL died of prostate cancer.[3]
• 98% of all prostate cancer deaths occur after age 54, 91% after age 70 years.
• PSA Velocity (PSAV) from age 40-55 can identify men at high-risk for aggressive prostate cancer.
• If PSAV exceeds 0.4ng/mL/year in two or more consecutive years, men had a 50% increased risk of aggressive prostate cancer.[4]
• In a screening study, a PSAV "risk count" (the number of times PSAV exceeded 0.4ng/mL/year) >2 corresponded to a five-fold risk of Gleason 8-10 disease.[5]
• PSAV is associated with prostate-cancer specific mortality after surgery.[6,7]
• Randomized trials and epidemiological evidence indicate that early diagnosis and treatment of aggressive prostate cancer improves prostate cancer survival.[8-10]
• Younger men are more likely than older men to have low-grade cancer with a longer lead time.[11]

Professional Organization in Favor of Baseline PSA Screening of Men in their 40's

• The National Comprehensive Cancer Network (NCCN)
• European Association of Urology 2013 Guidelines
• Melbourne Consensus Statement on Prostate Cancer Testing

Professional Organizations Against or Not in Favor of Routine Baseline PSA Screening of Men in their 40's

• The United States Preventive Services Task Force (USPTF) 
• American Urological Association (AUA)

Expert Commentary:

H. Ballentine Carter

H. Ballentine Carter, MD

Professor of Urology and Oncology

Director, Division of Adult Urology

Chair, AUA Early Detection of Prostate Cancer Panel

"Screening for prostate cancer using prostate specific antigen (PSA) is a form of prevention among asymptomatic men. PSA based screening has been shown to reduce prostate cancer deaths among men age 55-69 years, but not among men outside this age range that were part of a randomized screening trial. The American Urological Association panel that developed a Prostate Cancer Detection Guideline concluded that as a routine, screening was not recommended in average risk, asymptomatic men age 40-54 years. To do so would be to assume that benefits would outweigh harms and there is no data to support this assumption. The Malmo study demonstrates that to detect 70% of those cancers that become lethal would require PSA testing of half of the men below age 50 years. There is no evidence that this would reduce prostate cancer mortality, but plenty of evidence to suggest that over diagnosis and over treatment would occur with the associated side effects of treatment. Younger men are more likely, when compared to older men, to harbor the low-grade cancers for which treatment has been shown to provide the least benefit, and would live with any side effects of treatment for a longer period."

"There is no evidence that this would reduce prostate cancer mortality, but plenty of evidence to suggest that over diagnosis and over treatment would occur with the associated side effects of treatment."

Bruce J. Trock

Bruce J. Trock, Ph.D.

Professor of Urology, Epidemiology, Oncology, Environmental Health

Director, Division of Epidemiology

"Routine screening in men aged 40-54:  is the glass half-full or just twice as big as it needs to be?

Lets start by considering a few things that, hopefully, are beyond dispute:

1.  Men with PSA above the median at a baseline screen below age 55 have increased lifetime risk of prostate cancer and prostate cancer mortality compared to men with PSA below the median.
2.  PSA screening explains a portion of the decrease in U.S. prostate cancer mortality since the early 1990’s.
3.  PSA screening leads to over-diagnosis and over-treatment.

That was easy.

Now let’s consider the choice between engaging in some form of screening at ages 40-54 vs. beginning screening around age 55.  Who would be screened and how often if beginning at ages 40-54?  We often hear of “baseline” screening to segregate men into those with PSA below vs. above the age-specific median, with the latter being at significantly increased risk.  But what happens after baseline?

For men below age 55 most data relevant to PSA screening comes from large prospective cohorts where PSA was measured at baseline and men were followed for cancer outcomes.  Given the attention focused on the age to start screening it is surprising that there is so little data with detailed distributions of PSA by age group and associated prostate cancer outcomes from these cohorts.  Some of the most informative data come from the group that has evaluated PSA and prostate cancer outcomes in the cohort of men from the Malmo Preventive Project.  21,277 men aged 33-50 provided baseline blood samples for a study of cardiovascular disease; the samples were subsequently tested retrospectively for PSA and correlated to cancer outcomes.  Because this cohort represented 74% of the men in this age group in Malmo, the study is essentially a population study.  Active PSA screening was minimal in this population.

A case-control study nested in the Malmo cohort suggests that men with baseline PSA <1.0 ng/ml (median PSA at age 60) may require only 3 lifetime PSA tests – at age mid-to-late 40’s, early 50’s, and age 60, while those >1 ng/ml should repeat testing at intervals of 2-4 years, based on the literature.[2]  This sounds reasonable at first, after all, data from the same case-control study show that only 0.2% of men with PSA<1.0 at age 60 will die from prostate cancer by age 85.[12]

But how much is gained by beginning PSA testing in the 40’s vs. waiting until age 55?  In the same case-control study, the highest quartile of PSA in men 45-49 is >1.06 ng/ml, virtually identical to the cut-point above.  So the scheme proposed above would mean that 25% of men would undergo biennial or quadrennial screening beginning in their mid 40s, while 75% of men would not need to be screened until early 50s.  What happens if the 25% of men with PSA above the cut-point at age 45-49 wait until the early 50s to be screened?

Based on the data from the same Malmo cohort, [2] men in the upper PSA quartile at age 45-49 had a 2.7% risk of prostate cancer death within 25 years, that is by the early 70s.  If we assume that most of the men in the upper quartile at age 45-49 will also be in the upper quartile of PSA (>1.40 ng/ml) at ages 51-55*, their risk of prostate cancer death was 3.0% by the early 70s (within 20 years).  Thus, waiting to begin screening until the early 50s results in an increase in the risk of death of only 0.3% by the early 70s.  This is actually an upper limit on the increase in deaths because it is based on death rates in an unscreened population; if active screening were occurring some of the men in the upper quartile would be treated while still curable and death prevented.  It is likely that few men would progress from curable to incurable cancer by age 51-55, since the median time from baseline blood draw to cancer diagnosis was 18 years,[13] and 94% of advanced cancer cases were diagnosed after age 60.[14]  Another way to look at the deaths avoided is by analogy to number needed to treat, in this case number of men needed to evaluate at ages 45-49 to avoid one prostate cancer death that would occur if waiting until 51-55 = 100/0.3 = 333.

From this it seems clear that proposals to conduct a baseline screen in the early 40s, followed by targeted screening of those men with PSA above a cut-point will result in only a small decrease in the absolute risk of prostate cancer death, compared to beginning screening for all men in the early 50s.

Finally, we need to consider that interpretation of the guidelines depends on whether we are addressing the perspective of an individual man aged 40-54 facing the decision to screen, the physician who is talking to that man, or the public health scientist who is considering the impact of population screening for men 40-54.  From the perspective of the individual man the absolute probabilities may have little impact.  Individuals tend to think that outcomes will be either good or bad, which is closer to reality, i.e. an individual will either not die of prostate cancer (0% probability) or he will (100% probability).  So other factors may have greater weight (friends or relatives with prostate cancer, perceived harms of treatment).  In this regard the guidelines state “we are not explicitly stating that screening should be actively discouraged in this group of men.”[15]  The physician’s perspective (this is a personal view since the author is not a physician) is to balance risk of prostate cancer morbidity or death vs. harms of over diagnosis and over treatment.  So the physician tries to find common ground between the probabilistic risk information and the patient’s wishes and concerns.  This perspective is included in the guidelines:  “recommendation against routine screening in men aged 40-54 years is not a recommendation against screening per se, but a benefit to harm assessment of beginning screening before the age of 55 years vs initiating at the age of 55 years for those who wish to be screened.” [16]  Finally, the public health scientist, perhaps an epidemiologist, will focus primarily on the population probabilities of benefit vs. harm, which favor beginning screening in the early 50s, in accord with the guidelines statement:  “Routine screening in men aged 40-54 years at average risk is not recommended.”[15]"

_________________________________________________

* This seems reasonable since the highest quartile and highest 10% of PSA at age 45-49 capture 54% and 44%, respectively, of prostate cancer deaths, while the highest quartile and highest 10% of PSA at age 51-55 capture 59% and 44%, respectively.[2]
 

"Thus, waiting to begin screening until the early 50s results in an increase in the risk of death of only 0.3% by the early 70s. Another way to look at the deaths avoided is by analogy to number needed to treat, in this case number of men needed to evaluate at ages 45-49 to avoid one prostate cancer death that would occur if waiting until 51-55 = 100/0.3 = 333."

Ashley E. Ross

Ashley E. Ross, MD, PhD
Assistant Professor, Departments of Urology, Oncology and Pathology

"The new AUA guidelines aim to maximize the benefits of screening while reducing harms by targeting a select population of men where the incidence of clinically significant prostate cancer is relatively high and for whom level one clinical data exists.  As pointed out, perhaps the most controversial part of the guidelines was the somewhat radical change from recommendations to begin shared decision making regarding routine screening at 40 to now beginning this at 55 for those who are not at increased risk.

The AUA identifies African Americans and those with family history of prostate cancer as being of increased risk and as men in whom individualized decision making regarding screening during the ages of 40 and 55 can be considered, but what of the men who do not meet these criteria?  As a population yes, the majority of them who will develop clinically significant prostate cancer may be identified at curable stages of disease after age 55, That said, while the practice of medicine should be evidence based we should also treat our patients as individuals and it may not be sound to only use race and family history as the determinants of risk.  The guideline authors are correct, it is hard as a urologist to separate yourself from anecdotal experiences, particularly as we are not on the front lines of PSA screening and suffer from "denominator neglect."  Not to feed into that, but in defense of my bias for not lumping all the "average risk" men together and not screening them, there are a lot of anecdotes.     For instance, I looked back at our radical prostatectomy dataset of over 20,0000 men diagnosed in the PSA screening era which contained over 5,500 men who were under 55 years old at diagnosis of which about 3,800 were of "average risk" men.  For these average risk men men 37% were diagnosed with NCCN intermediate or high risk disease and at prostatectomy over 30% had Gleason 7 or above prostate cancer and about 30% had non-organ confined disease (all characteristics of cancer very likely to harm these young men in their lifetime).  Of note, among the NCCN intermediate or high risk men, only 7.3% and 4.6% respectively had PSA of less than 3 at diagnosis.  I find it hard to not want to diagnose these men.
This brings up the concept of a baseline prostate cancer risk assessment among those of "average risk" to then guide screening.  I think that over the next several years, structured on discoveries like those of Dr. Isaacs and others of genetic influences of prostate cancer (such as HoxB13 mutations) and as we find superior molecular markers for the disease (or propensity to develop it) we will see the increased availability of "Prostate Cancer Risk Tests" and these tests might help inform us on who may need screening.  Certainly if there was a test that told a young "average risk" man that he was at as high risk or more of having significant prostate cancer as say an African American man, and we think screening in African Americans makes sense then we logically would consider screening that previously average risk man, right?  In that regard, while we wait for the better tests on the horizon would it be helpful to use PSA to determine risk?  What was brought up in our discussion is that the data on using PSA for baseline risk assessment are flawed and hazy in both pro and con directions.  In addition, after 5 years a previous baseline PSA may not be meaningful and a new baseline may be needed.  Suddenly PSA based "risk assessment" seems very much like PSA screening.  And perhaps, until a better risk assessment tool is developed that is what we should do for younger men.  PSA screening but at wide intervals (every 4-5 years) with strict thresholds for action (i.e. PSA >3 for discussion of biopsy).  The argument can be made that we don't have enough self control to do this kind of long interval screening, but I think that perspectives towards cancer screening have evolved substantially among providers and patients alike in a very short time frame and will evolve more as health care and the structure of compensation changes.  I also believe we will become more comfortable screening younger men as better screening tests are developed (even incrementally better ones)."

"For these average risk men men 37% were diagnosed with NCCN intermediate or high risk disease and at prostatectomy over 30% had Gleason 7 or above prostate cancer and about 30% had non-organ confined disease (all characteristics of cancer very likely to harm these young men in their lifetime)...  I find it hard to not want to diagnose these men."

Additional reading on the PSA Screening Controversy for Men Aged 40-55

Judd W. Moul et al.  Re: Early Detection of Prostate Cancer: AUA guideline: H. B. Carter, et al.  J Urol 2013; 190: 419–426, The Journal of Urology, Volume 190, Issue 3, September 2013, Pages 1134-1139, ISSN 0022-5347, http://dx.doi.org/10.1016/j.juro.2013.07.002.

(http://www.sciencedirect.com/science/article/pii/S002253471304857X)

Catalona WJ and Carter HB.   Pro/ Con: Baseline PSA Testing for Men in Their 40s: Currently Available Evidence Strongly Supports Baseline PSA Measurements in This Age Group.  ONCOLOGY ( Feb 2014), pp 82-84.  http://www.cancernetwork.com/prostate-cancer

[1] Loeb S, Carter HB, Catalona WJ, Moul JW, Schroder FH.  Baseline prostate-specific antigen testing at a young age. Eur Urol. 2012 Jan;61(1):1-7. doi: 10.1016/j.eururo.2011.07.067. Epub 2011 Aug 10.

[2] Vickers AJ, Ulmert D, Sjoberg DD, et al. Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40-55 and long term risk of metastasis: case-control study. BMJ. 2013;346:f2023. doi: 10.1136/bmj.f2023.

[3]  Tang P1, Sun L, Uhlman MA, Polascik TJ, Freedland SJ, Moul JW.  Baseline PSA as a predictor of prostate cancer-specific mortality over the past 2 decades: Duke University experience.Cancer. 2010 Oct 15;116(20):4711-7. doi: 10.1002/cncr.25447.

[4] Carter HB, Kettermann A, Ferrucci L, Landis P, Metter EJ. Prostate-specific antigen velocity risk count assessment: a new concept for detection of life-threatening prostate cancer during window of curability. Urology 2007; 70: 685–90

[5] Loeb S, Metter EJ, Kan D, Roehl KA, Catalona WJ. Prostate-specific antigen velocity (PSAV) risk count improves the specificity of screening for clinically significant prostate cancer. BJU Int. 2012 Feb;109(4):508-13; discussion 513-4. doi: 10.1111/j.1464-410X.2011.10900.x. Epub 2012 Feb 1.

[6] D'Amico AV, Chen MH, Roehl KA, Catalona WJ. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 2004; 351: 125–35. 

[7] D'Amico AV, Renshaw AA, Sussman B, Chen MH. Pretreatment PSA velocity and risk of death from prostate cancer following external beam radiation therapy. JAMA 2005; 294: 440–7.

[8] Surveillance, Epidemiology and End Results. Fast stats. Available from: http://seer.cancer.gov/faststats/selections.php?#Output. Accessed May 19, 2013. 

[9] Schröder FH, Hugosson J, Roobol MJ, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med. 2012;366:981-90.

[10] Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 2010;11:725-32.

[11] Draisma G, Boer R, Otto SJ, et al. Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst. 2003;95:868-78.
[12] Vickers AJ, Cronin AM, Bjork T, et al.  Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer:  case-control study.  BMJ 2010; 341:c4521.
[13] Lilja H, Ulmert D, Bjork T, et al.  Long-term prediction of prostate cancer up to 25 years before diagnosis of prostate cancer using prostate kallikreins measured at age 44 to 50 years.  J Clin Oncol 2007; 25:431-6.
[14] Lilja H, Cronin AM, Dahlin A, et al.  Prediction of significant prostate cancer diagnosed 20 to 30 years later with single measure of prostate-specific antigen at or before age 50.  Cancer 2011; 117:1210-19.
[15] Carter HB, Albertsen PC, Barry MJ, et al.  Early dection of prostate cancer:  AUA guideline.  J Urol 2013; 190:419-426.
[16] Carter HB.  American Urological Association (AUA) guideline on prostate cancer detection:  process and rationale.  BJU Int 2013; 112:543-7.

Can your water bottle cause prostate cancer?

Bisphenol A, otherwise known as BPA, is a common chemical used to make hard plastics and epoxy resins.  It is commonly found in many household items including water bottles, cans and paper products like receipts.  BPA was initially synthesized as a synthetic estrogen, but has been used in manufacturing due to its strong chemical cross-linking abilities.  Estrogen exposure has been related to prostate carcinogenesis in rat models [1] and an increased risk of prostate cancer in men.[2]

A recent study in PLOS (Public Library of Science) One looked at the urine of 60 urology patients and found higher levels of BPA in the urine of prostate cancer patients when compared to non-prostate cancer patients.  Interestingly, they found this difference to be even more pronounced in men less than 65 years in age, indicating that early, lifelong exposure may lead to an increased rate of prostate cancer.  In addition, by looking at prostate cancer cell lines in vitro, the authors also found that even low levels of BPA could disrupt cell duplication cycle and lead to prostate cancer development.[3]

Tarapore et al. PLOS One. [3]

Another study, from researchers at the University of Cincinatti, demonstrated that exposing neonatal mice to estrogens or BPA created epigenetic changes in the DNA of prostate genes.  These epigenetic changes to methyl groups that bind to DNA constitutively turn on genes that lead to prostate cell growth and make prostate cancers more likely.[4]

In summation, these studies indicate that long-term, low-level exposure to BPA may make subtle changes to the DNA of prostate cells that make the progression to cancer more likely.

So does BPA cause prostate cancer?

While these studies (and others like them) are very provocative, they are merely studies of association.  They demonstrate some strong relationships between BPA and the development of prostate cancer, however, they do not demontrate that BPA causes prostate cancer.  There are many factors both genetic and from the environment that may cause prostate cancer, and BPA may play a role in the multifactorial development of cancer, but is not the primary cause of prostate cancer.

Your water bottles are safe... for now!



[1] Leav I, Ho S, Ofner P, Merk F, Kwan P, Damassa D. Biochemical alterations in sex hormone-induced hyperplasia and dysplasia of the dorsolateral prostates of Noble rats. J Natl Cancer Inst. 1988;80:1045–1053.
[2] Modugno F, Weissfeld JL, Trump DL, et al. Allelic variants of aromatase and androgen and estrogen receptors: toward a multigenic model of prostate cancer risk. Clin Cancer Res. 2001;7:3092–3096. 
[3] Tarapore P, Ying J, Ouyang B, Burke B, Bracken B, et al. (2014) Exposure to Bisphenol A Correlates with Early-Onset Prostate Cancer and Promotes Centrosome Amplification and Anchorage-Independent Growth In Vitro. PLoS ONE 9(3): e90332. doi:10.1371/journal.pone.0090332
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0090332
[4] Shuk-Mei Ho,1 Wan-Yee Tang,1 Jessica Belmonte de Frausto,2 and Gail S. Prins2.  Developmental Exposure to Estradiol and Bisphenol A Increases Susceptibility to Prostate Carcinogenesis and Epigenetically Regulates Phosphodiesterase Type 4 Variant 4. Cancer Res. Jun 1, 2006; 66(11): 5624–5632.  http://europepmc.org/articles/PMC2276876/reload=0;jsessionid=BkHVzQU6aLDs2MNLk4KD.12

BCG Complications for Bladder Cancer: Who, What, When and How to Treat?

Bacillus Calmette-Guérin (BCG) immunotherapy currently remains the most effective treatment for intermediate and high risk non-muscle-invasive bladder cancer, but has side effects that range from bothersome to life-threatening. To learn more about BCG treatment, please see our prior blog on the "Success Rates for Intravesical BCG Treatments for Bladder Cancer."

Here we review the common BCG side effects, the prevention and treatment of these effects.

Common BCG Side Effects:

• Mild Urinary Symptoms (5-90%) [1,2]
• Frequency
• Dysuria
• Hematuria (1-34%) [2]
• Malaise (Fatigue)
• Fever (3-17%) [3-5]

BCG works through a local immune response, therefore some side effects and indicative of BCG effectiveness.  In fact, fever has been reported to correlate with a reduction in the risk of recurrence; however, many patients have no symptoms from BCG and remain tumor free.

Patients should be instructed to expect mild urinary frequency and dysuria beginning after the second or third instillation. These symptoms should last only a few days and should not be disabling. Mild malaise, fatigue, and “flu-like” symptoms similar to those following a vaccination are seen less frequently, likely a consequence of immune stimulation and not generally of concern.

Unexpected or severe symptoms are often associated with increasing symptoms with successive instillations.

How to treat mild symptoms & side effects:

• Treatment for mild symptoms can include:
• phenazopyridine hydrochloride
• acetaminophen 
• nonsteroidal anti-inflammatory drugs
• If the side effects are tolerable (not increasing and not requiring medication), simply postponing treatment until all symptoms have resolved is the most appropriate approach. 
• While 6 weekly instillations are the optimal induction course for BCG, this is an arbitrary schedule that does not necessarily fit everyone. 
• Consider dose reduction.
• The recommended logarithmic reduction to 1/3, 1/10, 1/30 and 1/100th dose, for decades has shown that most symptoms can be managed with no observable reduction in efficacy. [6,7]
• Consider prophylactic antibiotics.
• Standard dose BCG plus ofloxacin 200 milligrams (mg) at 6 hours post instillation and the following morning has been demonstrated to have a significant reduction in local side effects with no reduction in efficacy. [8]
• Isoniazid prophylaxis did not reduce the side effects of BCG in a large EORTC study. [9] 

How to treat moderate symptoms or BCG cystitis:

Moderate symptoms are often characterized by prolonged malaise, loss of appetite, night sweats and low grade fever which suggest a systemic infection. BCG cystitis is characterized by persistent severe frequency, urgency and dysuria, characteristic of BCG cystitis. The response to fluoroquinolones often occurs more promptly than the response to other types of antibiotics but should not be given for significant BCG infection as a single antibiotic.

• A two-drug combination is generally sufficient for milder reactions treated early. 
• Fluoroquinolone 
• ofloxacin (200 to 400 mg every 12 hours)
• ciprofloxacin (500 mg every 12 hours) 
• levofloxacin (500 mg every 24 hours) 
• Isoniazid 300 mg daily
• For more intense or prolonged symptoms, a three drug combination is needed:
• Rifampin 600 mg daily and/or 
• Ethambutol 1200 mg daily 
• Monthly eye examinations are recommended to optic neuritis (6%). [10]
• Treatment is recommended for 3 to 6 months and symptoms may not even begin to improve for months after initiation of appropriate antibiotic therapy. 
• Prednisone (30-60 mg daily, gradual taper) may be used in addition to antimicrobials if symptoms are unresponsive and intolerable.
• Bladder contracture can occur is the rare circumstance that frequency and dysuria are not treated effectively.  

How to treat severe BCG-related symptoms and BCG-sepsis:

BCG sepsis is a rare complication (0.4%) [2] and is defined by high-fever and chills following BCG instillation.  The treatment of BCG sepsis includes:

• Prompt hospital admission 
• Broad-spectrum antibiotic coverage (triple antitubercular antibiotics)

Even with appropriate antibiotic treatment, hypotension followed by multisystem organ failure can occur. Due to an overwhelming immune response, steroid administration to suppress this immune hypersensitivity response (methylprednisolone 60-100 mg or more IV daily) can be life-saving. 

Patients with severe BCG reactions should not receive BCG in the future.Primates injected with one gram of BCG intravenously uniformly survive the infection, but a second intravenous injection in primates (like a second intraperitoneal BCG injection in rodents) is universally fatal.

How to treat patients who cannot tolerate BCG treatments:

Many patients would benefit from intravesical treatments but are unable to receive BCG due to side effects.  Options include dose-reduction and/or shortened course BCG treatments, radiation therapy,[11], heat-killed BCG [12] or other, novel BCG agents.  This will be the subject of a future blog.

Nilay M. Gandhi, MD

This entry was written by Nilay M. Gandhi, MD, senior assistant resident at the Brady Urological Institute at Johns Hopkins.  

Some of the data is extracted from the chapter Presentation and Management of Significant Side Effects from Bacillus Calmette-Guérin Bladder Instillation by Nilay M. Gandhi and Donald L. Lamm, which will appear in newest edition of The Textbook of Bladder Cancer.

[1] J.M. Molina, C. Rabian, M.F. D’Agay, J. Modai.  Hypersensitivity systemic reaction following intravesical bacillus Calmette-Guerin: successful treatment with steroids. J Urol, 147 (1992), p. 695
[2] D.L. Lamm, A.P.M. van der Meijden, A. Morales, S.A. Brosman, W.J. Catalona, H.W. Herr et al. Incidence and treatment of complications of bacillus Calmette-Guérin intravesical therapy in superficial bladder cancer.  J Urol, 147 (1992), p. 596
[3] P. Bassi, P. Nicola, R. Spinadin, R. Carando, F. Pagano, G.L. Papagallo. Low dose vs standard dose BCG therapy of superficial bladder cancer: final results of a phase 3 randomized trial. Eur Urol, 35 (1999), p. 152 suppl. abstract 
[4] J.A. Martínez-Piñeiro, J. Jiménez León, L. Martínez-Piñeiro Jr., L. Fiter, J.A. Mosteiro, J. Novarro et al.  Bacillus Calmette-Guerin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol, 143 (1990), p. 502
[5] P.D. Vegt, A.P.M. van der Meijden, R. Sylvester, M. Brausi, W. Holtl, C. de Balincourt. Does isoniazid reduce side effects of intravesical bacillus Calmette-Guerin therapy in superficial bladder cancer? Interim results of the European Organization for Research and Treatment of Cancer protocol 30911. J Urol, 157 (1997), p. 1246
[6] J.A. Martinez-Pineiro, N. Flores, S. Isorna, E. Solsona, J.L. Sebastian, C. Pertusa et al.
Long-term follow-up of a randomized prospective trial comparing a standard 81 mg dose of intravesical bacilli Calmette-Guerin with a reduced dose of 27 mg in superficial bladder cancer
BJU Int, 89 (2002), p. 671
[7] P. Rivera, M. Orio, J. Hinostroza, P. Venegas, P. Pastor, M. Gorena et al.
Nuestra experiencia con instilaciones de 1 mg de vacuna BCG en cancer vesical etapa T1
Actas Urol Esp, 23 (1999), p. 757
[8] Colombel M, Saint F, Chopin D, Nicolas L, Rischmann P. The effect of ofloxacin on bacillus Calmette-Guérin induced toxicity in patients with superficial bladder cancer: Results of a randomized, prospective, double-blind, placebo controlled, multicenter study. J Urol 2006; 176: 935–9.
[9] Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guérin, and bacillus Calmette-Guérin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol 2010; 57 (5): 766-73.
[10] Griffith DE, Brown-Elliott BA, Shepherd S, McLarty J, Griffith L, Wallace Jr, RJ. Ethambutol ocular toxicity in treatment regimens for Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2005; 172 (2): 250-3.

[11] Harland SJ, Kynaston H, Grigor K, Wallace DM, Beacock C, Kockelbergh R, Clawson S, Barlow T, Parmar MK, Griffiths GO. National Cancer Research Institute Bladder Clinical Studies Group: A randomized trial of radical radiotherapy for the management of pT1G3 NXM0 transitional cell carcinoma of the bladder. J Urol 2007; 178 (3): 807-13.

[12] Lamm DL, Gandhi NM, Iverson T, et al. Clinical experience with heat-inactivated bacillus Calmette-Guérin (BCG) immunotherapy. J Urol 2013; 4 (suppl): 733. 

Obesity and Urological Malignancies: Understanding the Impact

More than 1 in 3 adults in the United States are classified as obese, as defined by a Body Mass Index (BMI) greater than 30 kg/m2 [1]. Obese patients have been shown to be at an increased risk for a variety of health problems including cardiovascular disease, diabetes, and many types of cancer [2]. Significant evidence has demonstrated that obesity has a tremendous impact on the incidence and treatment outcomes of the most common types of genitourinary cancers.

Here we review the link between obesity and cancers of the bladder, kidney and prostate.

BLADDER

Several studies have attempted to demonstrate a definitive link between obesity and an increased incidence of urothelial carcinoma of the bladder. Two analyses of high-volume patient populations published in 2007-2008 showed conflicting data; one demonstrated a statistically significant increased risk for bladder cancer with increasing BMI while the other showed no correlation [3, 4].

Despite the lack of a definitive connection between obesity and the incidence of bladder cancer, there is a substantial amount of literature detailing that obesity has a clear impact on rates of operative complications and treatment outcomes. Patients with a BMI greater than 40 kg/m2 more frequently undergo incontinent urinary diversions rather than procedures that preserve continence at the time of radical cystectomy [5]. Additionally, patients with higher BMI are at increased risk for complications both during and after a procedure, and have been shown to have longer operative times and more blood loss during surgery [5-7]. Despite the increased risk of surgical complications, however, evidence has shown that there is no association between obesity and decreased survival following a radical cystectomy [6, 8].

KIDNEY

Renal cell carcinoma (RCC), which accounts for more than 90% of all kidney cancer cases, has been clearly demonstrated to have an increased incidence in the obese population [9]. A 2001 study summarized the findings of 22 prior reports, concluding that for every increase of 1 kg/m2 in BMI there was a 7% increase in the relative risk of having RCC (RR=1.07) [10]. Biologic changes at the molecular level may contribute to this observed association between obesity and kidney cancer. Specifically, metabolism and breakdown of lipid stores, which are increased in obese patients, have been shown to increase the amount of DNA damage in certain kidney cells. This DNA damage is thought to increase the risk of inactivation of genes, such as VHL, that prevent cells from ultimately becoming cancerous [11].

Interestingly, multiple studies have shown that obese patients with RCC have an improved survival following nephrectomy when compared with patients who have a normal BMI [12-14]. This phenomenon has been labeled the "obesity paradox."[15] One such analysis postulated that this survival advantage may be due to less aggressive and more localized cancers in obese patients at presentation, though this has yet to be definitively demonstrated [14].

PROSTATE

The relationship between obesity and prostate cancer has been widely studied. In 2006 a summary of 56 studies showed that there was a slight overall increased relative risk of prostate cancer with increasing BMI (RR=1.06 per 5 kg/m2 increase in BMI). This study also found that obese patients were at a significantly increased risk of developing advanced stage prostate cancer (RR=1.12 per 5 kg/m2 increase in BMI) [16].

Why do obese patients tend to present with more aggressive cancers? First, obese patients with prostate cancer are diagnosed later than patients with a normal BMI. A larger body habitus may make an accurate digital rectal examination more difficult to perform, leading to decreased detection rates. In addition, data has shown that in patients with diagnosed prostate cancer, PSA levels decrease as BMI increases, suggesting that the results of PSA testing may be complicated by obesity [17]. Thus, obese patients with prostate cancer are more likely to have PSA concentrations below the typical values suspicious for cancer in a patient with normal BMI, contributing to further decreased detection rates. Finally, several biologic mechanisms at the cellular level have been proposed to account for the increased incidence of aggressive cancers seen in the obese population. Excess fatty tissue in obese patients has been shown to lead to increased levels of several hormones in the blood, including insulin and IGF-1. These hormones have been shown in experimental animal models to increase growth rates in tumor cells, and it is thought that a similar effect occurs in humans with obesity [18].

Multiple studies have shown that obesity is associated with poorer treatment outcomes following prostatectomy, as obese patients have an increased risk of positive surgical margins and recurrence of PSA levels [19]. It has also been shown that procedures done on obese patients have lower rates of successful nerve sparing, leading to worse erectile function outcomes and impaired quality of life [20]. Ultimately, obese patients with prostate cancer in two large trials were shown to have a significantly increased cancer-specific mortality rate (RR=1.21-1.27) [21].

SUMMARY

• Obesity has been shown to increase the risk of developing renal cell carcinoma and aggressive prostate cancer, while its influence on the risk of bladder cancer remains less clear.
• Obesity is associated with poorer treatment outcomes in bladder and prostate cancer including increased rates of operative complications.
• Obesity has been shown to have varying effects on survival in cancers of the bladder (no effect), kidney (improved survival) and prostate (worsened survival).
• Biologic mechanisms have been implicated in the link between obesity and both kidney and prostate cancers.
• Lifestyle modification via weight reduction and exercise is important as it may reverse the increased risk for genitourinary cancers and improve treatment outcomes [22].

This blog was written by Jack Cooper, medical student at Johns Hopkins Medical School.  Jack recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "Obesity and Genitourinary Malignancies" from which this blog is inspired.  Jack is looking forward to a career in urology.







[1] Ogden CL, Carroll MD Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009-2010. NCHS Data Brief, Jan 2012.
[2] Calle EE. Obesity and cancer. BMJ 2007; 335:1107.
[3] Koebnick C, Michaud D, Moore SC, et al. Body mass index, physical activity, and bladder cancer in a large prospective study. Cancer Epidemiol Biomarkers Prev. 2008 May;17(5):1214-21.
[4] Holick CN, Giovannucci EL, Stampfer MJ, Michaud DS. Prospective study of body mass index, height, physical activity, and incidence of bladder cancer in U.S. men and women. Int J Cancer. 2007 Jan 1; 120(1):140-6.
[5] Lee CT, Dunn RL, Chen BT, et al. Impact of body mass index on radical cystectomy. J Urol. 2004 Oct;172(4 Pt 1):1281-5.
[6] Maurer T, Maurer J, Retz M, et al. Influence of body mass index on operability, morbidity and disease outcome following radical cystectomy. Urol Int. 2009;82(4):432-9.
[7] Chang SS, Jacobs B, Wells N, et al. Increased body mass index predicts increased blood loss during radical cystectomy. J Urol. 2004 Mar;171(3):1077-9.
[8] Hafron J, Mitra N, Dalbagni G, et al. Does body mass index affect survival of patients undergoing radical or partial cystectomy for bladder cancer? J Urol. 2005 May;173(5):1513-7.
[9] Li L, Kaelin WG Jr. New insights into the biology of renal cell carcinoma. Hematol Oncol Clin North Am. 2011 Aug;25(4):667-86.
[10] Bergstrom A, Hsieh CC, Lindblad P, et al. Obesity and renal cell cancer—a quantitative review. Br J Cancer. 2001 Sep 28;85(7):984-90.
[11] Gago-Dominguez M, Castelao JE, Yuan JM, et al. Lipid peroxidation: A novel and unifying concept of the etiology of renal cell carcinoma. Cancer Causes Control. 2002 Apr;13(3):287-93.
[12] Haferkamp A, Pritsch M, Bedke J, et al. The influence of body mass index on the long-term survival of patients with renal cell carcinoma after tumour nephrectomy. BJU Int. 2008 May;101(10):1243-6.
[13] Kamat AM, Shock RP, Naya Y, et al. Prognostic value of body mass index in patients undergoing nephrectomy for localized renal tumors. Urology. 2004 Jan;63(1):46-50.
[14] Parker AS, Lohse CM, Cheville JC, et al. Greater body mass index is associated with better pathologic features and improved outcome among patients treated surgically for clear cell renal cell carcinoma. Urology. 2006 Oct;68(4):741-6.
[15] Hakimi AA1, Furberg H, Zabor EC, Jacobsen A, Schultz N, Ciriello G, Mikklineni N, Fiegoli B, Kim PH, Voss MH, Shen H, Laird PW, Sander C, Reuter VE, Motzer RJ, Hsieh JJ, Russo P.  An epidemiologic and genomic investigation into the obesity paradox in renal cell carcinoma.J Natl Cancer Inst. 2013 Dec 18;105(24):1862-70. doi: 10.1093/jnci/djt310. Epub 2013 Nov 27.
[16] Macinnis, RJ, English DR. Body size and composition and prostate cancer risk: systematic review and meta-regression analysis. Cancer Causes Control. 2006 Oct;17(8):989-1003.
[17] Banez LL, Hamilton RJ, Partin AW, et al. Obesity-related plasma hemodilution and PSA concentration among men with prostate cancer. JAMA. 2007 Nov 21;298(19):2275-80.
[18] Calle EE, Kaaks R. Overweight, obesity, and cancer: Epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004 Aug; 4(8):579-91.
[19] Freedland SJ, Aronson WJ, Kane CJ, et al. Impact of obesity on biochemical control after radical prostatectomy for clinically localized prostate cancer: a report by the Shared Equal Access Regional Cancer Hospital database study group. J Clin Oncol. 2004 Feb 1;22(3):446-53.
[20] Sundi D, Reese AC, Mettee LZ, et al. Laparoscopic and robotic radical prostatectomy outcomes in obese and extremely obese men. Urology. 2013 Sep;82(3):600-5.
[21] Rodriguez C, Patel AV, Calle EE, et al. Body mass index, height, and prostate cancer mortality in two large cohorts of adult men in the United States. Cancer Epidemiol Biomarkers Prev. 2001 Apr;10(4):345-53.
[22] Chu KF, Rotker K, Ellsworth P. The impact of obesity on benign and malignant urologic conditions. Postgrad Med. 2013 Jul; 125(4):53-69.

Kidney Stones in the Elderly

Historically kidney stones affect adults aged 20-60 years-old.  However, 10-20% of patients presenting with stones are >65 years-old and as the population ages and the older demographic increases, it is important to understand how to evaluate, treat and prevent kidney stones in this population.[1-4]  Especially as older patients have higher risk of infectious complications and overall morbidity following treatment of stones.[5]  Here we review the important epidemiology and clinical management considerations for the elderly patient with kidney stones.

Epidemiological Considerations

• Historic estimates for stone disease in the elderly were 2%; contemporary estimates are closer to 12% (which is equivalent to the general population). [6]
• Elderly patients are more likely to have bladder stones (due to benign prostatic hyperplasia and obstructive symptoms in men).
• Stone size, laterality, location and recurrence rates do not vary with age.[3,7]
• Among all age groups, men are two to three times more likely than women to develop kidney stones.  
• Male predominance is most pronounced in middle-aged men (2.8x for age 5-59).
• Male predominance decreases with age:
• 2.49x compared to women for age 60-69
• 2.23x for age 70-79
• 1.8x for age 80-89
• 1.6x for age 90 or greater [8]
• Estrogens are known to have a protective effect on the formation of kidney stones and hypothesized to explain the narrowing of the gender-gap in post-menopausal age range.[9,10]

Clinical Presentation 

• Struvite and uric acid stones are more common in older patients calcium and cysteine stones are less common.
• Calcium stones: >80% of stones in patients 20-60 years-old; <50% in patients >80.[8]
• Struvite stones: 2% age <30 years-old; >30% in patients >80.[3,8]
• The most common metabolic profile in older patients is hypercalciuria, however elderly patients secrete less calcium than younger patients.[11]
• Hypocitraturia and hypernatriuria are the most common abnormalities in elderly men.[12]
• Elderly patients are more likely to: 
• present without symptoms or with atypical symptoms (fever, pyuria, diarrhea).
• have multiple comorbidities
• have urinary tract infections and bacteremia
• be hospitalized (2x)
• Elderly patients are less likely to receive pain medications or medications for medical expulsive therapy.[7,13]

Preventive Therapies and Dietary Modifications in the Elderly

• For elderly patients, low urine output and low fluid intake may contribute to stone formation.
• Increased fluid intake (goal 2L urine daily) may lower the incidence of stone formation and decrease recurrence rates.[14,15]
• To combat the hypocitraturia and hypernatriuria common in elderly men, decreasing salt and protein intake while increasing citrate intake will promote a balanced intracellular pH.
• Vitamin C supplementation increases the risk of kidney stones in older men; compared to men who take <90mg/day:
• men who take 250-500mg/day have a 20% increased risk of stones
• men who take >1000mg/day have a 40% increased risk [16]
• Many elderly patients have osteopenia and osteoporosis for which they take calcium supplementation.
• It is well established that a diet of increased calcium and restricted animal protein and sodium decreases recurrence rates in known stone-formers,[17] however routinely checking 24-hour urinalyses may help balance the risks of bone disease and kidney stone formation.  
• Weight reduction is a non-age-specific intervention that is proven to reduce stone formation.[18]

Treatment Considerations for Elderly Patients

• Older patients are more likely to fail medical expulsive therapy.[13]
• Complication rates of percutaneous nephrolithotomy (PCNL) can be significant and morbid in the elderly.
• Transfusion rates were higher in the elderly, but have declined among all age groups over the past 20 years.[19-21]
• Stone-free rates are similar among all age groups undergoing PCNL.[22-24]
• Extracorporeal Shock Wave Lithotripsy (ESWL) has a 52-71% stone clearance rate in the elderly with low rates of major complications.[25,26]
• Ureteroscopy and laser lithotripsy has a higher stone-free rate but higher complication rate in the elderly.[27]

Elderly patients are an increasing demographic in the management of kidney stones.  These patients can present with different symptoms, different stones and metabolic abnormalities than their younger counterparts and therefore warrant different consideration when applying behavioral and medical therapies.  In addition, the morbidity profile of PCNL, ESWL and ureteroscopy is different for the older patient and while each approach is valid, the risk-benefit profile should be considered on an individual basis.

Max Kates, MD

Brian Matlaga, MD

This blog entry is extracted from "Stones in the Elderly," which appears in Current Geriatric Reports, by Max Kates and Brian Matlaga.  The entire publication is available at link.springer.com.
Max Kates, MD is a resident at the Brady Urological Institute at Johns Hopkins.  Brian Matlaga, MD, is an Associate Professor of Urology, Director of Stone Disease and Director of Ambulatory Care at the Brady Urological Institute at Johns Hopkins.

1. Bartoletti R, Cai T, Mondaini N, et al. Epidemiology and risk factors in urolithiasis. Urol Int. 2007;79 Suppl 1:3–7. 

2. Knoll T, Schubert AB, Fahlenkamp D, Leusmann DB, Wendt-Nordahl G, Schubert G. Urolithiasis through the ages: data on more than 200,000 urinary stone analyses. J Urol. 2011;185:1304–11.

3. Usui Y, Matsuzaki S, Matsushita K, Shima M. Urolithiasis in geriatric patients. Tokai J Exp Clin Med. 2003;28:81–7.

4.Yoshida O, Terai A, Ohkawa T, Okada Y. National trend of the incidence of urolithiasis in Japan from 1965 to 1995. Kidney Int. 1999;56:1899–904.

5. Worcester E, Parks JH, Josephson MA, Thisted RA, Coe FL.Causes and consequences of kidney loss in patients with nephrolithiasis. Kidney Int. 2003;64:2204–13.

6. Gentle DL, Stoller ML, Bruce JE, Leslie SW. Geriatric urolithiasis. J Urol. 1997;158:2221–4.

7. Arampatzis S, Lindner G, Irmak F, Funk GC, Zimmermann H, Exadaktylos AK. Geriatric urolithiasis in the emergency department: Risk factors for hospitalisation and emergency management patterns of acute urolithiasis. BMC Nephrol. 2012;13:117-2369-13-117.

8. Daudon M, Dore JC, Jungers P, Lacour B. Changes in stone composition according to age and gender of patients: a multivariate epidemiological approach. Urol Res. 2004;32:241–7.

9. Heller HJ, Sakhaee K, Moe OW, Pak CY. Etiological role of estrogen status in renal stone formation. J Urol. 2002;168:1923–7.

10. Yasui T, Iguchi M, Suzuki S, et al. Prevalence and epidemiologic characteristics of lower urinary tract stones in Japan. Urology. 2008;72:1001–5.

11. Goldfarb DS, Parks JH, Coe FL. Renal stone disease in older adults. Clin Geriatr Med. 1998;14:367–81.

12. Freitas Junior CH, Mazzucchi E, Danilovic A, Brito AH, Srougi M. Metabolic assessment of elderly men with urolithiasis. Clin (Sao Paulo). 2012;67:457–61.

13. Krambeck AE, Lieske JC, Li X, Bergstralh EJ, Melton 3rd LJ, Rule AD. Effect of age on the clinical presentation of incident symptomatic urolithiasis in the general population. J Urol. 2013;189:158–64.

14. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med. 1993;328:833–8.

15. Borghi L, Meschi T, Amato F, Briganti A, Novarini A, Giannini A. Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol. 1996;155:839–43.

16. Taylor EN, Curhan GC. Diet and fluid prescription in stone disease. Kidney Int. 2006;70:835–9.

17. Heaney RP. Calcium supplementation and incident kidney stone risk: a systematic review. J Am Coll Nutr. 2008;27:519–27.

18. Obligado SH, Goldfarb DS. The association of nephrolithiasis with hypertension and obesity: a review. Am J Hypertens. 2008;21:257–64.

19. Stoller ML, Bolton D, St Lezin M, Lawrence M. Percutaneous nephrolithotomy in the elderly. Urology. 1994;44:651–4.

20. Sahin A, Atsu N, Erdem E, et al. Percutaneous nephrolithotomy in patients aged 60 years or older. J Endourol. 2001;15:489–91.

21. Kuzgunbay B, Turunc T, Yaycioglu O, et al. Percutaneous nephrolithotomy for staghorn kidney stones in elderly patients. Int Urol Nephrol. 2011;43:639–43.

22. Kane CJ, Bolton DM, Stoller ML. Current indications for open stone surgery in an endourology center. Urology. 1995;45:218–21.

23. Matlaga BR, Assimos DG. Changing indications of open stone surgery. Urology. 2002;59:490–3. discussion 493-4.

24. Paik ML, Wainstein MA, Spirnak JP, Hampel N, Resnick MI. Current indications for open stone surgery in the treatment of renal and ureteral calculi. J Urol. 1998;159:374–8. discussion 378-9.

25. Sighinolfi MC, Micali S, Grande M, Mofferdin A, De Stefani S, Bianchi G. Extracorporeal shock wave lithotripsy in an elderly population: how to prevent complications and make the treatment safe and effective. J Endourol. 2008;22:2223–6.

26. Philippou P, Lamrani D, Moraitis K, Bach C, Masood J, Buchholz N. Is shock wave lithotripsy efficient for the elderly stone formers? Results of a matched-pair analysis. Urol Res. 2012;40:299–304.

27. Aboumarzouk OM, Kata SG, Keeley FX, Nabi G. Extracorporeal shock wave lithotripsy (ESWL) versus ureteroscopic management for ureteric calculi. Cochrane Database Syst Rev. 2011;(12):CD006029.

Active Surveillance for Prostate Cancer: 16 years of Knowledge Gained

H. Ballentine Carter, MD

H. Ballentine Carter, Professor of Urology and Oncology at the Brady, initiated the Active Surveillance (AS) Program for Prostate Cancer at Johns Hopkins 16 years ago.  This was one of the first of its kind and is now among the longest-running AS program for prostate cancer in the world.

There have been a variety of important questions answered and lessons learned over the past two decades. First, at 10 years approximately 60% of patients will undergo some intervention for prostate cancer.  The prompt for intervention is a change in Gleason score or increase in volume of disease in 75%.  Importantly, no patient had died of prostate cancer (median follow-up 6.5 years, maximum 15 years).[1]

Jeff Tosoian, MD

Second, figuring out who will "progress" and have worse prostate cancer while on AS can be difficult.  To be enrolled in the Active Surveillance Program at Hopkins, a man must have low-grade and small-volume disease – cancer categorized as "very low risk" (see below for defintions) .  Jeff Tosoian, M.D., a urology resident at the Brady, studied men with very low-risk and low-risk disease who underwent surgery at Hopkins. "Since they underwent surgery, it was possible to compare the extent of cancer in the two groups," says Carter. After evaluating the extent of cancer among 7,333 men classified as low-risk, and 153 men diagnosed with very low-risk disease, Tosoian concluded that men with low-risk disease were approximately two times more likely than very low-risk men to have a cancer that turned out to be of higher grade and/ or to have spread beyond the prostate gland. "This finding suggests that surveillance may be more risky in the presence of low-risk versus very low-risk disease, especially in younger men," says Carter. "Men who can expect to live at least 20 more years who have low-risk disease may rather accept the risks of treatment than take the chance that their cancer will cause harm later, especially if they are otherwise healthy. Men with very low-risk disease can take comfort that their disease can safely be managed by surveillance."[2]

Low Risk Prostate Cancer

• PSA is below 10 ng/ml
• Biopsy has a Gleason score of 6
• Cancer is not palpable or is minimally palpable on a digital rectal examination

Very-Low Risk Prostate Cancer

• Your biopsy has a Gleason score of 6,
• 2 cores or fewer are found to contain cancer,
• Cancer makes up half or less of any core that contains cancer,
• PSA divided by the prostate volume is 0.15 or less, and
• Cancer is not palpable on a digital rectal examination

Third, determining the potential benefits of RP or AS can be difficult since no trial directly compares surgery (radical prostatectomy, RP) to AS.  Therefore, complex simulation models need to be employed to detect potential benefits among patients undergoing either RP or AS.  Investigators from Hopkins, the Fred Hutchinson Cancer Center, and the University of California-San Francisco (UCSF) teamed up to compare the outcomes of men enrolled in the AS Program at Hopkins with those of men who underwent surgery immediately at Hopkins and UCSF after their cancer was diagnosed. The scientists projected that 2.8 percent of men on AS and 1.6 percent of the men who underwent immediate RP would die of their disease in 20 years. They estimated that the average increase in life expectancy associated with immediate RP was 1.8 months, and that men on AS would remain free of treatment for an additional 6.4 years as compared to men who had immediate treatment. "These findings suggest that men enrolled in the Johns Hopkins AS Program are at low risk of losing a window of opportunity for cure if they are carefully monitored," Carter says.[3]

Some of this blog has been extracted from Prostate Cancer Discovery, Volume 10, Winter 2014.

1. Tosoian JJ, Trock BJ, Landis P, Feng Z, Epstein JI, Partin AW, Walsh PC, Carter HB.Active surveillance program for prostate cancer: an update of the Johns Hopkins experience.J Clin Oncol. 2011 Jun 1;29(16):2185-90. doi: 10.1200/JCO.2010.32.8112. Epub 2011 Apr 4.
2. Tosoian JJ, JohnBull E, Trock BJ, Landis P, Epstein JI, Partin AW, Walsh PC, Carter HB.Pathological outcomes in men with low risk and very low risk prostate cancer: implications on the practice of active surveillance.J Urol. 2013 Oct;190(4):1218-22. doi: 10.1016/j.juro.2013.04.071. Epub 2013 Apr 30.
3.  Xia J, Trock BJ, Cooperberg MR, Gulati R, Zeliadt SB, Gore JL, Lin DW, Carroll PR, Carter HB, Etzioni R.Prostate cancer mortality following active surveillance versus immediate radical prostatectomy. Clin Cancer Res. 2012 Oct 1;18(19):5471-8. doi: 10.1158/1078-0432.CCR-12-1502. Epub 2012 Sep 24.

Classic Manuscripts in Urology: Reiner and Gearhart, 2004

William G. Reiner, MD, was a Professor of Psychiatry and Urology at Johns Hopkins who, working with John P. Gearhart, MD, Professor and Director of Pediatric Urology at the Brady Urological Institute at Johns Hopkins, had a special interest in the development of children and adolescents with disorders of sexual development.   Dr. Reiner is currently at the University of Oklahoma, however he continues to work to improve the psychosocial development of these children by exploring gender identity, the impact of genital appearance and function, as well as urinary function and their impact on these children.  We review this seminal work:

Reiner WG, Gearhart JP.  Discordant sexual identity in some genetic males with cloacal exstrophy assigned to female sex at birth.  New England Journal of Medicine. 2004 Jan 22;350(4):333-41.  

Manuscript.  Pubmed.

In this manuscript, Drs. Reiner and Gearhart examined 16 male children born with cloacal exstrophy.  Due to the marked phallic inadequacy or, in some cases, absence of a phallus, genetic males born with cloacal exstrophy were often assigned to female sex in the neonatal period. Fourteen of the 16 males underwent surgical, social and legal assignment to female sex.  For two patients, the parents refused gender reassignment.

At last follow-up, eight of the 14 subjects assigned to female sex declared themselves male, six of whom reassigned themselves to male sex.  Five patients were living as females and three had an unclear sexual identity.  Interestingly, all 16 subjects had moderate-to-marked interests and attitudes considered typical of males.

Take Home:  This manuscript was and is incredibly important in the discussion of gender identity.  Specifically, this manuscript addresses disorders of sexual differentiation, but it has been touted as some of the best evidence regarding androgen-imprinting and gender identity.  It has been mentioned in the national and international debate on same-sex marriage and shared benefits.  In local news, this manuscript has been cited in the discussion of gender identity as Maryland debates a new Gender Identity Bill.

Dr. Reiner is quoted on ProCon.org, "I would argue that there is evidence that sexual orientation in the male has a strong tendency to be affected by and at least partly induced by androgens prenatally (but there is no evidence that female sexual orientation is brought about prenatally). That said, homosexual males are also exposed to probably the same dose of androgens as heterosexual males. Thus, sexual orientation is too complex in its origins at present to understand."

Classic Manuscripts in Urology will be posted on this blog on regular basis.  These articles are meant to highlight the achievements of our predecessors, recognize the work from which we build our careers and stimulate new conversations and discussion on a variety of urological topics.  Please feel free to comment on this manuscript, help point out its strengths and weaknesses, or suggest a new manuscript and topic.