Historical Contribution: HH Young, Interstitial Radiotherapy, 1917

1917

Interstitial Radiotherapy:  The use of radium and the punch operation in desperate cases of enlarged prostate.  Young H.H.  Ann Surg. 1917;65:633-41.

The idea of brachytherapy, or inserting radioactive implants directly into tissue, was first proposed by Pierre Curie in 1901.  Intraurethral radium was used by Pasteau and Degrais in 1914 and the first prostate brachytherapy was administered transperineally in 1917 by Barringer.

In the same year, 1917, at Johns Hopkins Hospital, Hugh Hampton Young reported a series of patients treated with radium needles implanted transperineally, transrectally, and transurethrally.[1]  In the manuscript featured in this entry, Dr. Young "determined to attempt to cause atrophy of the prostate and shrinking of the intravesical lobes by simple means-radium and fulguration-and the history will show that this was remarkably successful."

He noted "a remarkaible shrinking of the hypertrophied gland, with the peculiar tissue changes ... but also without complete relief of obstruction, which generally has remained unchanged, so that radium alone is apparently not a cure for prostatic hypertrophy."  Therefore Dr. Young coupled the radiation treatments with his "punch" procedure to treat his patients.  While radiation treatment fell out of favor for the treatment of benign prostatic diseases, Young astutely predicted that

"in radium we undoubtedly have a therapeutic agent of great value in urology and with improved apparatus... many brilliant results should be obtainable."

In addition to those observations, take note of the scientific precision with which Dr. Young administered the radium, the devices he created to administer the doses safely and diligence with which he recorded clinical outcomes.

Read the entire manuscript here.

[1] Young HH, Fronz W (1917) Some new methods in the treatment of carcinoma of the lower genitourinary tract with radium. J Urol 1: 505–536

Positive Surgical Margins after Partial Nephrectomy: Cause for Concern?

A positive surgical margin implies that cancer is left behind at the time of surgery.  For many cancer surgeries, including prostate and bladder cancer, positive surgical margins are a surrogate for quality of surgery and have implications for additional treatments and cancer survival.  For some cancers, including renal cell cancer (RCC), the implications of a positive surgical margin are less clearly defined.  In this blog, Mohamad E. Allaf, Director of Minimally-Invasive and Robotic Surgery, reviews the data regarding positive surgical margins following partial nephrectomy for the treatment of renal cancer.

Defining Positive Surgical Margins in the Context of the Evolution of Nephron-Sparing Surgery

As kidney surgery evolved from radical to partial nephrectomy (PN), and then from open to minimally-invasive surgery, the definition of a safe margin also evolved. Initially definitions decreased from strict size criteria (i.e. 5mm)[1,2] to any tumor-free margin regardless of size,[2,3] and now consideration of tumor enucleation when possible.  Enucleation is defined by incision of the renal parenchyma within a few millimeters of the tumor, and removal of the tumor by blunt dissection of the plane between the capsule of the tumor  and the healthy renal tissue.[4]  Minervini and colleagues examined oncologic outcomes after standard PN and simple enucleation.  They found a lower rate of positive surgical margins in the patients undergoing enucleation compared to PN (0.2% vs 3.4%) but no difference in recurrence-free or cancer-specific survival.  Interestingly, patients with high-grade disease (Fuhrman Grade 4) who underwent enucleation had worse cancer-specific survival (CSS) compared to those undergoing PN.  Despite these reports , there is still a widespread belief among urologists that enucleation is unsafe with a high risk of incomplete tumor excision, especially for larger lesions.[5]

Rates and Predictors of Positive Surgical Margins

Positive surgical margins have been reported in 0.7-10% of PN series.[6,7]  There are surgical considerations and tumor characteristics that are related positive margins.  Surgical considerations included impaired intraoperative visibility and poor orientation; and can be modified by surgeon experience, intraoperative ultrasound or better clamping techniques.  Tumor characteristics include tumor size, location and invasion;[6] however, due to the relatively low rate of positive surgical margins, parsing out which characteristics are most important remains controversial.

Implications of Positive Surgical Margins

In the case of a positive surgical margins, some surgeons will advocate re-resection or salvage radical nephrectomy.  However, the nephrectomy specimen will only have viable tumor in 6.9% to 15% of cases.[8,9]  The historic CSS after PN is 95% or better.  Several retrospective studies, including one by Besalah and colleagues, fail to demonstrate a difference in survival for patients with positive surgical margins.[10]  A recent large, multi-center study investigated 943 patients undergoing robotic PN; these authors found a low positive surgical margin rate (2.2%), but a higher rate of recurrence and metastases in the patients with positive margins.[11]

Summary

• Positive surgical margins after partial nephrectomy for renal cell carcinoma are rare.
• A positive surgical margin may reflect difficulties with a technical aspect of surgery or imply adverse tumor biology.
• The data regarding recurrence and survival for patients with a positive surgical margin is inconclusive; however the strongest data suggests that: 
• patients with positive surgical margins are at higher risk for recurrence.
• this is more evident in patients with high-grade cancer.
• long-term cancer-specific survival is not affected by margin status.

Recommendations from Dr. Allaf

A "gross" positive margin, meaning a positive margin noticed at the time of initial partial nephrectomy, should be addressed.  This could involve taking additional tumor or completion nephrectomy.

A "microscopic" positive margin, a margin noted by the pathologist under the microscope after the tumor has been removed, warrants careful consideration.  Sometimes the surgeon is certain that all tumor was removed at the time of surgery and can alleviate patient anxiety (frozen margins at the time of surgery can be helpful here).  Regardless, these patients warrant a careful period of active surveillance.  For patients with high-grade or high-stage tumors this should involve frequent imaging and early consideration of a re-operative intervention.

 

Mohamad E. Allaf, M.D. 
Associate Professor of Urology, Oncology, and Biomedical Engineering
Johns Hopkins Medical Institutions
Director, Minimally Invasive and Robotic Surgery
Johns Hopkins Hospital






[1] Li Q-L, Guan H-W, Zhang Q-P et al. Optimal margin in nephron-sparing surgery for renal cell carcinoma 4 cm or less. Eur Urol. 2003; 44: 448.
[2] Castilla EA, Liou LS, Abrahams NA et al. Prognostic importance of resection margin width after nephron-sparing surgery for renal cell carcinoma. Urology. 2002; 60: 993.
[3] Timsit MO, Bazin JP, Thiounn N, et al: Prospective study of safety margins in partial nephrectomy: intraoperative assessment and contribution of frozen section analysis. Urology. 2006; 67: 923.
[4] Minervini A, Ficarra V, Rocco F, et al. Simple enucleation is equivalent to traditional partial nephrectomy for renal cell carcinoma: results of a nonrandomized, retrospective, comparative study. J Urol. 185:1604-1610
[5] Touijer K, Jacqmin D, Kavoussi LR et al. The expanding role of partial nephrectomy: a critical analysis of indications, results, and complications. Eur Urol. 2010; 57: 214.
[6] AnI, Finelli A, Alibhai SMH, et al. Prevalence and impact on survival of positive surgical margins in partial nephrectomy for renal cell carcinoma: a population-based study. BJU Int. 2013;111: E300–E305.
[7] Marszalek M, Carini M, Chlosta P et al. Positive surgical margins after nephron-sparing surgery. Eur Urol. 2012; 61: 757.
[8] Raz O,Mendlovic S, Shilo Y, et al. Positive surgical margins with renal cell carcinoma have a limited influence on long-term oncological outcomes of nephron sparing surgery. Urology. 2010;75:277–80.
[9] Sundaram V, Figenshau RS, Roytman TM, et al. Positive margin during partial nephrectomy: does cancer remain in the renal remnant? Urology. 2011;77:1400–3.
[10] Besalah K, Pantuck AJ, Rioux-Leclercq N, Thuret R, et al. Positive surgical margin appears to have negligible impact on survival of renal cell carcinomas treated by nephron-sparing surgery. Eur Urol. 2010;57:466-473.
[11] Khalifeh A, Kaouk JH, Bhayani S, et al. Positive surgical margins in robot-assisted partial nephrectomy: a multi-institutional analysis of oncologic outcomes (leave no tumor behind). J Urol. 2013;190:1674-1679.

Renal Cell Carcinoma: Risk Factors and Epidemiology

Renal cell carcinoma (RCC) is the most common kidney tumor worldwide. Many patients are curious as to why they have a tumor and if there is anything they did to cause it? There are not many, well-established risk factors for RCC.  We will discuss what is known below.

RCC Epidemiology Facts

RCC is more common in the developed, rather than the developing world as the incidence increases with age and other age-related risk factors.

• Countries of Northern America, Europe, Australia and New Zealand have the highest risk of RCC in the world.
• Countries with the lowest-risk of RCC are in Africa and the Caribbean. [1]  
• In the US, there are approximately 64,000 new cases of renal cancer per year and 13,500 people die of renal cancer each  year.  
• The incidence of renal cancer has steadily risen over the past few decades due to the increased use of axial imaging. 
• This corresponds to a steady increase in localized cancers while the rates of locally-advanced and metastatic disease have remained stable. [2]  
• Interestingly, despite the steady increase in the number of cancers, the mortality from kidney cancer has remained stable.

RCC Risk Factors

RCC is more common in men than women.  It is the 6th most common cancer in men and the 8th most common cancer in women.  The other well-established risk factors that will be discussed in this blog include tobacco exposure and obesity.  Putative risk-factors for RCC are listed below and will not be discussed in this blog as there is neither strong evidence in favor of or against each risk.  In addition, there are a number of genetic causes of RCC.  While these genetic causes are strong predictors of RCC, they are rare and will be the focus of a later blog.  

Well-Established Risk Factors for RCC

Tobacco Exposure
Obesity
Genetic Causes

Possible Risk-Factors for RCC

Hypertension
Chemical Exposures (lead compounds, aromatic hydrocarbons)
Occupational Exposures (asbestos)
Radiation Therapy
Dietary Factors (high fat, low fruit/vegetables)

Tobacco Exposure and Renal Cell Carcinoma

Cigarette smoking is the most well-established risk factor for RCC.  It is believed that chronic smoking leads to DNA damage through chronic tissue hypoxia. The risk of RCC is proportional to the dose and duration of exposure.  A meta-analysis of 24 studies demonstrated a 38% increased risk of RCC with any smoking exposure; that risk was modified by male sex and more cigarette exposure on a daily basis.  This study also demonstrated that smoking cessation alleviates the risk of RCC, but only 10 years after quitting.[3]

Hunt et al. Int J Cancer, 2005.

Not only has smoking been attributed to an increased risk of RCC, but smokers also have a higher risk of death from RCC.  In fact, it has been demonstrated that for every pack-year of smoking history a patient has a 1% increased risk of death from RCC.[4]

Obesity and Renal Cell Carcinoma

Rates of RCC increase with increasing Body Mass Index.  In 11 studies comparing RCC and BMI, each 5kg/m3 increase in BMI corresponds to a 25% increase in the rate of RCC in men, and 34% increase in women.[5]  Obesity leads to an altered endocrine milieu, led by compensatory hyperinsulinemia and production of adipokines, which creates an environment of inflammation and oxidative stress leading to the formation of RCC.[6]

Renehan et al. Lancet, 2008.

Contrary to the relationship with smoking, obese patients with RCC have an improved long-term survival after diagnosis.[7]  This has been termed the "obesity paradox" and exists in a number of other disease states like patients with chronic kidney disease on dialysis, diabetes and heart failure.  Recent evidence indicates that obese patients may present with smaller, earlier-stage and lower grade tumors - indicating for the relative improvement in survival.[8]

Summary

• Renal cell carcinoma is more common in the developed world than developing nations.
• The incidence of RCC has increased dramatically in the US - this corresponds to an increased use of axial imaging.
• The number of deaths from RCC has remained stable over the same time period, reflecting the stable rates of advanced and metastatic disease.
• Risk factors for RCC include:
• Male Sex: men are more likely than women to develop RCC
• Smoking: 
• The risk of RCC increases with increasing exposure to tobacco smoke.
• The risk of death from RCC also increases with tobacco exposure.
• Obesity:
• The risk of RCC increases with increasing BMI.
• The risk of death from RCC is lower in patients with a larger BMI (this is termed the "obesity paradox").

This blog was written by Michael Gorin, MD, resident at the Brady Urological Institute at Johns Hopkins.  Visit the Brady Urological Website for more information on kidney cancer and its treatment.







[1] Ljungberg B, Campbell SC, Choi HY, Jacqmin D, Lee JE, Weikert S, Kiemeney LA. The epidemiology of renal cell carcinoma.Eur Urol. 2011 Oct;60(4):615-21. doi: 10.1016/j.eururo.2011.06.049. Epub 2011 Jul 5.
[2] Chow WH, Dong LM, Devesa SS.  Epidemiology and risk factors for kidney cancer.
Nat Rev Urol. 2010 May;7(5):245-57.
[3] Hunt JD, van der Hel OL, McMillan GP, Boffetta P, Brennan P.Renal cell carcinoma in relation to cigarette smoking: meta-analysis of 24 studies.  Int J Cancer. 2005 Mar 10;114(1):101-8.
[4] Kroeger N, Klatte T, Birkhäuser FD, Rampersaud EN, Seligson DB, Zomorodian N, Kabbinavar FF, Belldegrun AS, Pantuck AJ.  Smoking negatively impacts renal cell carcinoma overall and cancer-specific survival.  Cancer. 2012 Apr 1;118(7):1795-802. doi: 10.1002/cncr.26453. Epub 2011 Aug 25.
[5]  Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M.Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies.Lancet. 2008 Feb 16;371(9612):569-78.
[6] Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med. 2010;61:301–316.
[7] Choi Y, Park B, Jeong BC, et al. Body mass index and survival in patients with renal cell carcinoma: a clinical-based cohort and meta-analysis. Int J Cancer. 2013;132(3):625–634.
[8] 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.

Exstrophy Bootcamp 2014

May 14^th-15^th, 2014

Charlotte Bloomberg Children’s Center of the Johns Hopkins Hospital

Baltimore, MD

Programming generously underwritten by support from Alison and Ralph Ho.

The Division of Pediatric Urology is very excited to be hosting a two-day intensive course, which will review all facets of the modern approach to the evaluation and management of exstrophy patients. This course promises to be one of the most comprehensive events to ever focus entirely on exstrophy.

Through the generosity of several important benefactors, the training will be free of charge for all registrants. This is quite fortunate since we have sought to enroll many residents and fellows, who may have a limited budget. Indeed, the course has currently enrolled about seventy participants, including residents, fellows, junior faculty, senior faculty and even a few medical students. Another important enrollment goal has been to include a large international contingent of participants. At present we have physicians coming to Baltimore from six continents and 27 countries to participate in the course! We scheduled the course for the days just before the annual meeting of the American Urological Association and the Society for Pediatric Urology, so that international physicians will be able to attend both events while they are here in the U.S.

We are quite fortunate to have the following esteemed group of faculty who will offer their extensive experience and insights to the management of exstrophy:

Course Chairmen:
Programming generously underwritten by support from Alison and Ralph Ho.

John P. Gearhart, MD

John P. Gearhart, M.D.

Robert D. Jeffs Professor and

Director of Pediatric Urology

Brady Urological Institute

The Johns Hopkins Children’s Center

Paul D. Sponseller, M.D.

Professor and Division Chief

of Pediatric Orthopaedics

The Johns Hopkins Children’s Center

Ranjiv I. Mathews, M.D.

Adjunct Associate Professor

of Pediatric Urology

Brady Urological Institute

The Johns Hopkins Children’s Center

Hopkins Faculty:

Richard J. Redett, M.D.

Shabine Kost-Bylerly, M.D.

E. James Wright, M.D.

Heather N. DiCarlo, M.D.

Jessica Hankinson, Ph.D.

Marlo Eldridge, C.P.N.P.

Invited Lecturers:

Douglas A. Canning, M.D.

Fernando A. Ferrer, M.D.

Kirsten K. Meldrum, M.D.

Yegappan Lakshmanan, M.D.

Dominic D. Frimberger, M.D.

J. Todd Purves, M.D.

Thomas E.Novak, M.D.

Timothy M. Phillips, M.D.

Max Cervellione, M.D.

Andrew A. Stec, M.D.

Kristina D. Suson, M.D.

Eric Z. Massanyi, M.D.

Anthony J. Schaeffer, M.D.

Invited Moderators:

Joseph Borer, M.D.
Dennis Peppas, M.D.

Caleb Nelson, M.D.

While physicians play the central role in reconstruction, it is hard to overstate the importance that nurses and other allied health professionals play in the care of exstrophy patients. Accordingly, there will be a separate section of the course that will focus specifically on these critical aspects of patient care. This section will run concurrently and will take place on the first day, Wednesday May 14^th.  We are lucky to have two members of the division who each have tremendous experience caring for exstrophy patients. They will be leading this component of the course:

Marlo A. Eldridge, RN, MSN, CPNP

Director of Voiding Improvement Program

Faculty Pediatric Urology/Brady Urological Institute

The Johns Hopkins Children’s Center

Karen L. Spriggs, RN

Senior Clinical Nurse, Pediatric Urology

The Johns Hopkins Children’s Center

Both sections of the course will take place on the beautiful Mt. Washington campus of Johns Hopkins University:

Mt. Washington Conference Center:

5801 Smith Avenue, Suite 1100

Baltimore, MD  21209

Tel: 410-735-7964 or 800-488-8734

www.acc-mtwashingtonconferencecenter.com

For more information about the course please refer to the following website:

http://www.hopkinschildrens.org/exstrophy-bladder-bootcamp/

Or follow us on FACEBOOK.

This blog was written by Ezekial Young, MD and Pediatric Urology Fellow at the Brady Urological Institute at Johns Hopkins.  If you have questions or are interested in participating in the course please contact:

Ezekiel E. Young, M.D.

E-Mail:  eyoung31@jhmi.edu

Phone: (401)569-6913

Historical Contribution: HH Young, The Punch Procedure, 1913

1913

Transurethral prostatectomy: A new procedure (punch procedure) for small prostatic bars and contracture of the prostatic orifice. Young H.H. JAMA 1913;9:253

In 1904, Hugh Hampton Young performed the first perineal prostatectomy for the treatment of prostate cancer.  Continuing his innovation in the treatment of urologic and prostatic diseases, HH Young developed instruments and surgeries to treat men with a "median bar," what many urologist's would refer to today as a high-riding bladder neck without the classic bilateral hypertrophy seen in many patients with benign prostatic hyperplasia (BPH).  In this manuscript, HH Young describes a variety of patients, instruments and outcomes for men suffering from urinary retention.  Its a fascinating look at the status of urology in the early 1900's.

Read the entire article here.

Micropapillary Bladder Cancer: I Have It, Now What Does it Mean?

More than 75k people in the United States are diagnosed with bladder cancer on an annual basis and its estimated that >500k people in the US are living with the disease.[1,2]  Greater than 90% of bladder cancers are urothelial cancer (UC; of the lining of the bladder); and 75% of UC are non-muscle invasive or growing out of the lining of bladder.  There are rare variants of UC including nested, microcystic, inverted, squamous and glandular differentiation, sarcomatoid, clear cell and micropapillary variants.

Micropapillary is currently the most well-studied, independent histology.  Although rare relative to the large number of patients with undifferentiated, conventional UC, micropapillary cancer still affects a significant proportion of patients.  Here we will review the definitions and implications of micropapillary bladder cancer for those patients with a new diagnosis.

Epidemiology and Statistics [3]

• 0.7-2.2% of all UC are micropapillary
• Average age at diagnosis: 65
• Male-to-female ratio  10:1

Histology and Pathology [4-8]

• Micropapillary tumors grow in delicate filiform processes in infiltrating clusters lacking vascular stalks (see images from WebPathology.com)
• Vascular and lymphatic invasion is common.
• 80% cases found with conventional UC

• The amount of micropapillary cancer does not have bearing on outcomes; outcomes are consistent if 10% or greater of the tumor contains micropapillary cancer
• Less than 9% have non-muscle invasive disease; 70% will progress to invasive disease.
• At cystectomy for non-muscle invasive disease:
• >50% can be upstaged
• >25% had occult lymph node metastases
• 50% present as muscle-invasive, node-positive or metastatic disease

Treatment and Outcomes

Retrospective studies show an overall worse prognosis for micropapillary cancer when compared to conventional UC of the bladder.[9-10]  However, micropapillary cancer often presents at and advanced stage and two case-matched series did not show a survival difference between micropapillary and conventional UC when matched stage-for-stage.[11,12]  

It is clear that micropapillary urothelial cancer is an aggressive variant of bladder cancer; it is unclear if it is independently worse than conventional urothelial cancer.

In general, surgical removal of the bladder (radical cystectomy) is the most effective treatment for micropapillary cancer.  Rare cures are achieved with transurethral resection if non-invasive cancer and complete resection is achieved; although BCG treatments are ineffective if tumors are incompletely resected.[8,13]   

In a few studies, neoadjuvant chemotherapy (NAC; chemotherapy before cystectomy) does not appear to be effective for micropapillary cancer.[8,14]  In the initial report of micropapillary cancer from MD Anderson Cancer Center demonstrated a 5-year survival of 71% for those undergoing immediate cystectomy and 63% for those receiving NAC before surgery.[8]  However, the data regarding the use of NAC is sparse and other centers have reported beneficial outcomes with NAC.  For instance, Meeks et al demonstrated 45% downstaging from transurethral resection to cystectomy and a significant survival advantage to patients downstaged to pT0 (no residual cancer in the bladder) with NAC.[15]  Ghonheim and colleagues argue for the use of NAC citing an 86% rate of micrometastatic lymph node metastases.

Therefore, the use of neoadjuvant chemotherapy remains controversial - with some centers advocating its use and some centers believing that neoadjuvant chemotherapy may actually worsen survival by delaying therapy.   

Survival Statistics for Micropapillary Cancer of the Bladder

All Patients [11,12,16]

• Overall Recurrence-Free Survival: 58% at 5 years
• Local Recurrence-Free Survival: 62% at 10 years
• Distant Metastases-Free Survival: 44% at 10 years
• Cancer-Specific Survival: 31% at 10 years
• Overall Survival: 40-67% at 5 years, 21% at 10 years

Non-Muscle Invasive Micropapillary Bladder Cancer

BCG failure: 67% progressed, of which 22% developed metastases

Immediate Cystectomy: 72% alive at 5-years

Cystectomy after Intravesical Treatment: 60% alive at 5-years

Muscle-Invasive Micropapillary Bladder Cancer

Immediate Cystectomy: 70% alive at 5-years

If pT0 (no cancer at found at cystectomy) or carcinoma-in-situ (CIS): no deaths at 38 months

If Locally Advanced Cancer: 22% alive at 4 years

If Non-Organ Confined Disease: 38.1 months median survival

If Non-Resectable Disease: 17 month median survival

1. American Cancer Society, Facts & Figures 2014; Accessed March 21, 2014.  http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf
2. Surveillance, Epidemiology, and End Results (SEER) Stat Fact Sheets: Bladder Cancer; Accessed March, 21, 2014.  http://seer.cancer.gov/statfacts/html/urinb.html  
3. Amin MB, Ro JY, el-Sharkawy T,et al: Micropapillary variant of transitional cell carcinoma of the urinary bladder. Histologic pattern resembling ovarian papillary serous carcinoma. Am J Surg Pathol 1994; 18: 1224-1232.
4. Johansson SL, Borghede G, Holmang S,et al: Micropapillary bladder carcinoma: a clinicopathological study of 20 cases. J Urol 1999; 161: 1798-1802.
5. Kamat AM, Dinney CP, Gee JR,et al: Micropapillary bladder cancer: a review of the University of Texas M.D. Anderson Cancer Center experience with 100 consecutive patients. Cancer 2007; 110: 62-67.
6. Lopez-Beltran A, Cheng L: Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications. Hum Pathol 2006; 37: 1371-1388.
7. Johansson SL, Borghede G, Holmang S,et al: Micropapillary bladder carcinoma: a clinicopathological study of 20 cases. J Urol 1999; 161: 1798-1802.
8. Kamat AM, Dinney CP, Gee JR,et al: Micropapillary bladder cancer: a review of the University of Texas M.D. Anderson Cancer Center experience with 100 consecutive patients. Cancer 2007; 110: 62-67.
9. Comperat E, Roupret M, Yaxley J, et al. Micropapillary urothelial carcinoma of the urinary bladder: a clinicopathological analysis of 72 cases. Pathology 2010; 42:650–654. 
10. Samaratunga H, Khoo K. Micropapillary variant of urothelial carcinoma of the urinary bladder; a clinicopathological and immunohistochemical study. Histopathology 2004; 45:55–64. 

11. Wang JK, Boorjian SA, Cheville JC, et al. Outcomes following radical cystectomy for micropapillary bladder cancer versus pure urothelial carcinoma: a matched cohort analysis. World J Urol 2012; 30:801–806.

12. Fairey AS, Daneshmand S, Wang L, et al. Impact of micropapillary urothelial carcinoma variant histology on survival after radical cystectomy. Urol Oncol 2013.

13. Gaya JM, Palou J, Algaba F, et al. The case for conservative management in the treatment of patients with nonmuscle-invasive micropapillary bladder carcinoma without carcinoma in situ. Can J Urol 2010; 17:5370–5376.

14. Bristow RE, Gossett DR, Shook DR,et al: Micropapillary serous ovarian carcinoma: surgical management and clinical outcome. Gynecol Oncol 2002; 86: 163-170.

15. Meeks JJ, Taylor JM, Matsushita K, et al. Pathological response to neoadjuvant chemotherapy for muscle-invasive micropapillary bladder cancer. BJU Int 2013; 111:E325–E330.
16. Ghoneim IA, Miocinovic R, Stephenson AJ, et al. Neoadjuvant systemic therapy or early cystectomy? Single-center analysis of outcomes after therapy for patients with clinically localized micropapillary urothelial carcinoma of the bladder. Urology 2011; 77:867–870.

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.