Classic Manuscripts in Urology: Neoadjuvant Hormones Prior to Radical Prostatectomy

With the emergence of prostate specific antigen (PSA) testing in the late 1980's and 1990's, the incidence of prostate cancer, specifically localized prostate cancer, increased dramatically. While the proportion of patients with localized treatment increased, a significant proportion of patients harbored cancer that extends beyond the prostatic capsule (pT3). Patients with disease outside of the prostate gland were known to be at higher risk for PSA recurrence, metastasis and death from prostate cancer. It was also know that advanced and metastatic prostate cancers could be treated with androgen deprivation therapy (ADT) – which could create a dramatic decrease in PSA level, metastases and prostate gland size (if present). It was therefore hypothesized that neoadjuvant (treatment before surgery) ADT could consolidate prostate cancers and facilitate a more complete, "better" surgical resection. 

 A number of urologists employed neoadjuvant ADT and retrospective analyses of these patients confirmed that the prostate would shrink under the influence of castration and hinted that the incidence of positive surgical margins may be decreased. Therefore a number of prospective, clinical trials were designed to investigate the role of neoadjuvant ADT, opened in the early 1990's and were published within a few years of each other. The results of those trials offer level I evidence regarding the use of neoadjuvant ADT still used today.

 
Soloway MS, Sharifi R, Wajsman Z, McLeod D, Wood DP Jr, Puras-Baez A. Randomized prospective study comparing radical prostatectomy alone versus radical prostatectomy preceded by androgen blockade in clinical stage B2 (T2bNxM0) prostate cancer. The Lupron Depot Neoadjuvant Prostate Cancer Study Group. J Urol. 1995 Aug;154(2 Pt 1):424-8.

Soloway MS, Pareek K, Sharifi R, Wajsman Z, McLeod D, Wood DP Jr, Puras-Baez A; Lupron Depot Neoadjuvant Prostate Cancer Study Group. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results. J Urol. 2002 Jan;167(1):112-6.

 
The Lupron Depot Neoadjuvant Prostate Cancer Study Group led by Dr. Mark Soloway, MD, was the largest, prospective study of the time to investigate neoadjuvant ADT. Three-hundred three patients were randomized to radical prostatectomy or radical prostatectomy after 3-months of ADT with 7.5mg lueprolide acetate depot. All patients had biopsy-proven cT2b (able tumor occupying more than half of 1 lobe in a mobile gland) prostate cancer. All patients underwent radical prostatectomy with a consistent lymph node dissection template and all pathological specimens were analyzed in the same fashion according to protocol.

While the radical prostatectomies performed after ADT were rated as more difficult by the surgeons involved, there were no differences in blood loss, operative time or blood transfusion between the groups; and the surgery only group had a higher rate of rectal and ureteral injuries! With regard to oncologic outcomes, there were a number of important outcomes noted in the initial study:

• There was no difference in rates of patients with seminal vesical invasion or positive lymph nodes in either group.
• The neoadjuvant ADT group demonstrated:
  • decreased prostate volume/weight
  • decrease in preoperative PSA
  • less extraprostatic extension
  • a lower rate of positive surgical margins (18% vs. 48%, P<0.001)
    • specifically, rates of urethral margin involvement were lower
  • increased rate of Gleason upgrading to high-risk (8-10) disease
• In the neoadjuvant ADT group 29% of the patients had positive surgical margins, positive seminal vesicles or positive lymph nodes compared to 57% in the radical prostatectomy alone group (P<0.001).

Importantly, the follow-up study with 5-years of data demonstrated no difference in biochemical (PSA) recurrence rates, leading the authors to conclude:

"Although 3 months of androgen deprivation before radical prostatectomy resulted in an apparently significant decrease in positive surgical margins, a 5-year follow-up does not indicate any difference in the recurrence rate. Until studies document improvement in biochemical or clinical recurrence with longer periods of treatment, induction androgen deprivation before radical prostatectomy is not indicated."

To explain this phenomenon, the authors demonstrated that biochemical (PSA) recurrence rates were, as expected, higher in patients with positive surgical margins. However, for patients undergoing neoadjuvant ADT, the biochemical recurrence rates were nearly double for patients with negative margins (33% vs. 17%) – indicating that ADT exerted a pathological effect that did not alter the biology of the disease. Explanations included that the lower rate of positive surgical margins may have been an artifact of ADT, making prostate cancer appear to be clear of the margin under hemaotxylin and eosin staining while it may, in fact, still be present at the border of the resection. Alternatively, ADT may have "pulled" prostate cancer back into the specimen leading to lower rates of positive surgical margins, but did not change the ability of that cancer to escape the gland.

 
Take home: This study confirmed the findings of other neoadjuvant ADT trials [1-3] that neoadjuvant ADT decreased the rates of positive surgical margins at the time of radical prostatectomy but did not influence long-term biochemical recurrence rates. This work is cited as the seminal work putting the "nail in the coffin" of neoadjuvant ADT before radical prostatectomy.



[1] C.C. Schulman, F.M.J. Debruyne, G. Forster, et al. 4-Year follow-up results of a European prospective randomized study on neoadjuvant hormonal therapy prior to radical prostatectomy in 3N0M0 prostate cancer Eur Urol, 38 (2000), p. 706
[2] G. Aus, P. Abrahamsson, G. Ahlgren, et al. Hormonal treatment before radical prostatectomy: a 3-year followup J Urol, 159 (1998), p. 2013.

[3] F. Meyer, L. Moore, I. Bairati, et al. Neoadjuvant hormonal therapy before radical prostatectomy and risk of prostate specific antigen failure. J Urol, 162 (1999), p. 2024.

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. 

Classic Manuscript in Urology: Einhorn and Donohue. Journal of Urology, 1977.

Lawrence Einhorn, MD

In the 1960's, metastatic testicular cancer was a death sentence - with a greater than 90% mortality within 1 year of diagnosis.  In 1965,  cisplatinum  chemotherapy was discovered by Dr. Rosenberg at Michigan State University.[47] The drug was tried in testicular cancer in 1971, with a number of complete responses to treatment but with terrible side effects including permanent renal failure.[49]  Shortly thereafter, Drs. Einhorn and Donahue added cisplatinum to the combination of vinblastine and bleomycin, a chemotherapy with some known efficacy in testicular cancer.  The results were astounding - the cure rate went from 10% to 70% and the treatment of testicular cancer was changed forever.

Einhorn LH, Donohue JP.  Improved chemotherapy in disseminated testicular cancer.  J Urol. 1977 Jan;117(1):65-9.
Pubmed.
Journal of Urology.

In this manuscript, Drs. Einhorn and Donohue describe their initial experience with a platinum-based regimen for the treatment of metastatic testis cancer.  Twenty-seven patients received either a regimen of adriamycin, bleomycin and vincristine or platinum, vinblastine and bleomycin (PVB).  The patients receiving PVB had an outstanding response with 16 of 21 (76%) achieving a complete response (no visible cancer), 4 (20%) with a partial response and only 1 with no response.  Considering all patients treated by Dr. Einhorn during this time period, complete remission was achieved with PVB chemotherapy alone in 85% and 93% with additional surgery.

Unfortunately, the response was not durable in all patients. In the manuscript, Dr. Einhorn speculates in the discussion,

"Although we do not have long-term followup data on any of our patients treated with [PVB], it seems quite reasonable to expect at least 50 percent of our patients in complete remission will have cures..."

In fact, the durable cure rate was closer to 70% -- a logarithmic increase in the survival for men with advanced germ cell tumors!

Another important point from this paper was that the "Einhorn Regimen" involved more than just PVB.  By hydrating patients with copious fluids, Dr. Einhorn mitigated many of the toxicities, including nephrotoxicity.  Shortly after this publication, Dr. Einhorn would work to design, implement and add antiemetics to the regimen.  The results were so impressive the FDA (Food & Drug Administration) approved the "Einhorn Regimen" for advanced testicular cancer without any further studies.

Take home: Metastatic testis cancer was fatal in nearly all patients before this study.  Careful selection of chemotherapeutic agents based on mechanistic principles changed the paradigm for testis cancer (and many other malignancies).  Attention to side effect profiles and adjuvant therapies to mitigate side effects can improve outcomes in patients receiving cytotoxic chemotherapy.

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. 

Classic Manuscripts in Urology: Flanigan, NEJM, 2001 and Mickisch, Lancet, 2001

In most metastatic cancers, surgery has a limited role as the most rationale management strategies often involve treating the systemic illness with systemic chemotherapy and bypassing or delaying treatment of the primary tumor.  However, cytoreductive nephrectomy (removing the kidney in the face of metastatic disease) remains the mainstay of treatment for metastatic renal cell carcinoma (RCC).  There is good rationale and evidence for this treatment paradigm in kidney cancer:

1. traditional chemotherapeutic agents and radiation treatments have no role (efficacy) in RCC.
2. RCC is an immunogenic tumor, and removing the primary tumor may have systemic effects
• laboratory data demonstrates inhibition of the immune system by RCC
• the only systemic therapies shown to improve survival in advanced RCC are immunotherapies or immunomodulators
3. rare but well-described cases of complete regression of metastatic disease once the primary tumor is removed

The best evidence for cytoreductive nephrectomy comes from two landmark trials published in 2001:

• The first was the SWOG (Southwest Oncology Group) 8949 Trial led by Dr. Robert Flanigan and published in the New England Journal of Medicine.  

Flanigan RC, Salmon SE, Blumenstein BA,et al: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001; 345: 1655-1659

N Engl J Med 2001; 345: 1655-1659

The Flanigan study was a Phase III randomized trial of 241 patients with metastatic RCC who received either interferon-alpha-2b (IFN-alpha) as primary therapy or after cytoreductive nephrectomy.  All patients were surgical candidates with an excellent performance status, a histologic diagnosis of RCC (all subtypes allowed) and no prior treatments.  The primary endpoint was overall survival and the secondary endpoint was tumor response.  There was no difference in objective measures of response to IFN-alpha, however the 120 patients undergoing surgery had a median survival of 11 months while the median survival of the 121 patients received IFN-alpha alone was 8 months (P=0.05). 

• The second was a smaller study led by Dr. Mickisch for the European Organization for Research and Treatment of Cancer (EORTC) published in The Lancet.

Mickisch GH, Garin A, van Poppel H,et al: Radical nephrectomy plus interferon-alfa–based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001; 358: 966-97

The EORTC study was a similarly designed trial of 85 patients receiving IFN or IFN after cytoreductive nephrectomy.  The time to progresion was longer in the nephrectomy arm (5 versus 3 months, p=0.04); as was overall survival (17 versus 7 months, P=0.03).   In addition, 5 patients in the nephrectomy arm achieved a complete response, while one patient did so in the IFN-alone group.

Lancet 2001; 358: 966-97

These manuscripts collectively were the first to demonstrate a meaningful benefit to cytoreductive nephrectomy - a combined analysis in 2004 solidified the benefit of cytoreductive nephrectomy in the urologic literature.[1]  In addition, they define the characteristics of patients who will possibly benefit from surgery (i.e. good performance status, resectable primary and favorable sites (lung) of metastases).  The figures above are some of the most prevalent figures in talks on kidney cancer and the articles are cited nearly 2,000 times.  Finally, they serve as the impetus for subsequent trials in the tyrosine kinase inhibitor era that have improved the overall survival for patients with metastatic RCC to 2-3 years.[2,3]


[1] Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED.  Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis.J Urol. 2004 Mar;171(3):1071-6.
[2] Robert J. Motzer, M.D., etal.  Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma.  N Engl J Med 2013; 369:722-731August 22, 2013DOI: 10.1056/NEJMoa1303989
[3] Bernard Escudier, M.D., etal. for the TARGET Study GroupSorafenib in Advanced Clear-Cell Renal-Cell Carcinoma.  N Engl J Med 2007; 356:125-134January 11, 2007DOI: 10.1056/NEJMoa060655

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. 

Classic Manuscript in Urology: Schoor et al, Testicular Biopsy & Infertility, 2002

Azoospermia is the condition in which there are no sperm in the semen (ejaculate fluid).
In the past, almost all men with azoospermia underwent a diagnostic testicular biopsy to distinguish obstructive (blockage) from non-obstructive (sperm production) causes; normal sperm production found in the tissue suggests obstructive causes. Previously, most men with non-obstructive azoospermia had no options to father biologically related children. However, with the emergence of assisted reproductive techniques (ART) such as in-vitro fertilization  (IVF) and intracytoplasmic sperm injection (ICSI), a pregnancy could be initiated using very low numbers of sperm.

For men with non-obstructive azoospermia, we typically offer microsurgical-dissection testicular sperm extraction (microTESE), which gives the best chance of finding sperm within the testis that can be used with ART. In contrast, men with obstructive azoospermia can seek reconstruction to relieve the obstruction and attempt natural conception, or they can use surgically retrieved sperm with similar assisted reproductive techniques. To plan for the most appropriate treatment, it is highly valuable to be able to characterize the cause of azoospermia without a diagnostic biopsy.

Schoor RA, Elhanbly S, Niederberger CS, Ross LS.  The Role of Testicular Biopsy in the Modern Management of Male Infertility.  J Urol 2002; 167(1):197-200.

PubMed.
Journal of Urology.

In this study, Dr. Schoor and colleagues retrospectively reviewed the records of 153 azoospermic men.  The authors recognized that classic texts of infertility described men with obstructive azoospermia having “normal” endocrine profiles, testicular volumes and long axis length, while men with nonobstructive azoospermia will have an abnormality in 1 or more of these parameters.  However, the importance of these abnormalities had not been defined in the modern era of infertility.

They investigated a number of parameters including follicle stimulating hormone (FSH), leutenizing hormone (LH), prolactin, and testicular size, were analyzed as predictors for obstructive vs. non-obstructive azoospermia.  FSH and testicular long axis were found to be the best individual diagnostic predictors:

• 96% of men with obstructive azoospermia had:
• FSH <7.6 mIU/mL
• Testicular Long Axis > 4.6cm
• 89% of men with nonobstructive azoospermia had: 
• FSH >7.6 mIU/mL
• Testicular Long Axis < 4.6cm 

Take Home: Not only did this study define clinical parameters to distinguish obstructive and nonobstructive azoospermia, but is also implies that testicular biopsy is generally unnecessary in the initial evaluation of azoospermia.  Avoiding testicular biopsy reduced the cost and risk associated with evaluation of azoospermia for many men.

For the majority of patients with findings suggesting non-obstructive azoospermia, we now proceed directly to microTESE. Diagnostic biopsy is still performed for a small subset of patients whose findings suggest obstructive azoospermia, as a significant fraction of them may still have a sperm production problem within the testis. For more information, see: http://malefertility.jhu.edu/fertility_evaluation.php

This blog entry was written by Pravin Rao, MD, Director of Reproductive Medicine and Surgery at the Brady Urological Institute at Johns Hopkins.

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. 

Classic Manuscripts in Urology: Landmark Trials in BPH

Benign prostatic hyperplasia (BPH) is extremely common, affecting up to 25% of men throughout their lifetime.  Over the past 25 years, a number of important clinical trials were completed that define our current medical management of BPH.  These trials should be familiar to all urologists and urology residents; and patients with BPH should know these trials exist and may want to be familiar with their outcomes.

Here we review some of the landmark trials in the medical management of BPH. 

Tamsulosin Investigator Group

Alpha-Blocker Trial
Lepor H.  Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin Investigator Group.  Urology. 1998 Jun;51(6):892-900.

765 men randomized to placebo, 0.4mg or 0.8mg of tamsulosin with the inclusion criteria: age >45, AUA symptom score >13, urinary flow rate (Qmax) 4-15mL/second and post-void residual (PVR) <300cc.  At the study endpoint, improvement in AUA-SS was 5.5, 8.3 and 9.6 points in the placebo, 0.4mg and 0.8mg groups respectively.  This correlated to a 25% AUA-SS improvement in 51%, 70% and 74% of patients.  Urinary flow rates (Qmax) improved by 0.5, 1.75 and 1.78; corresponding to a 30% Qmax improvement in 21%, 31% and 36% of men.

North American Finasteride Trial

5-Alpha Reductase Inhibitor Trial
Gormley GJ, Stoner E, Bruskewitz RC, et al: The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med 1992;327:1185-1191.

Over a 12 month period, Dr. Gormley and colleagues demonstrated that 5mg of finasteride demonstrated a consistent improvement in symptoms after week 2 through month 12, defining the few week lag period often observed in patients starting finasteride.  In addition, they demonstrated a maximum improvement of 2.7 points on the AUA-SS.  This correlated to an increase in Qmax of 3 mL/sec, a decrease in prostate volume of 19% and the 50% decrease in serum PSA (defining the adjustment in PSA needed for prostate cancer screening).

Proscar Long-term Efficacy and Safety Study (PLESS)

5-Alpha Reductase Inhibitor Trial

McConnell JD, Bruskewitz R, Walsh P, et al: The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338:557-563.

Dr. McConnell and colleagues evaluated 3,040 men in a multicenter, double-blind, placebo controlled study of finasteride (5mg) over 4 years.  The finasteride group had an average improvement in AUA-SS of 3.3 (compared to 1.8 in the placebo group) that only became evident after 1 year.  Importantly, there was a 57% reduction in acute urinary retention and 55% reduction in surgical intervention at 4 years.

Dutasteride ARIA Studies

5-Alpha Reductase Inhibitor Trial
Roehrborn CG, Boyle P, Nickel JC, et al: Efficacy and safety of a dual inhibitor of 5 alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002;60:434-441.
Roehrborn CG,Marks LS, Fenter T, et al: Efficacy and safety of dutasteride in the four-year treatment of men with benign prostatic hyperplasia. Urology 2004;63:709-715.

Dr. Roerhborn and colleagues published short- and long-term outcomes of men on the dual-5-ARI inhibitor dutasteride.  Men in this study had moderate-to-severe symptoms based on AUA symptoms score, peak flow <15mL/s and a prostate volume >30cc (average prostate volume 54cc).  AUA symptom scores improved a 6 months and reached a maximum at 24 months compared to placebo.  Similar to the PLESS trial, they found a 25% reduction in prostate volume, 2.2mL/s increase in Qmax, 57% risk reduction of urinary retention and 48% reduction in surgical intervention.

Veterans Affairs Cooperative Study 359

Combination Alpha-Blocker / 5ARI Trial

Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med. 1996;335:533–539.

This was the first trial directly comparing an alpha-blocker and 5ARI, and the first time combination therapy was explored.  1,229 men were randomized to terazosin, finasteride, combination or placebo for 1 year.  This study failed to demonstrate an improvement in finasteride when compared to placebo with respect to symptom scores or urinary flow rates. However, the average prostate size in this study was only 37cc and when subset analyses were performed, it was confirmed that the improvement due to terazosin was independent of prostate volume while finasteride was most effective in larger prostates.

Barry MJ1, Williford WO, Chang Y, Machi M, Jones KM, Walker-Corkery E, Lepor H.  Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association symptom index and the benign prostatic hyperplasia impact index is perceptible to patients?  J Urol. 1995 Nov;154(5):1770-4.

In this analysis of the VA359 study, Dr. Barry and colleagues defined slight, moderate and marked improvement in AUA-SS as 3, 5 and 8 points respectively.

Medical Therapy of Prostate Symptoms (MTOPS)

Combination Alpha-Blocker / 5ARI Trial
McConnell JD1, Roehrborn CG, Bautista OM, Andriole GL Jr, Dixon CM, Kusek JW, Lepor H, McVary KT, Nyberg LM Jr, Clarke HS, Crawford ED, Diokno A, Foley JP, Foster HE, Jacobs SC, Kaplan SA, Kreder KJ, Lieber MM, Lucia MS, Miller GJ, Menon M, Milam DF, Ramsdell JW, Schenkman NS, Slawin KM, Smith JA; Medical Therapy of Prostatic Symptoms (MTOPS) Research Group.The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia.N Engl J Med. 2003 Dec 18;349(25):2387-98.


The MTOPS Trial was a prospective, multi-center, randomized, double-blind trial where 3047 patients randomized to doxazosin, finasteride or both versus placebo.  Mean prostate volume was 36cc, mean IPSS 16.7 and Qmax ranged from 4-15mL/s.  Over an average follow-up of 4.5 years, the risk reduction for progression (increase in IPSS of 4, acute urinary retention or surgery) was 39% for doxazosin, 34% for finasteride, and 67% for combination therapy compared with placebo.  The risk of acute urinary retention did not change for patients on doxazosin (although time to AUR was longer), but was reduced 68% for men on finasteride and 81% for patients on combination-therapy.  Similarly, there was no difference in surgical rates for patients on doxazosin, but a 64% and 67% reduction for men on finasteride or combination therapy respectively.  Importantly, the MTOPS trial also demonstrated a dramatic reduction in hematuria for patients on finasteride (63% hematuria recurrence on placebo, 14% recurrence in finasteride).

Combination of Avodart and Tamsulosin Trial (CombAT)

Combination Alpha-Blocker / 5ARI Trial

Roehrborn CG, Siami P, Barkin J, Damião R, Becher E, Miñana B, Mirone V, Castro R, Wilson T, Montorsi F; CombAT Study Group.  The influence of baseline parameters on changes in international prostate symptom score with dutasteride, tamsulosin, and combination therapy among men with symptomatic benign prostatic hyperplasia and an enlarged prostate: 2-year data from the CombAT study.  Eur Urol. 2009 Feb;55(2):461-71. doi: 10.1016/j.eururo.2008.10.037. Epub 2008 Nov 6.

Roehrborn CG, Siami P, Barkin J, Damião R, Major-Walker K, Nandy I, Morrill BB, Gagnier RP, Montorsi F; CombAT Study Group. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study.  Eur Urol. 2010 Jan;57(1):123-31. doi: 10.1016/j.eururo.2009.09.035. Epub 2009 Sep 19. Erratum in: Eur Urol. 2010 Nov;58(5):801.

In the multicenter, randomised, double-blind, parallel-group CombAT Trial, 4,844 men with age >50, IPSS>12, and prostate volume >30cc were randomized to tamsulosin, dutasteride or combination.  These researchers found improvements in acute urinary retention and surgical interventions in men who were taking dutasteride or combination therapy compared to those on tamsulosin alone.  These improvements were most evident in men with a prostate volume >42cc.  

In summary, we can draw the following conclusions from these studies:

• Significant improvements in AUA-SS are considered greater than 3 points.
• Alpha blockers can begin working as quickly as 8 hours.
• The effects of 5ARI may not be felt for 2 weeks to 2 months, and may take 6-12 months to reach their maximum benefit. 
• 5ARIs reduces the risk of acute urinary retention and surgical treatment associated with BPH.
• 5ARIs are effective only on men with larger prostates (>40g).

This blog was written by Mark W. Ball, MD, urology resident at the Brady Urological Institute at Johns Hopkins.

Classic Manuscripts in Urology: Borghi, NEJM 2002

Idiopathic hypercalciuria is one of the most common risk factors for the formation of kidney stones.  It is a modifiable risk factor that can be altered with medications (like thiazide diuretics) or changes in diet.  Prior to this landmark trial it was common practice to recommend a low-calcium diet to patients with kidney stones and hypercalciuria.  However, some short-term and retrospective trials indicated that low calcium diets could adversely affect urinary stone parameters, high calcium diets improved rates of stone formation and protein and salt restriction influenced calcium excretion.  With this background, Loris Borghi and colleagues from the University of Parma initiated a study comparing the effects of a low-calcium diet compared to normal-calcium diet with low animal protein and salt intake.  The results are discussed below and serve as the best evidence for the "stone former" diet recommended by most urologists.

Loris Borghi, M.D., Tania Schianchi, M.D., Tiziana Meschi, M.D., Angela Guerra, Ph.D., Franca Allegri, M.D., Umberto Maggiore, M.D., and Almerico Novarini, M.D.  Comparison of Two Diets for the Prevention of Recurrent Stones in Idiopathic Hypercalciuria.  N Engl J Med 2002; 346:77-84January 10, 2002DOI: 10.1056/NEJMoa010369

NEJM.

Summary

In this manuscript, 120 men with recurrent calcium oxalate stones and hypercalciuria were randomized to one of two diets:

NORMAL CALCIUM, REDUCED ANIMAL PROTEIN SALT DIET (DIET 1)

normal calcium (30 mmol per day)
reduced animal protein (52 grams per day)
reduced salt intake (50 mmol sodium chloride daily)

LOW CALCIUM DIET (DIET 2)

low calcium intake (10 mmol per day)


After 5 years of follow-up, only 12 of 60 men on Diet 1 had recurrent stones while 23 on Diet 2 had stones.  The relative risk of stones in Diet 2 was therefore 0.49 (p=0.04).  The increased rate of stone recurrence while on Diet 2 was most pronounced after 3 years.  This "delayed effect" was due to the fact that most of the early recurrences occurred in patients at high-risk for stone formation (5 or more colic episodes in the year prior to randomization and/or 10 or more stones prior to randomization) regardless of the diet to which they were randomized.

Borghi et al. NEJM, 2002.

In addition, urinary calcium levels dropped in both groups.  However, urinary oxalate levels increased dramatically in patients on Diet 2 - confirming the probable mechanism that a low-calcium diet promotes hyperoxaluria and increased stone formation.

Take home: Low-calcium diets do not prevent, and in fact increase, the risk of urinary calcium stone formation.  A normal calcium diet with restricted animal protein and salt intake is the best diet to prevent recurrent stones in patients with hypercalciuria.  Along with increased hydration, the diet validated by Borghi and colleagues is the basis for the dietary modifications most widely suggested to recurrent stone formers worldwide.

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. 

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. 

Classic Manuscripts in Urology: McGuire, 1981

Dr. Edward McGuire continues to have a long and distinguished career in urology, spanning several decades.  He is a decorated veteran of the Vietnam War.  He trained at Yale and has been faculty at Yale University; the University of Michigan, serving as Head of the Section of Urology and Neurourology and Pelvic Reconstructive Surgery; and the University of Texas Health Science Center in Houston, as Director of the Division of Urology.  Dr. McGuire has made a number of important contributions to urology including the principle of the leak point pressure, understanding surgical corrections of lower urinary tract dysfunction and pioneered the collaborative joint fellowship programs in urology and gynecology. Here we review one of his most important manuscripts and its lasting effect on urology.

McGuire EJ, Woodside JR, Borden TA, Weiss RM. Prognostic value of urodynamic testing in myelodysplastic patients. The Journal of  Urology. 1981 Aug;126(2):205-9.  
Pubmed.

In this paper, Dr. McGuire and colleagues evaluated 42 myelodysplastic patients with urodynamics over an average of 7 years.  They carefully defined the urodynamic characteristics of these patients:

• 86% had an open bladder neck and non-functional proximal urethra
• Only 9% had coordinated micturation while 83% had areflexic detrusor activity
• 71% had poor compliance (increased bladder pressure with increasing volume)

Most importantly, this manuscript demonstrated that 85% of patients with a detrusor leak point pressure >40cm H20 had hydronephrosis or vesicoureteral reflux (VUR) [Table 3].  Conversely, no patient in the low-pressure (<40cm H20) had VUR and only 2 had hydronephrosis.

Take Home: This manuscript is a landmark paper as it defined deleterious effects of high detrusor leak point pressures on the upper urinary tracts and defined the cutpoint at 40cm H20, widely used by urologists around the world for patients with a variety of urological issues.  

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. 

Classic Manuscripts in Urology: Jewett, 1946

Hugh Judge Jewett III

Hugh J. Jewett III (1903-1990) finished the Brady Residency at Johns Hopkins Hospital under Hugh Hampton Young in 1936, became a Professor in the School of Medicine, reaching emeritus in 1969.  His work on the prognostication and evaluation of urological malignancies earned him the Barringer Medal by the American Association of Genitourinary Surgeons and the Ramon Guiteras Award by the American Urological Association.  The theme of that body of work is epitomized in this 1946 manuscript.

Hugh J. Jewett and George H. Strong. Infiltrating Carcinoma of the Bladder: Relation of Depth of Penetration of the Bladder Wall to Incidence of Local Extension and Metastases.  The Journal of Urology, 1946: 55, 366-372.

Pubmed.

In this paper, Dr. Jewett reviewed the autopsies of 127 patients with infiltrating bladder cancer from 1919-1944.  The depth of penetration of tumor into the bladder wall was documented in 107 cases and related to the incidence of 1) metastases, 2) lymphatic capillary invasion and 3) perivesical fixation.  From this data, Dr. Jewett was able to stratify patients into three groups: those with submucosal invasion, those with invasion into the detrusor muscle and those with invasion through the detrusor.  These groups served as the basis for and correspond to today's modern staging categories of non-muscle invasive (pTa, pT1), muscle invasive (pT2) and locally invasive (pT3, pT4) urothelial cancer.

Importantly, Dr. Jewett demonstrated that the number of lymph node and distant metastases, as well as the likelihood of pelvic fixation increased as the tumor grew into and through the bladder wall.  He therefore deduced that 100% of patients with submucosal invasion were potentially curable and only 26% of those with perivesical fixation were potentially curable.

In addition, this manuscript defined the lymphatic drainage of the bladder in relation to the peritoneum and abdominal wall and detailed
the principle sites of invasion of urothelial metastases (regional lymph nodes, liver, lungs and vertebral column).

This manuscript was a landmark paper, in that it described the basis for our modern-day staging of bladder cancer and developed a prognostic model that could be easily shared among physicians and patients.  It has been cited over 400 times since its original publication.

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.