Robotics in Urologic Oncology: Partial Nephrectomy for Kidney Cancer

Robotic surgery is the latest evolution in laparoscopic surgery. Traditional laparoscopic surgery was and is performed with rigid instruments, a two-dimensional view with the surgeon at the patient's bedside and an assistant controlling the camera (or view) of the operation. Robotic surgery makes use of a three-dimensional, dual-camera system; instruments that mimic natural hand motions leading to improved ergonomics, and while the surgeon sits at a console away from the patient, he or she has full control of the camera and view of the operation. The robotic systems used today are termed "master-slave" systems where the robot transforms human movements into scaled robotic movements, but the robotic instruments cannot function independently or autonomously.

The most widely-used robotic system is the daVinci system by Intuitive Surgical. This system was first cleared by the FDA in 1997 for surgical assistance, for radical prostatectomy in 2001 and broad urological surgery in 2005. There are currently over 2,000 daVinci units in use in the United States and nearly 1,000 additional units worldwide. Urology and urologic oncology as specialties represent a major proportion of the utilization of robotic surgery. For many diseases and operations, robotic technology has improved perioperative and long-term outcomes – for other operations the benefit is marginal at best. In this series of blog entries, we will review the utilization and impact of robotic technology on a number of urologic oncology disease states.

The first blog in this series will focus on kidney cancer and the use of robotic partial nephrectomy.

 

THE HISTORY OF LAPAROSCOPIC NEPHRECTOMY AND PARTIAL NEPHRECTOMY

The first laparoscopic radical nephrectomy was performed in 1991 by Dr. Clayman and colleagues at the Washington University School of Medicine, St Louis.[1] Unlike appendectomy (appendix removal) and cholecystectomy (gallbladder removal) in general surgery, the adoption of laparoscopic nephrectomy was slow in the US with only 30% of nephrectomies being performed laparoscopically by 2005.[2] In comparison, 70% of gallbladders were removed laparoscopically 15 years after the first laparoscopic cholecystectomy. During the same time period, partial nephrectomy (PN, or removal of just a kidney tumor and the surrounding normal kidney tissue) was historically underutilized in the US. In the 1990's and early 2000's, only approximately 10% of kidney surgeries were PN – and most of these were performed at large, academic, urban and teaching hospitals.[3] While the rates oif both laparoscopy and PN increased during the 2000's, the majority of PN were performed through an open incision, once again in large urban and teaching hospitals.[4]

 
In the late 2000's, a number of national and worldwide trends changed the way kidney surgery was performed. First, robotic technology was taking off – the daVinci system was approved for radical prostatectomy in 2001 and over the next decade hospitals all over the US were acquiring robots. As the number of robotic prostatectomies and surgeries increased nationwide, surgeons became more comfortable with robotic technology and began looking for more uses. In addition, in 2009, the AUA (American Urological Association) released the "Guidelines for the Management of the Clinical Stage 1 Renal Mass." The Guideline states that "Nephron-sparing surgery should be considered in all patients with a clinical T1 renal mass as an overriding principle," and within a year of releasing the Guidelines, the utilization of PN increased from 27% to 32% nationwide.[5]

 
Data from Johns Hopkins and the State of Maryland indicate that the rate of PN increased from 9% to 27% from 2000 to 2010. The proportion of open PN decreased by 1/3^rd and robotic and other minimally-invasive PN increased to nearly 60% of all PN. Importantly, after 2008 (a time period which robotic technologies were widely disseminated), being treated at a university hospital was no longer a predictor of PN – PN was finally becoming widespread!![6] 

The increasing using of robotic and minimally-invasive partial
nephrectomy in the State of Maryland. From Patel et al. [6]

This local trend was reflected in national data, indicating modest increases in open PN (8%) but dramatic increases in robotic PN (45%) in the National Inpatient Sample (a large all-payer inpatient care database cataloguing over 7 million inpatient hospitalizations).[7]

 

COMPARATIVE OUTCOMES FOR ROBOTIC PARTIAL NEPHRECTOMY: 

DO THE DATA SUPPORT THIS TREND?

In general, the increasing use of robotic PN is supported by data and represents one of the true "success stories" for robotic surgery. Robotic surgery is beneficial to patients undergoing PN as the wristed robotic instruments and three-dimensional views facilitate better and faster removal of tumors and reconstruction of the kidney.  The video below is a representative example of a robotic PN: the artery is temporarily clamped to facilitate a bloodless resection and reconstruction (ischemia time), the tumor is resected and the kidney is reconstructed.

In a systematic review of eight studies comparing robotic PN to open PN, robotic PN was associated with:

• Longer operative time (+40.89 minutes ; p = 0.002)
• Lower perioperative complication rate (19.3% for RPN and 29.5% for OPN)
  • Odds ratio: 0.53; 95%CI, 0.42–0.67; p<0.001
• Shorter hospital stay (−2.78 days; p<0.00001)
• Less estimated blood loss (−106.83mL; p = 0.003)

There was no difference observed in transfusions, conversion to radical nephrectomy, ischemia time, estimated GFR change (kidney function), surgical margin status, or overall cost.[8]
Comparing robotic to laparoscopic PN in a systematic review of 12 studies and over 700 patients, demonstrated no difference in operative times, estimated blood loss, conversion rates, length of hospital stay, complications, or positive margins between the surgeries. In fact, the only notable difference was that robotic PN was associated with less warm ischemic time (quicker removal of the tumor and reconstruction of the kidney). It should be noted that laparoscopic surgery was performed by fewer, but expert surgeons while robotic PN was performed by a greater variety of surgeons of varying experience level.[9]

When comparing our data at Johns Hopkins, we found that robotic PN was associated with improved operative parameters (operative time, blood loss, ischemia time) and fewer serious complications.[10] In addition, we determined that the learning curve for robotic PN was much quicker than laparoscopic surgery – about 25 patients.[11]

While long-term oncologic data is lacking, surrogate oncologic measure (i.e. surgical margin status) and short-term recurrence and survival data indicate that robotic PN is equivalent to open and laparoscopic surgery with regards to oncology outcomes, and likely superior with regard to perioperative outcomes.

 

SUMMARY

• The emergence of robotic technology dramatically changed the management of kidney cancer in the United States, with more patients undergoing partial nephrectomy now than ever before.
• The comparative data demonstrates improved outcomes for many peri-operative and surrogate oncologic outcomes. Longer-term data will likely confirm robotic PN as the standard-of-care for small renal masses requiring treatment.

 

 

This blog was adapted from a lecture titled "Robotics in Urologic Oncology," given by Phillip M. Pierorazio, MD, Assistant Professor of Urology and Oncology, at the Emirates Oncology Conference, 2014 in Abu Dhabi.

 

 

1. Clayman et al. Laparoscopic Nephrectomy. N Engl J Med 1991; 324:1370-1371May 9, 1991. http://www.nejm.org/doi/full/10.1056/NEJM199105093241918
2. Miller, D. C. et al. JAMA 2006;295:2480-2482
3. Hollenbeck, Urology, Volume 67, Issue 2, 2006, 254 - 259
4. Patel et al., J Urol, Volume 187, Issue 3, 2012, 816 - 821
5. Bjurlin et al., Urology, Volume 82, Issue 6, 2013, 1283 - 1290
6. Patel et al., J Urol, 2013 Apr;189(4):1229-35.
7. Ghani et al., J Urol, Volume 191, Issue 4, 2014, 907 - 913
8. Wu etal. PLoS One. 2014; 9(4): e94878.
9. Aboumarzouka etal. Eur Urol. 2012 Dec;62(6):1023-33.
10. Mullins etal. Urology. 2012 Aug;80(2):316-21.
11. Pierorazio et al., Urology, 78 (2011), p. 813

Historical Contribution: 1945, Lewis, Bladder Dysfunction after Trauma

1945
Lewis LG. Treatment of Bladder Dysfunction after Neurologic Trauma. J Urol. 1945; 54; 3: 284-95.    

 

Lloyd G. Lewis, MD

LLoyd G. Lewis graduated the Brady Residency in 1933. He was remembered as a superb surgeon and co-author of The Physiology of Micturation, 1940 after undertaking a number of laboratory experiments involving the innervation of the feline bladder. During World War II, Lewis served as Chief of Urology at Walter Reed General Hospital in Washington, DC and succeeded in having Walter Reed approved for residency training during his time there. This manuscript was written while Chief of Urology at Walter Reed.

To understand the neurogenic bladder, one must first understand the normal mechanisms of bladder function. Therefore, Dr. Lewis begins this manuscript with a thorough description of the normal anatomy and neurophysiology of bladder storage and micturition as it was understood in the 1940's. Interestingly, the pathophysiology for abnormal bladder function came from studies of advanced syphilis patients (with tabes dorsalis) and pelvic surgery patients. Through careful observation and meticulous attention to detail, Lewis noted neurologic consistencies among patients with similar neurologic diseases or injuries, and tabulated the following observations:

• The immediate effect of severe injury to the brain or spinal cord is urinary retention (a concept called spinal shock).
• Spinal shock was believed to be relieved within 48 hours.
• Failure to decompress the spinal cord within 48 hours would lead to permanent disability.
• Lewis demonstrates 10 circumstances where bladder function was restored weeks to months following surgical decompression of the spinal cord.
• Until the permanent neurourologic state is determined, treatment should focus on:
• Prevention of ascending urinary tract infections (UTI).
• Protection of paralyzed muscles.
• Restoration of function.
• To prevent UTI, HH Young preached "no instrumentation" of the urinary tract. Lewis noted that failure to drain the urinary system would lead to permanent dysfunction of the bladder, likely due to overstretching. Therefore, Lewis recommended:
• No instrumentation for 24 hours.
• If no voiding after 24 hours, a one-time, straight urethral catheter should be employed.
• If the patient is unable to void, a second, indwelling urethral or suprapubic drainage should be instituted. 
• Changing of the urinary catheter every 5 days in the acute setting.
• Chronic catheter changes at 6 week intervals if needed. 
• Use of acidic-solution irrigation if needed to prevent encrustation and infection of the catheter.
• Perineal urethrostomy with catheter drainage (performed under local anesthetic) if periurethral abscesses.
• Lewis described the outcomes of 16 patients with a variety of complete and incomplete spinal cord injuries resulting in urinary retention. From these observations, he concluded that:
• Permanent drainage is indicated for complete injuries below L1.
• Outlet obstruction cannot be relieved with surgical operations.
• Presacral neurectomy (surgical transection of the parasympathetic nerves to the bladder) can be considered as an experimental treatment in patients with residual urine and no concern for ejaculatory function.
• Patients are more comfortable with permanent cystostomy tubes than permanent incontinence.
• Surgery to decompress or treat the neurologic injury should be instituted immediately; any surgery to treat bladder dysfunction should be delayed for months to years, as adequate neurologic function may return.

Interestingly, many of the principles laid forth by Lewis in 1945 remain the standard principles practiced by urologists today.

To read the entire manuscript: follow the link above, visit the Centennial Website or click here.

HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Acute Kidney Injury: Understanding the Causes

Acute kidney injury (AKI), previously known as acute renal failure, is a rapid reduction in kidney function that can represent a spectrum of injuries that involve failure to maintain fluid, electrolyte and acid-base balances. A variety of patients suffering from a variety of medical conditions can develop AKI. Patients with urological issues often experience AKI as a result of their disease, or occasionally treatments thereof. 

A prior blog reviewed the "Basics of Renal Failure and Acute Kidney Injury," click here to read the prior blog.

This blog will review the causes of AKI, specifically as they may affect urological patients.

In general, AKI is grouped into three categories that describe the etiology (cause) and subsequent management:

• Pre-renal
• Intra-renal
• Post-renal

Most patients who develop AKI in the community do so as a result of a pre-renal etiology. In contrast, of the patients who develop AKI in the hospital, upwards of 45%, do so as a result of acute tubular necrosis (ATN) – a form of intra-renal AKI. For surgical patients, there are 11 established pre-operative predictors of AKI following surgery:

• Age ≥ 56 years
• Male Sex
• Congestive Heart Failure (CHF)
• Diabetes Mellitus on oral medications or requiring insulin
• Hypertension
• Emergency Surgery
• Intraperitoneal (Abdominal) Surgery
• Ascites (fluid in the abdomen)
• Mild or moderate renal insufficiency preoperatively

The strongest predictors of post-operative AKI are intraperitoneal (abdominal) surgery, pre-existing renal insufficiency and abdominal ascites.[1]

From Kheterpal etal. [1]

PRE-RENAL ACUTE KIDNEY INJURY

All causes of pre-renal AKI result from decreased perfusion of the kidney. Common causes include decreased blood volume, dehydration, heart failure and other disease states that decrease blood flow to the kidneys. Most commonly, pre-renal AKI is due to transient hypoperfusion (or decreased blood flow to the kidney over a short period of time). Pre-renal AKI can be further classified into three causes of hypoperfusion:

• Volume depletion: not enough blood volume to perfuse the kidney
  • Traumatic or surgical blood loss
  • Gastrointestinal losses (dehydration) from vomiting, diarrhea, etc.
  • Dehydration due to kidney disease (overdiuresis, salt-wasting diseases)
• Cardiac: blood volume is normal, but the heart cannot "pump" the blood effectively
  • Acute causes: myocardial infarction (heart attack), arrhythmia
  • Chronic causes: valvular disease, cardiomyopathy
• Redistribution of fluid: blood volume is normal, the hear can pump effectively, but the body cannot keep fluid in the blood vessels
  • Hypoalbuminemia (low body protein): liver disease, malnutrition/starvation
  • Physical injury: burns, crush injury
  • Vascular:
    • Vasodilation (opening of blood vessels all over the body, preventing blood from reaching the kidneys): serious infections, sepsis, anti-hypertensive medications
    • Obstruction of the renal blood vessels: artherosclerotic disease, renal artery stenosis

Hallmarks of pre-renal AKI include a reversible state, lack of structural damage to the kidney or the nephron (microscopic filtering apparatus of the kidney), and response to replacement of fluids. Often patients will return to normal kidney function within 24-72 hours of fluid replacement.

 

INTRA-RENAL ACUTE KIDNEY INJURY

Intra-renal AKI can be further classified into diseases that affect either: (1) the microscopic blood vessels of the kidney, (2) the glomerulus, or filtering mechanism of the kidney), (3) the tubules of the kidney that resorb fluids and electrolytes, or (4) the interstitium (the space between strictures) in the kidney.
Microscopic blood clots and a number of diseases termed microangiopathies can affect the small blood vessels in the kidney. The glomerulus is most often affected by a number of autoimmune disease states including: anti-glomerular basement membrane disease, glomerulonephritis (inflammation of the glomerulus) related to SLE (systemic lupus erythematosus) or Wegener's (ANCA-associated). In addition, glomerulonephritis can occur after a number of serious bacterial infections – termed post-infectious glomerulonephritis.
The most common cause of tubular injury is ATN (Acute Tubular Necrosis) caused by a combination of renal hypoperfusion and ischemic (no blood flow) injury, usually in combination with a toxic exposure to medication, prolonged surgery or disease-state that makes the kidney more sensitive to injury. ATN usually presents as oliguria (very low urine output, 150-300cc/day; normal is 800-2,000cc/day). During the early phases of ATN, the serum creatinine will rise (see "Basics of Renal Failure and Acute Kidney Injury" for description of serum creatinine and its relationship to AKI) while the patient continues to make an unconcentrated form of urine. Most patients will recover from ATN, however due to the tubular injuries patients can experience serious fluid and electrolyte abnormalities – about 25% of deaths related to AKI occur in the initial phases of ATN.
Interstitial diseases of the kidney are often caused by medications, infections and autoimmune diseases (similar to glomerulonephritis). AIN (Acute Interstitial Nephritis) is a rare but serious cause of drug-induced AKI. The most common meidcations to cause AIN are antibiotics, non-steroidal anti-inflammtory medications (ibuprofen, aspirin), diuretics and proton-pump inhibitors for gastroesophageal reflux. Patients may develop a fever, demonstrate white blood cells (specifically eosinophils, inflammatory cells associated with allergy-like reactions) in their urine without infection, and have a rising serum creatinine.

 

POST-RENAL ACUTE KIDNEY INJURY

Post-renal AKI refers to any obstruction of the urinary system. Obstructions can occur in the kidney, ureter(s) or at the level of the bladder, prostate (in men) or urethra. The obstruction is usually mechanical in nature and can be caused by a variety of benign and malignant conditions. Kidney stones, blood clots, stricture disease and malignancy can obstruct the ureters. Obstruction should involve both ureters to cause AKI; however in some circumstances, when pre-existing renal insufficiency is present, obstruction of one ureter can cause AKI. Similar causes including bladder stones, urethral strictures, benign growth (benign prostatic hyperplasia in men, uterine disease or prolapse in women) and pelvic malignancies can cause obstruction of the bladder and/or urethra. Post-renal AKI is easily treated with resolution of the obstruction. The obstruction can be relieved with a catheter in the bladder or nephrostomy tubes in the kidneys until the offending cause can be treated.

 

SUMMARY

• AKI can be grouped into three etiologies that describe the cause and management of the injury:
  • Pre-renal
  • Intra-renal
  • Post-renal
• Pre-renal AKI refers to hyoperfusion or not enough blood flow to the kidney.
• Intra-renal AKI is usually due to disease states that affect the kidney and its micropscopic filtering unit, the nephron.
• Post-renal AKI is caused by mechanical obstruction of the urinary system and is treated by drainage until the offending obstruction can be removed.

 

 

 

 
[1] Kheterpal S et al. Development and validation of an acute kidney injury risk index for patients undergoing general surgery: Results from a national data set. Anesthesiology 2009; 110 (3): 505-15.

Radiation Therapy after Prostate Surgery, Part III: Salvage Therapy

Some men prostate cancer are faced with the realization that treatment of their prostate cancer may require multimodal treatment including some combination of surgery, radiation therapy and/or hormone therapy. The combined ASTRO/AUA (American Society for Therapeutic Radiology and Oncology/American Urological Association) Guideline for "Adjuvant and Salvage Radiotherapy after Radical Prostatectomy" makes a number of statements regarding the use of radiation therapy after surgery that can be confusing to patients and practitioners. 

In the third part in this blog series, we review the statements from the ASTRO/AUA Guideline regarding salvage radiation therapy and the data supporting them.
To read Part I: Adjuvant Radiation following Surgery for Prostate Cancer click here.
To read Part II: Subgroup Analyses of Adjuvant Radiation for Prostate Cancer click here.
The Guideline Statements regarding adjuvant radiation therapy and three randomized studies (SWOG 8794, EORTC 22911, and ARO 96-02/AUO 09/95) that support their conclusions are detailed in Part I. To summarize, Part I: Adjuvant radiation therapy (ART), or radiation therapy given without evidence of cancer in men at high-risk for recurrence, is an option for men with advanced prostate cancer and adverse features after radical prostatectomy. Patients who undergo ART can expect an improvement in biochemical (PSA) and locoregional recurrence, although the benefits on distant metastases and overall survival is less clear. Part II reviews the subgroups of patients who may benefit from ART. Based on these subgroup analyses, ART appears to have the most benefit for patients with positive surgical margins and Gleason score 7-10. The benefit of ART in patients with Gleason 6, extraprostatic extension (in the absence of a positive surgical margin) and seminal vesicle invasion is less clear.

Salvage radiotherapy (RT) is defined as RT with clinical evidence of prostate cancer recurrence. Clinical evidence of prostate cancer recurrence can include any combination of:

• Elevated PSA level
• Recurrent mass or lymph node on imaging (CT scan usually)
• Biopsy-proven cancer in a recurrent mass

The guideline statements regarding salvage RT are detailed below. There are no randomized studies regarding the use of salvage RT, however several well-designed retrospective studies provide evidence for the use of this treatment.

The Guideline Statements

Guideline Statement 4.

• Patients should be informed that the development of a PSA recurrence after surgery is associated with a higher risk of development of metastatic prostate cancer or death from the disease. Congruent with this clinical principle, physicians should regularly monitor PSA after radical prostatectomy to enable early administration of salvage therapies if appropriate. (Clinical Principle)

Guideline Statement 5.

• Clinicians should define biochemical recurrence as a detectable or rising PSA value after surgery that is ≥ 0.2 ng/ml with a second confirmatory level ≥ 0.2 ng/ml. (Recommendation; Evidence Strength: Grade C)

Guideline Statement 6.

• A restaging evaluation in the patient with a PSA recurrence may be considered. (Option; Evidence Strength: Grade C)

Guideline Statement 7.

• Physicians should offer salvage radiotherapy to patients with PSA or local recurrence after radical prostatectomy in whom there is no evidence of distant metastatic disease. (Recommendation; Evidence Strength: Grade C)

Guideline Statement 8.

• Patients should be informed that the effectiveness of radiotherapy for PSA recurrence is greatest when given at lower levels of PSA. (Clinical Principle)
  

The Evidence

Based on a number of studies, including a study from Johns Hopkins, prostate cancer specific survival is significantly worse in men with a biochemical (PSA) recurrence after radical prostatectomy. In this study of over 600 men, the 5- and 10-year prostate-cancer survival for men receiving no salvage RT were 88% and 62%. For men receiving salvage RT, the prostate-cancer survival rates were 96% and 82-86% at 5- and 10-years respectively. This translates into a 3-fold increase in prostate-cancer survival for men receiving salvage RT.[1]

Importantly, these men only had a PSA recurrence and no evidence of distant metastatic disease. Men with distant metastatic disease are best treated by systemic therapy, either hormones and/or chemotherapy, and do not benefit from salvage radiation therapy. In addition, the benefit was only seen in men with a PSA doubling time of six months or less who underwent salvage RT within 2 years of biochemical recurrence. Another study of 500 men over 11 years demonstrated that salvage RT benefits men with both a PSA doubling time less than and greater to 6 months; however the benefit may be greater for men with PSA doubling time less than 6 months.[2]

Two additional studies provide evidence for the benefits of salvage RT in men with a rising PSA after surgery. A study of 500 patients from five centers demonstrated that more than two thirds of patients receiving salvage RT had a complete response (PSA became undetectable). In this study, patients with a PSA <0.6 had the best response to RT and patients with a PSA >2.0 had the highest risk of failure of salvage RT.[2] A follow-up study of over 1,500 patients confirmed the importance of pre-RT PSA value on prognosis. Patients treated with salvage RT alone at PSA levels of 0.5 ng/mL or lower had a 6-year progression-free survival rate of 48% compared with 26% for those treated at higher PSA levels.[3]

These data do not necessarily indicate that there is a causal relationship between PSA value and response to salvage RT. Likely, the PSA phenomenon reflect the biology of the recurrent prostate cancer and indicate groups of men most likely to have a meaningful benefit to RT.

 

Summary

Salvage RT should be offered to men with a biochemical (PSA) recurrence after radical prostatectomy. The benefits of RT are greatest in men with a low PSA level and low PSA doubling time.

This blog was written by Mark W. Ball, MD.  Mark is a 5^th year urology resident at the Brady Urological Institute at Johns Hopkins and looking forward to a career in urologic oncology.

 





[1] Trock BJ, Han M, Freedland SJ, Humphreys EB, DeWeese TL, Partin AW, Walsh PC. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008 Jun 18;299(23):2760-9. doi: 10.1001/jama.299.23.2760.
[2] Cotter SE, Chen MH, Moul JW, Lee WR, Koontz BF, Anscher MS, Robertson CN, Walther PJ, Polascik TJ, D'Amico AV. Salvage radiation in men after prostate-specific antigen failure and the risk of death. Cancer. 2011 Sep 1;117(17):3925-32. doi: 10.1002/cncr.25993. Epub 2011 Mar 22.
[3] Stephenson AJ, Shariat SF, Zelefsky MJ, et al . Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 2004;291:1325–1332.
[4] Stephenson AJ, Scardino PT, Kattan MW, et al . Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25:2035–2041. Erratum in: J Clin Oncol 2007;25:4153.

Historical Contribution: 1929, Young, Posterior Urethral Valves

1929
Posterior urethral valves: Congenital valve obstruction of the prostatic urethra. Young HH, McKay RW. Surg Gynecol Obstret 1929; 48:509.


 
Within this manuscript is the "classic" description of posterior urethral valves (PUV) and the first classification system taught to urologists to define the disease. PUV, or congenital valvular obstruction of the prostatic urethra, was described as a medical entity in the late-1700's and was first described in the medical literature by Dr. Conrad Johann Martin Langenbeck in 1802. In the first portion of this manuscript, Young and McKay detail the history of PUV from Langenbeck to their description including thoughtful descriptions of autopsy series, case reports and clinical outcomes from around the world. Common among all these reports was that all cases were found at autopsy or incidental discoveries during other genitourinary operations.

From Tolmatschew in 1870.

The etiology of PUV was unknown with a number of hypotheses put forward including: persistence of the urogenital membrane, or anomalous development of the Wolffian and Muellerian ducts. Young recognized that PUV was a clinical heterogeneous entity, with patients having a variety of clinical presentations and outcomes. Part of the objectives of this manuscript was to present a unifying theory of PUV – a challenging feat that Young recognized, "Apparently no single theory, as stated previously, will explain satisfactorily the formation of [PUV]."

 

The History of PUV at Johns Hopkins

The first cystoscopic diagnosis of PUV was at Johns Hopkins in 1912. The first curative, transurethral surgery was performed one year later, in 1913, by HH Young. By 1915, with a combination of cystoscopic evaluation and cystogram, Young and colleagues were able to demonstrate the clinical association between PUV and significant vesicoureteral reflux (VUR) often seen in the disease. In 1916, Young modified his famous "punch" operation for the prostate to the treatment of PUV in two patients. By 1919, Young, Frontz and Baldwin from Johns Hopkins reported 12 cases of PUV, of which 8 were treated transurethrally. The four patients who did not undergo treatment died of complications of urinary obstruction and renal failure.

Description of Cases and Clinical Outcomes from Hopkins

In this manuscript from 1929, Young added 21 cases from the Brady Urological Institute to the world's literature of 41 treated cases of PUV. This can be considered a very early, systematic review of PUV before that concept existed. In typical HH Young fashion, the clinical circumstances and outcomes of each case are recorded and reported with meticulous detail. Young reviews the "Symptomatology" or clinical presentation of patients, the diagnostic algorithm including differential diagnosis, treatment strategies including the prepatory treatment, and prognosis.
Importantly, incorporating all these concepts with careful attention to detail, Young was able to classify PUV into three main types (figure below):

• Type I: valves of the distal verumontanum, classified into (a) two separate valves, (b) two fused valves, and (c) and unilateral single valve.
• Type II: a bifurcated valve from the distal verumontanum to the more proximal prostatic urethra.
• Type III: an "iris-like" valve above the verumontanum.

 
When describing the clinical outcomes the first nine patients treated with the modified "punch procedure," HH Young demonstrated: six curative treatments, one curative treatment with resulting incontinence and two deaths (one due to sepsis following treatment, one death due to sepsis prior to treatment). Young was extremely selective in choosing patients for an operation, as he recognized many patients had end-stage renal disease – a terminal condition at the time. According to Young, "These results show conclusively that the punch operation was the method of choice but should always be preceded by thorough prepatory drainage until functional tests show sufficient improvement in renal function to warrant an operation."

The "punch procedure" modified for posterior urethral valves (PUV).

 
In summation, Young stressed the following points in the work-up and treatment of PUV – much of which are still relevant today!

• Initial evaluation should involve:
  • Anatomic investigation of the upper tracts
  • Investigation of renal function
• Initial management can involve insertion of small catheters to gain adequate drainage of the bladder and evaluate subsequent renal function.
• Cystoscopic evaluation and possible treatment (punch procedure) is the second step in management of these children and can be very effective in carefully selected patients.

 

To read the entire manuscript: follow the link above, visit the Centennial Website or click here.

HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

A Social Media Experiment in Childrens’ Urinary Tract Infections

It has been reported that the incidence of urinary tract infections (UTI) in children younger than 6 years is 3-7% for girls and 1- 2% for boys.

Studies on UTIs are important because the disease not only causes acute illness, but can also result in long-term complications such as hypertension and reduced renal function. One of the many challenges in the treatment and prevention of UTIs is the rising rate of antibiotic-resistant bacteria due to the widespread use of antibiotics.

Dr. Ming-Hsien Wang

Dr. Ming-Hsien Wang is an Assistant Professor of Pediatric Urology at Johns Hopkins, whose research focus is on children with urinary tract infections, a common infection in infants and young children.  Dr. Wang is collaborating with other Johns Hopkins faculty to study how infections develop in the urinary tract and establish safer protocols for the evaluation of children with UTIs. Read more about Dr. Wang's research and previous studies by reading the blog, "Is a DMSA Scan Necessary for UTI in Children?" 

With the reduction in national funding for medical research, especially in pediatric medical research, Dr. Wang is working through gofundme.com – a "crowdfunding" resource, to further her work on pediatric UTI. Crowdfunding was made most popular by websites like kickstarter.com. However, kickstarter.com is designed for entry-level venture capitalism and for-profit companies. Sites like gofundme.com are designed strictly for non-profit organizations like Johns Hopkins and researchers like Dr. Wang. 

To complete this important work, Dr. Wang is relying on the support of men and women who deeply care about the health and well-being of all children. If you have interest in funding Dr. Wang's research, please click here: http://www.gofundme.com/h45avw.

Radiation Therapy after Prostate Surgery, Part II: Subgroups Who May Benefit From Adjuvant Therapy

Some men prostate cancer are faced with the realization that treatment of their prostate cancer may require multimodal treatment including some combination of surgery, radiation therapy and/or hormone therapy. The combined ASTRO/AUA (American Society for Therapeutic Radiology and Oncology/American Urological Association) Guideline for "Adjuvant and Salvage Radiotherapy after Radical Prostatectomy" makes a number of statements regarding the use of radiation therapy after surgery that can be confusing to patients and practitioners. 

In the second part of this blog series, we review the statements from the ASTRO/AUA Guideline regarding subgroups who may benefit from adjuvant radiation therapy and the data supporting them.

To read Part I: Adjuvant Radiation following Surgery for Prostate Cancer click here.

The Guideline Statements and three randomized studies (SWOG 8794, EORTC 22911, and ARO 96-02/AUO 09/95) that support their conclusions are detailed in Part I. To summarize, Part I:
Adjuvant radiation therapy (ART) is an option for men with advanced prostate cancer and adverse features after radical prostatectomy. Patients who undergo ART can expect an improvement in biochemical (PSA) and locoregional recurrence, although the benefits on distant metastases and overall survival is less clear.

Looking closely at the data regarding ART, some patients – or subgroups – may be more likely to benefit from immediate treatment than others. It is important to mention before delving into the data from these studies, that these trials were not designed to investigate sub-groups and conclusions need to be drawn with care.

For instance, the SWOG trial demonstrated a benefit for all patients receiving ART. However, when looking at subgroups, patients with high Gleason score (7-10) had the largest significant effect.

From Thompson et al. Journal of Urology, 2009.

In the ARO/AUO trial, benefit was seen for patients with positive surgical margins, high PSA, extraprostatic extension only and all Gleason scores – rather confusing.

From Wiegel et al. JCO 2009; 27: 2898.

To gain a better perspective, we will analyze each adverse feature individually.

 

POSITIVE SURGICAL MARGINS

For patients without a positive surgical margin, there was no benefit to ART for biochemical recurrence, metastasis-free survival (MFS) or overall survival (OS) in the EORTC or ARO studies (SWOG did not report data for patients without positive margins).
For patients with a positive surgical margin, all three studies demonstrated a benefit to ART with regard to biochemical recurrence. SWOG and the EORTC study demonstrated improved recurrence-free survival (or MFS) – ARO did not report this data. OS was not improved in the EORTC study – the only trial that demonstrated this data.

 

GLEASON SCORE

For patients with Gleason Score 2-6:

• Both the EORTC and ARO study demonstrated an improvement in biochemical recurrence.
• SWOG did not show a benefit in MFS.

For patients with Gleason Score 7-10:

• ARO demonstated a benefit to biochemical-free survival
• SWOG demonstrated an improvement in MFS
• EORTC did not demonstrate a benefit in biochemical recurrence for either patients with Gleason 7 or patients with Gleason 8-10.
  • The effect for patients with Gleason 7 was apparent, but not statistically significant (Hazard Ratio: 0.63, 95% Confidence Interval: 0.38-1.0).

 

EXTRAPROSTATIC EXTENSION

For patients with extraprostatic extension (pT3a),

• EORTC and ARO demonstrated a benefit with regard to biochemical recurrence.
• EORTC did not demonstrate a benefit for recurrence-free survival or OS.
• SWOG did not report on patients with extraprostatic extension.

 

SEMINAL VESICLE INVASION

For patients with seminal vesicle invasion (pT3b),

• SWOG and EORTC demonstrated a benefit with regard to biochemical recurrence, ARO did not.
• Neither SWOG nor EORTC demonstrated a benefit to recurrence-free survival or MFS.
• EORTC did not demonstrate an OS benefit to ART.

CONCLUSIONS

Based on the subgroup analyses, adjuvant ART appears to have the most benefit for patients with positive surgical margins and Gleason score 7-10. The benefit of ART in patients with Gleason 6, extraprostatic extension (in the absence of a positive surgical margin) and seminal vesicle invasion is less clear.


This is most likely explained by the fact that patients with a high Gleason score and positive surgical margin are at risk for residual, local disease and benefit from additional local therapy (in the form of radiation). Patients with Gleason 6 are unlikely to benefit as Gleason 6 is believed to be indolent disease and extra therapy to the pelvis is unlikely to affect an already slow-growing, benign-behaving disease process. Patients with seminal vesicle invasion have the opposite problem – they are at extremely high-risk for systemic disease, or disease that has spread from the prostate. Therefore, treating the pelvis is unlikely to benefit patients who are likely to have disease in their lymph nodes or bones – and catching the prostate cancer in the pelvis with additional radiation therapy is unlikely.
Stay tuned for this continued series on Radiation Therapy after Surgery for Prostate Cancer.

 

This blog was written by Mark W. Ball, MD. Mark is a 5^th year urology resident at the Brady Urological Institute at Johns Hopkins and looking forward to a career in urologic oncology.


 

Historical Contribution: 1923, Young & Hill,Mercurochrome & Gentian Violet

1923
HH Young, Hill JA. The Treatment of Septicemia and Local Infections By Intravenous Injection of Mercurochrome 220 Soluble and of Gentian Violet. JAMA. 1924;82:669-75.


 
In 1919, Hugh Hampton Young published the first report of mercurochrome-220 to sterilize the bladder in the Journal of the American Medical Association (JAMA) (click here for link to Historical Contribution: 1919). Four years later, he writes the follow-up manuscript demonstrating the effectiveness of mercurochrome in the treatment of a variety of bacterial infections. In addition, he describes the use of gentian violet, a potent antimicrobial for gram-positive staphylococci. After proving intravenous instillation of gentian violet in rabbits is safe – Young endeavors on human treatment with the medication.

In total, Young presents 12 cases treated and cured with mercurochrome – the first one in 1922. In patients 1-7, Young meticulously details the tenuous clinical course of patients afflicted with septicemia, retroperitoneal and abdominal abscesses, kidney and bladder infections treated by intravenous mercurochrome.

In patients 8-12, Young describes the use of intravenous gentian violet. The first intravenous dose of gentian violet was given July 12, 1923 to a patient with staphylococcus aureus urinary tract infection related to a ureteral calculus. The remaining cases demonstrated cure of systemic staphylococcal infections including those stemming from complications of diabetes, osteomyelitis, urinary system infections. Importantly, gentian violet cleared the source of infection, improved systemic infection, and cleared sequealae of the systemic infection (i.e. abscesses).
In his typical fashion, Young took meticulous notes regarding the clinical course and laboratory values associated with each patient. Not only was the defervescence and normalization of vital signs in septic patients impressive, but the hourly documentation of blood and urine cultures demonstrating true sterilization of the infection.

 
To summarize, in the early 1900's, septicemia was almost universally fatal and mercurochrome ushered in a new era of antimicrobial treatment and hope for the treatment of infectious disease. Patients in this series were described as "desperate cases" – in which experimental antimicrobial treatments were justified. Young was extremely pleased with the results; he describes the sure and sterilization of the blood by intravenous mercurochrome "miraculous" and goes on to say,

"In these cases we have the first demonstration that gentian violet may be used intravenously to combat general septicemia or local infections, and with remarkable success in the case of gram-positive staphylococci. Coupled with the equally amazing results obtained by mercurochrome, these cases represent a splendid therapeutic achievement, and one is tempted to soar into realms of fancy and see a great variety of infectious processes treated and cured intravenously;"

Read more about mercurochrome in publications by Hugh Hampton Young by clicking on the following links:
Historical Contribution, 1919
Historical Contribution, 1925

To read the entire manuscript: follow the link above, visit the Centennial Website or click here.

HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Oncocytoma: A Benign Kidney Tumor Often Confused for Cancer

Upwards of 15-20% of kidney tumors may be benign lesions. While physicians and surgeons can use patient information, radiographic imaging and biopsy to provide information, the definitive diagnosis of cancer or benign tumor is established only after the tumor has been removed. For instance, smaller tumors, female sex and age are associated with benign tumors - younger women are nearly twice as likely as age-matched men to have benign masses.[1-5] While certain characteristics are indicative of benign tumors (i.e. fat always indicates an angiomyolipoma), many other benign tumors – like oncocytoma – can appear similar to renal cell carcinoma (RCC) on CT scan and biopsy.

This blog will review oncocytoma, one of the most common benign tumors of the kidney.

Epidemiology and Etiology

Renal oncocytoma is one of the most common of benign renal masses, accounting for 3-7% of kidney tumors.[6] Oncocytomas appear as enhancing renal masses and are often indistinguishable from clear-cell RCC on CT scans (see Diagnosis below). Both oncocytomas and clear-cell RCC pick up contrast material and enhance brightly. However, oncocytoma is a distinct entity from RCC with unique cell of origin and cytogenetic abnormalities.[7-8]

Oncocytomas are more common in older patients with small, incidentally discovered renal masses. [4,9] Generally, they are more common in men than women (2:1 ratio), present in the 4th to 6th decade of life and can present bilaterally, multifocally or recur in 6-13% of cases.[10] Patients with the rare, Birt-Hogg-Dubé, genetic syndrome can present with oncocytomatosis – the presence of multiple oncocytomas in both kidneys. [11] Oncocytomas are benign tumors and rare case reports of metastatic oncocytoma represent either malignant degeneration, coexistence of RCC or pseudometastases (not really metastatic disease).[12]

Diagnosis

In general, oncocytoma appear similar to RCC on imaging. However, a number of characteristic radiographic findings are common in oncocytoma:

• On CT scan, bright, rapidly-enhancing pattern and a central stellate scar [13]
• On angiography, a spoke wheel pattern of feeding arteries may be present
• On MRI, a well-defined capsule, central stellate scar, and distinctive pattern on T1 and T2 images may indicate oncocytoma.[14,15]

The similar appearance of clear-cell RCC and oncocytoma on contrast-enhanced CT scan.

The Houndsfield Unit (HU) -based enhancement patterns for clear-cell RCC and oncocytoma are overlapping on CT scan. [13]

Renal biopsy has a limited role in the diagnosis of oncocytoma, particularly because it can be difficult to distinguish from chromophobe RCC (see our blog entry on Renal Cell Carcinoma: Implications of Histology for more information about chromophobe RCC), the eosinophilic-variant of clear-cell RCC (a rare and potentially aggressive form of kidney cancer) and may be co-exist with RCC in 7-32% of cases. However, surgical series indicate that if oncocytoma is present with RCC in the same tumor, the tumor is often low-grade and indolent (benign-behaving).[16]

Histology and Pathology

Oncocytomas appear grossly as tan, homogenous tumors with a distinct border (composed of a well-formed pseudocapsule) and typically have a central stellate scar. Microscopically, cells are derived from distal tubules, are rounded and highly-eosinophlic (pink) due to an abundance of mitochondria (the energy producing portion of the cell). As stated above, it can extremely difficult to distinguish oncocytoma from chromophobe RCC or the eosinophilic-variant of clear-cell RCC under the microscope. Cells are typically arranged in a nested pattern and can demonstrate perinephric extension, pleomorphism (variability in size and shape), prominent nucleoli and atypia, making the distinction between RCC difficult.[17,18] On a percutaneous renal biopsy, where only a portion of tumor is present and cellular architecture is incomplete, distinguishing oncocytoma from RCC can be extremely challenging.

From pathologyatlas.com

To distinguish ococytoma from RCC, a number of features can be examined. Chromosomal abnormalities associated with RCC are not present in oncocytoma, and oncocytoma will commonly present with loss of chromosome 1p, loss of Y- or 14q- and rearrangements of 11q13. [7,8] Hale's colloidal iron stain has traditionally been used to identify oncoctyoma, however can have nonspecific staining patterns leading to difficult interpretation.[19] One of the distinguishing cellular features of oncocytoma is uniform, round mitochondria with lamellar cristae – in chromphobe RCC, mitochondria are variable in size and shape with tubulocystic cristae; and in eosinophilic-variant of clear-cell RCC, mitochondria are pleomorphic and have attenuated cristae.[20] Researchers at Johns Hopkins are taking advantage of differences in mitochondria among oncocytoma and RCC to come up with a better, preoperative diagnostic test to distinguish oncocytoma before a sending a patient to surgery.

Electron micropscopy of oncocytoma with uniform, round mitochondria (left) and chromophobe RCC with the pale area around the nucleus is predominantly occupied by microvesicles and irregular mitochondria (right).[20]

Management

Most often oncocytoma are clinically assumed to be RCC and have the same management strategies available including active surveillance, radical nephrectomy (for large tumors of uncertain etiology) and nephron-sparing surgeries including partial nephrectomy and thermal ablation. Oncocytomas under active surveillance can demonstrate rapid growth and are often the fastest growing tumors in active surveillance studies! Therefore, growth rate is not able to distinguish oncocytoma from RCC during periods of AS.[21,22] When the diagnosis of oncocytoma is known or highly-suspected, nephron-sparing approaches should be employed due to the benign nature of these lesions. At Johns Hopkins, partial nephrectomy is preferred to thermal ablation as a definitive diagnosis can be made from analysis of the tumor rather than biopsy specimens.

This blog is adapted from the Handbook of Urology, Chapter 24: Angiomyolipoma, Oncocytoma and Retroperitoneal Fibrosis, by Phillip M. Pierorazio, MD; Edited by John Kellogg Parsons, John B. Eifler, and Misop Han available from Wiley.


 

1. Kutikov A, Fossett LK, Ramchandani P, et al.: Incidence of benign pathologic findings at partial nephrectomy for solitary renal mass presumed to be renal cell carcinoma on preoperative imaging. Urology 2006; 68(4): 737-40.
2. Kouba E, Smith A, McRackan D, Wallen EM, Pruthi RS: Watchful waiting for solid renal masses: insight into the natural history and results of delayed intervention. J Urol 2007; 177(2): 466-70; discussion 470.
3. Pierorazio PM, Murphy AM, Benson MC, McKiernan JM: Gender discrepancies in the diagnosis of renal cortical tumors. World J Urol 2007; 25(1): 81-5.
4. Cao Y, Paner GP, Perry KT, Flanigan RC, Campbell SC, Picken MM: Renal neoplasms in younger adults: analysis of 112 tumors from a single institution according to the new 2004 World Health Organization classification and 2002 American Joint Committee on Cancer Staging System. Arch Pathol Lab Med 2005; 129(4): 487-91.
5. Snyder ME, Bach A, Kattan MW, Raj GV, Reuter VE, Russo P: Incidence of benign lesions for clinically localized renal masses smaller than 7 cm in radiological diameter: influence of sex. J Urol 2006; 176(6 Pt 1): 2391-5; discussion 2395-6.
6. Morra MN, Das S: Renal oncocytoma: a review of histogenesis, histopathology, diagnosis and treatment. J Urol 1993; 150(2 Pt 1): 295-302.
7. Lindgren V, Paner GP, Omeroglu A, et al.: Cytogenetic analysis of a series of 13 renal oncocytomas. J Urol 2004; 171(2 Pt 1): 602-4.
8. Paner GP, Lindgren V, Jacobson K, et al.: High incidence of chromosome 1 abnormalities in a series of 27 renal oncocytomas: cytogenetic and fluorescence in situ hybridization studies. Arch Pathol Lab Med 2007; 131(1): 81-5.
9. Skolarus TA, Serrano MF, Berger DA, et al.: The distribution of histological subtypes of renal tumors by decade of life using the 2004 WHO classification. J Urol 2008; 179(2): 439-43; discussion 443-4.
10. Minor LD, Picken MM, Campbell SC: Benign renal tumors. AUA Update 2003; 22: 170-175.
11. Al-Saleem T, Cairns P, Dulaimi EA, Feder M, Testa JR, Uzzo RG: The genetics of renal oncocytosis: a possible model for neoplastic progression. Cancer Genet Cytogenet 2004; 152(1): 23-8.
12. Oxley JD, Sullivan J, Mitchelmore A, Gillatt DA: Metastatic renal oncocytoma. J Clin Pathol 2007; 60(6): 720-2.
13. Pierorazio PM1, Hyams ES, Tsai S, Feng Z, Trock BJ, Mullins JK, Johnson PT, Fishman EK, Allaf ME. Multiphasic enhancement patterns of small renal masses (≤4 cm) on preoperative computed tomography: utility for distinguishing subtypes of renal cell carcinoma, angiomyolipoma, and oncocytoma. Urology. 2013 Jun;81(6):1265-71. doi: 10.1016/j.urology.2012.12.049. Epub 2013 Apr 17.
14. Licht MR: Renal adenoma and oncocytoma. Semin Urol Oncol 1995; 13(4): 262-6.
15. Harmon WJ, King BF, Lieber MM: Renal oncocytoma: magnetic resonance imaging characteristics. J Urol 1996; 155(3): 863-7.
16. Ginzburg S, Uzzo R, Al-Saleem T, Dulaimi E, Walton J, Corcoran A, Plimack E, Mehrazin R, Tomaszewski J, Viterbo R, Chen DY, Greenberg R, Smaldone M, Kutikov A. Coexisting hybrid malignancy in a solitary sporadic solid benign renal mass: implications for treating patients following renal biopsy. J Urol. 2014 Feb;191(2):296-300. doi: 10.1016/j.juro.2013.07.059. Epub 2013 Jul 27.
17. Amin MB, Crotty TB, Tickoo SK, Farrow GM: Renal oncocytoma: a reappraisal of morphologic features with clinicopathologic findings in 80 cases. Am J Surg Pathol 1997; 21(1): 1-12.
18. Perez-Ordonez B, Hamed G, Campbell S, et al.: Renal oncocytoma: a clinicopathologic study of 70 cases. Am J Surg Pathol 1997; 21(8): 871-83.
19. Leroy X, Moukassa D, Copin MC, Saint F, Mazeman E, Gosselin B: Utility of cytokeratin 7 for distinguishing chromophobe renal cell carcinoma from renal oncocytoma. Eur Urol 2000; 37(4): 484-7.
20. Tickoo SK, Lee MW, Eble JN, Amin M, Christopherson T, Zarbo RJ, Amin MB. Ultrastructural observations on mitochondria and microvesicles in renal oncocytoma, chromophobe renal cell carcinoma, and eosinophilic variant of conventional (clear cell) renal cell carcinoma. Am J Surg Pathol. 2000 Sep;24(9):1247-56.
21. Kawaguchi S, Fernandes KA, Finelli A, Robinette M, Fleshner N, Jewett MA: Most renal oncocytomas appear to grow: observations of tumor kinetics with active surveillance. J Urol 2011; 186(4): 1218-22.
22. Siu W, Hafez KS, Johnston WK, 3rd, Wolf JS, Jr.: Growth rates of renal cell carcinoma and oncocytoma under surveillance are similar. Urol Oncol 2007; 25(2): 115-9.

Bladder Preservation Strategies in the Treatment of Muscle-Invasive Bladder Cancer

It is estimated that in 2014, there will be 74,690 new cases bladder cancer and 15,580 deaths secondary to bladder cancer.1 Approximately 20-30% of patients with bladder cancer present with muscle-invasive bladder cancer (MIBC). The standard of care for MIBC is a radical cystectomy with removal of the pelvic lymph nodes, with some patients undergoing chemotherapy prior to surgery (neoadjuvant chemotherapy). While radical cystectomy is the preferred treatment option, it has significant morbidity and implications on quality of life.2,3 Therefore, bladder preservation therapies for MIBC have been developed, and may be an option for a select group of patients.4

Bladder preservation strategies include combination therapies as well as single modality therapies. Trimodal therapy, consisting of an aggressive transurethral resection of bladder tumor followed by concurrent chemotherapy and radiation therapy, is the most strongly supported and accepted bladder preservation option. In a recent systematic review, the 5-year cancer specific survival in medically operable patients undergoing trimodal therapy was 50-82%.5 These numbers are comparable to large radical cystectomy series. While there are no randomized trials comparing trimodal therapy to radical cystectomy, there is a growing body of accumulated data suggesting that trimodal therapy is a reasonable treatment option in well-selected patients.

While trimodal therapy is the most accepted option for bladder preservation, for the remainder of this post, we will discuss the role of each individual modality (transurethral resection, chemotherapy, and radiotherapy) in trimodal therapy, and outline some non-traditional approaches to bladder preservation.

Transurethral resection of bladder tumor

Transurethral monotherapy involves excising all visible tumor with deep resection. In highly selected patients, Dr. Harry Herr presented a series of 151 patients with MIBC that underwent an aggressive transurethral resection of bladder tumor with 10 years of follow-up.6 Of these patients, 99 underwent transurethral resection alone and 52 underwent radical cystectomy. There was no significant difference in survival between these groups, and overall, 57% of patients in this study survived more than 10 years with a functioning bladder. While these results are noteworthy, limited data overall supporting radical transurethral resection as monotherapy. Furthermore, there is a lifelong risk of developing recurrent invasive tumor in retained bladder: 42% of patients in this study underwent salvage radical cystectomy. The general consensus is that transurethral resection alone provides inadequate cancer control with high rate of recurrence and progression.

Chemotherapy

While the primary role for chemotherapy in the treatment of MIBC is neoadjuvant chemotherapy, there are circumstances where a patient will have no evidence of tumor following chemotherapy, and will subsequently refuse a cystectomy. Small series have described this scenario with good outcomes. In a recent retrospective review of 32 patients with muscle-invasive bladder cancer that had a clinical complete response to neoadjuvant chemotherapy, 25 patients refused to undergo an immediate cystectomy.7 Of the 25 patients that refused immediate cystectomy, 7 patients underwent delayed cystectomy for relapse and 18 patients successfully maintained their bladders. There was no difference in the cancer specific survival between patients that underwent immediate cystectomy and patients that opted for a bladder preservation strategy. We see that in select patients that achieve a complete response to neoadjuvant chemotherapy, bladder preservation may be achieved. However, at this point, it is difficult to determine who will have a response to neoadjuvant chemotherapy, and of those, who will be able to durably maintain their bladders.

Radiation Therapy

A multicentered randomized phase 3 trial examined the role of radiation alone versus radiation with chemotherapy in the treatment of MIBC.8 The authors found that the locoregional and invasive disease free survival was significantly better in the patients that underwent chemoradiation therapy as opposed to radiation alone. Furthermore, there was no increased toxicity with the addition of chemotherapy. The authors did not compare these modalities to patients undergoing cystectomy. Overall, when examining bladder preservation options, there is no role for radiation therapy alone, as concurrent chemoradiation is more effective.

SUMMARY

In conclusion, there are multiple options for bladder preservation. There are large trials reporting outcomes for trimodal therapy and small series for single modality treatments. From these experiences, we see that bladder preservation strategies can lead to acceptable outcomes, and may be considered a reasonable treatment option in select patients. Bladder preservation is not an option for all patients with MIBC, and patient selection is of paramount importance. Furthermore, it is essential to recognize that in these studies, only select patients were included. Bladder preservation is a treatment approach under investigation, and prospective trials comparing trimodal therapy and single modality bladder preservation options to radical cystectomy are needed to better define their role in the treatment of MIBC.

This blog was written by Alexa Meyer, Medical Student at Columbia University College of Physicians & Surgeons in New York, New York.  Alexa recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "Trimodal Therapy for Bladder Cancer" from which this blog is inspired. Alexa is looking forward to a career in urology.






1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29.
2. Aghazadeh MA, Barocas DA, Salem S, et al. Determining factors for hospital discharge status after radical cystectomy in a large contemporary cohort. J Urol 2011;185:85-9.
3. Goodney PP, Stukel TA, Lucas FL, Finlayson EV, Birkmeyer JD. Hospital volume, length of stay, and readmission rates in high-risk surgery. Ann Surg 2003;238:161-7.
4. Smith ZL, Christodouleas JP, Keefe SM, Malkowicz SB, Guzzo TJ. Bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC): a review of the literature and a practical approach to therapy. BJU Int 2013;112:13-25.
5. Ploussard G, Daneshmand S, Efstathiou JA, et al. Critical analysis of bladder sparing with trimodal therapy in muscle-invasive bladder cancer: a systematic review. Eur Urol 2014;66:120-37.
6. Herr HW. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol 2001;19:89-93.
7. Meyer A, Ghandour R, Bergman A, et al. The natural history of clinically complete responders to neoadjuvant chemotherapy for urothelial carcinoma of the bladder. J Urol 2014;192:696-701.
8. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477-88.