Journal Spotlight: Laser vs. TURP for BPH, The GOLIATH Trial

For men with bothersome lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH), transurethral surgery can improve urinary flow and symptoms for men who are not helped by medications. Transurethral resection of the prostate (TURP) is the traditional method for removing the obstructive tissue of a large, benign prostate. This involves using electrocautery to resect tissue, which is then collected from the bladder and removed from the patient. Historically, TURP is associated with a significant and excellent improvements in LUTS with a complication rate of approximately 10%.[1]

Over the past two decades a number of technologies have emerged to improve TURP including laser vaporization, bipolar TURP or vaporization, and laser enucleation of the prostate. Laser vaporization technologies are the most widely used as they were among the first new technologies introduced, are relatively easy to use and are believed the have less bleeding and improved visualization. However, no rigorous, head-to-head study has evaluated laser technology compared to the gold standard TURP – which has the benefits of being a faster operation with well-established, long-term benefits.

The GOLIATH Trial, a European multicenter, randomized study of laser vaporization versus TURP for BPH was recently published in European Urology and the 12-month update in the Journal of Urology.

Bachmann A, Tubaro A, Barber N, etal. 180-W XPS GreenLight laser vaporisation versus transurethral resection of the prostate for the treatment of benign prostatic obstruction: 6-month safety and efficacy results of a European Multicentre Randomised Trial--the GOLIATH study. Eur Urol. 2014 May;65(5):931-42. doi: 10.1016/j.eururo.2013.10.040. Epub 2013 Nov 11.

Bachmann A, Tubaro A, Barber N, etal. A European Multicenter Randomized Noninferiority Trial Comparing 180 W GreenLight XPS Laser Vaporization and Transurethral Resection of the Prostate for the Treatment of Benign Prostatic Obstruction: 12-Month Results of the GOLIATH Study. J Urol. 2014 Sep 16. pii: S0022-5347(14)04377-8. doi: 10.1016/j.juro.2014.09.001. [Epub ahead of print]

 
Vital statistics of the GOLIATH Study:

• 291 patients
• 29 centers in 9 European countries
• Laser vaporization: 180 Watt Greenlight-XPS™
  
• TURP: monopolar or bipolar (42%) technology

Important results from this trial include:

• No difference between laser vaporization and TURP with regard to urinary outcomes (see table):
  • IPSS (International Prostate Symptom Score)
  • IPSS Quality of life score (IPSS QOL)
  • Maximum flow rate (Qmax)
  • Post-void residual urine
  • Both treatments were associated with short-term dysuria (discomfort with voiding that resolved spontaneously) in approximately 18% of men.
• Decreases in PSA and prostate volume were also similar among treatments.
  • Six men undergoing TURP were found to have prostate cancer; tissue is not analyzed after laser vaporization.
• Outcomes that favored laser vaporization included:
  • Length of stay
  • Catheterization time
  • Return to stable health status
  • Fewer 30-day re-operations
• Adverse events and re-operative rates were similar at 12 months:
  • Laser vaporization patients were more likely to undergo re-operation for bladder neck contractures and urethral strictures
  • TURP patients were more likely to undergo re-operation for bleeding
• No difference between monopolar and bipolar TURP for any outcome.

	Baseline			12 Months
(Mean Value)	GL-XPS	TURP	p Value	GL-XPS	TURP	p Value
I-PSS:	21.2±5.9	21.7±6.4	0.541	7.0±6.0	5.7±5.3	0.079
I-PSS-QOL:	4.6±1.1	4.5±1.4	0.721	1.4±1.4	1.2±1.3	0.287
Qmax (ml/sec):	9.5±3.0	9.9±3.5	0.266	23.0±10.7	24.7±10.1	0.221
PVR (ml):	110.1±88.5	109.8±103.9	0.453	43.0±57.1	33.7±43.8	0.107
PSA (ng/ml):	2.7±2.1	2.6±2.1	0.816	1.3±1.3	1.1±1.0	0.116
Prostate vol (ml):	48.6±19.2	46.2±19.1	0.301	21.9±11.0	21.0±12.8	0.574

 
Proponents of laser technology claim this study as a victory for laser technology given economic and quality of life implications of decreased length of stay, catheterization time, return to stable health and lower, 30-day reoperation rate. However, this should be balanced with a higher rate of urethral stricture disease – which not only requires re-operation but may have serious implications for cost, quality of life and urinary continence with longer follow-up – and inability to diagnose prostate cancer (as tissue is destroyed rather than evaluated) in select patients.

Take-home: Both laser vaporization and TURP are excellent procedures for the management of LUTS due to BPH. Both result in marked improvements in symptoms at 1 year. Both are associated with short-term dysuria. Patients undergoing TURP have a higher likelihood of re-operation within 30 days due to bleeding from surgery. Patients undergoing laser vaporization have a higher likelihood of requiring a secondary procedure for bladder neck contracture or stricture disease. No one surgery is right for all patients and a surgeon may have a preference to the technology they use. The decision on type of surgery should not rely on technology, but should take into account patient characteristics and preferences as well as surgeon experience and skill set.

 
[1] Wasson JH, Reda DJ, Bruskewitz RC, Elinson J, Keller AM, Henderson WG. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate. N Engl J Med. 1995 Jan 12;332(2):75-9.

Journal Spotlight: Surgery vs. Radiation for Prostate Cancer

A number of US-based, observational studies demonstrate that surgery (radical prostatectomy) is superior to radiation therapy for younger patients and those with high-risk prostate cancer. However, most US databases use "representative" data sets, meaning they capture and follow small populations of patients that are believed to be similar to the entire US population. Each data set has its own strengths and weaknesses – and none is perfect. A recent publication by Sookrakumaran and colleagues examined the National Prostate Cancer Registry (NPCR) of Sweden – a comprehensive Swedish database that captures 98% of prostate cancer patients since 1998.

Sooriakumaran P, Nyberg T, Akre O, Haendler L, Heus I, Olsson M, Carlsson S, Roobol MJ, Steineck G, Wiklund P. Comparative effectiveness of radical prostatectomy and radiotherapy in prostate cancer: observational study of mortality outcomes. BMJ. 2014 Feb 26;348:g1502. doi: 10.1136/bmj.g1502.


This study examined over 34,000 men treated with surgery or radiation therapy for prostate cancer followed for up to 15 years. With regard to prostate cancer and total mortality after treatment, the authors found:

• In the 21,000 men undergoing radical prostatectomy:
• 339 prostate cancer deaths
• 1,064 deaths from other causes
• In the 13,000 men undergoing radiation therapy:
• 697 prostate cancer deaths
• 1,127 deaths from other causes

The authors used a number of complex statistical methods and demonstrated that surgery was associated with lower mortality for most patients, specifically those at the greatest risk from death from prostate cancer (young men with intermediate- or high-risk prostate cancer). Men with low-risk disease, especially older men, who have a low-risk of death from prostate cancer had no difference in survival after either treatment. The authors went to great statistical efforts to control for variables that could alter the outcomes of the analysis. Specifically, radiation therapy was given with lower doses early in the experience of the database – a sensitivity analysis demonstrated that radiation dose should not affect outcomes.

From Sooriakumaran etal. 

A number of prospective, randomized studies are underway to examine the question of surgery vs. radiation therapy for prostate cancer. However, due to the slow-progression rate of prostate cancer, results are at least 10 years away. These include the ProtecT Study in the United Kingdom and the SPCG-15 (Surgery versus Radiotherapy for Locally Advanced Prostate Cancer) Study.

Journal Spotlight: The RIVUR Study, Are Daily Antibiotics Necessary for Patients with Urinary Reflux?

Vesicoureteral reflux (VUR), or simply "reflux," is a congenital condition in which urine flows from the bladder back up towards the kidneys. An estimated 17% of children are born with or develop VUR. Reflux is present up to 30% of children with febrile urinary tract infections (UTI).[1] Urinary reflux predisposes these children to kidney infection, or pyelonephritis, which can be a serious infection requiring hospitalization. In very young babies, a single episode of pyelonephritis can lead to kidney damage and scar formation. Because of this risk, many pediatric urologists prescribe low dose, daily antibiotics to children with VUR, in an effort to prevent episodes of kidney infections. However, the benefit of prophylactic antibiotics remains controversial.

 
Hoberman, A., Greenfield, S., Matoo, K. et al.: Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux. NEJM, 370: 2367, 2014


 
Recently, results from the RIVUR study (Randomized Intervention for Children with Vesicoureteral Reflux) were published and shed some light on the effects of using daily antibiotic prophylaxis in children with VUR.[above, 2] The RIVUR study was an ambitious effort by many physicians at 19 hospitals across the U.S. – Johns Hopkins was one of the leading sites. Over 600 children diagnosed with VUR were randomized to either once daily antibiotic (Bactrim, otherwise known as sulfamethoxazole and trimethoprim, TMP-SMX) versus placebo. They were followed closely with regular check-ups over the next 2 years.
    
The RIVUR study demonstrated two key things: First, children given prophylaxis had 50% fewer febrile infections over time when compared to children not taking antibiotics. 

In the RIVUR Study, fewer children assigned to TMP-SMX prophylaxis had a UTI than children assigned to placebo (P<0.001 by log-rank test).  As presented in the New England Journal of Medicine (2014;370:2367-2376).

However, children given antibiotics did not show less kidney scarring compared to the children not given antibiotics. This may mean that the antibiotics did not prevent scarring, OR it may mean that the kidney scarring was too small to see based on our current imaging techniques. Parents, pediatricians, and pediatric urologists may interpret the results of the RIVUR study as a reason to stop the use of antibiotics in children with VUR. In our own practice, at Johns Hopkins Children's Center, we continue to emphasize the importance of incorporating science and tailoring the treatment plan based on each child/family.

Overall, the benefits of daily antibiotics on preventing kidney damage remain controversial and the use of daily antibiotics should be balanced with patient factors, frequency of febrile UTIs and family dynamics.

Jason Michaud, MD, PhD

Ming Hsien Wang, MD

This blog was written by Jason Michaud, MD, PhD, PGY4 urology resident, and Ming-Hsien Wang, MD, Assistant Professor of Urology and Director of the Pediatric Urology Fellowship Program at the Brady Urological Institute and Johns Hopkins Children's Center.

 





References
1. Sargent, MA. What is the normal prevalence of vesicoureteral reflux? Pediatr. Radiol. Sep;30(9):587-93, 2000.
2. Hoberman, A., Greenfield, S., Matoo, K. et al.: Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux. NEJM, 370: 2367, 2014

Journal Spotlight: Randomized Trial of Open and Robotic Radical Cystectomy

Robotic surgery disseminated rapidly over the past decade and is now the most common approach for radical prostatectomy for prostate cancer in the United States.  The dissemination of this technology was fueled by surgeon preference and a number of retrospective and case-series studies that demonstrate improvements in blood loss, convalescence, and hospital stays.[1,2]  However, randomized and/or controlled prospective studies were not performed before robotic surgery took over for prostate cancer.

There is growing interest in robotic surgery for bladder cancer.  The cystectomy (bladder removal) population is often an older, sicker population who undergoes a morbid, radical surgery.  In order to address the utility of robotic surgery for bladder cancer, researchers from MSKCC (Memorial Sloan Kettering Cancer Center) in New York City, reported the results of a small, randomized trial of open versus robotic radical cystectomy for the treatment of bladder cancer.  The results were shared as a Letter to the Editor in the July 24th edition of the NEJM (New England Journal of Medicine).

Bochner BH, Sjoberg DD, Laudone VP.  A Randomized Trial of Robot-Assisted Laparoscopic Radical Cystectomy.  N Engl J Med 2014; 371:389-390July 24, 2014DOI: 10.1056/NEJMc1405213

One-hundred eighteen (118) patients were randomly assigned to undergo open (60) or robotic surgery (58) by a number of experienced surgeons at MSKCC.  The study was designed to detect a difference in complication rates among the two types of surgery.  Given a historic complication rate of radical cystectomy of about 50%,[3] the researchers predicted robotic surgery should improve the complication rate by 20%.  The study was initially designed to enroll over 200 patients, but was stopped early when the complication rates were found to be similar at a pre-determined interim analysis.    

In fact the complication rate was 62% in the robotic group and 66% in the open group at 30 days; high-grade (severe) complications occurred in 22% and 21% respectively.  Important differences in the short-term analysis were:

• decreased blood loss in the robotic group (mean difference, 159 cm3)
• decreased length of surgery in the open group (mean difference, 127 minutes)

This communication was picked up by a number of medical and non-medical publications.  Given the recent skepticism regarding the use of robotic technology, as evidenced an increased reporting of complications in the gynecologic literature, and the increased associated costs with robotic technology,[4,5] a number of sources reflected on this report as a negative study. For instance, the Wall Street Journal ran with the headline, Surgical Robot Fails to Show Advantages in Treating Bladder Cancer, and stated, "This small study may cast further doubt on the benefits of Intuitive Surgical's da Vinci robot."[6]

While this study may not demonstrate a significant benefit to the robotic surgery, it does also not show any detrimental effects, increased complications or worse cancer outcomes for the patients undergoing robotic surgery.  In fact, while the robotic surgery may take longer, the significant lower blood loss may be a worthy trade-off.  In the contemporary radical cystectomy population, a group of patients that often receives chemotherapy before surgery and is subsequently anemic entering the operating room, upwards of 40% of patients will receive a perioperative blood transfusion.  This is especially significant, as recent studies indicate that blood transfusions may be linked to worse cancer outcomes in the bladder cancer population.[7]  Robotic surgery is another tool in the armamentarium of surgeons.  As found in other surgeries, outcomes are often surgeon- and experience-dependent,[8] and this study should not dissuade people from undergoing robotic surgery by an expert surgeon.  The authors and members of this study from MSKCC should be commended for running a successful study comparing a surgical innovation to standard-of-practice and should serve as a model for studies in the future.   

[1] Ficarra V, Cavalleri S, Novara G, Aragona M, Artibani W. Evidence from robot-assisted laparoscopic radical prostatectomy: a systematic review. Eur Urol. 2007;51:45-55; discussion 56. 
[2] Hu JC, Gu X, Lipsitz SR, et al. Comparative effectiveness of minimally invasive vs open radical prostatectomy. JAMA. 2009;302:1557-1564
[3] Shabsigh A, Korets R, Vora KC, et al. Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol 2009;55:164-176
[4] Rabin RC. New Concerns on Robotic Surgeries.  The New York Times, September 9, 2013; D4. 
[5] Kolata G. Results unproven, robotic surgery wins converts. The New York Times. February 14, 2010; A1.
[6] Walker, J. Surgical Robot Fails to Show Advantages in Treating Bladder Cancer.  The Wall Street Journal.  July 23, 2014.

[7] Linder BJ, Frank I, Cheville JC, Tollefson MK, Thompson RH, Tarrell RF, Thapa P, Boorjian SA.

The impact of perioperative blood transfusion on cancer recurrence and survival following radical cystectomy. Eur Urol. 2013 May;63(5):839-45. doi: 10.1016/j.eururo.2013.01.004. Epub 2013 Jan 11.

[8] Klein EA, Bianco FJ, Serio AM, Eastham JA, Kattan MW, Pontes JE, Vickers AJ, Scardino PT.Surgeon experience is strongly associated with biochemical recurrence after radical prostatectomy for all preoperative risk categories.J Urol. 2008 Jun;179(6):2212-6; discussion 2216-7. doi: 10.1016/j.juro.2008.01.107. Epub 2008 Apr 18.

Journal Spotlight: How to Treat Non-Invasive Bladder Cancer

Approximately 60k new patients are diagnosed with bladder each year in the United States.[1]  Most of those cancers (upwards of 70-80%) are non-muscle invasive urothelial cancers of the bladder (NMIUC) - meaning these are cancers that arise from the lining of the bladder and grow outward into the lumen of the bladder.[2,3] Fortunately, most of these cancers are not inherently dangerous and can be safely managed with close surveillance and a variety of interventions.  However, NMIUC represent a wide variety of tumor types and has a wide range of prognoses and therapeutic options.  Most NMIUC are treated with a combination of surgical resection (or transurethral resection of bladder tumor, TURBT) and intravesical treatment (BCG is the most common).

The American Urological Association and other groups have attempted to stratify NMIUC patients based on their risk of recurrence, progression to muscle-invasive disease and effective treatment options.  Low- and high-risk groups are well agreed upon by a number of professional urologic and oncologic organizations. However, the risk of progression and treatment options are not well flushed out in the intermediate-risk group.  A recent publication by the International Bladder Cancer Group (IBCG), in the Journal of Urology, creates a framework for intermediate-risk patients.[4]

This blog will put this manuscript in a Journal Spotlight and review the suggested definitions and treatments for patients with low-, intermediate- and high-risk NMIUC.  For more details regarding the methodology and evidence behind these conclusions, you can access the manuscript by clicking on the subsequent link:

Kamat AM, Witjes JA, Brausi M, Soloway M, Lamm D, Persad R, Buckley R, Böhle A, Colombel M, Palou J.  Defining and Treating the Spectrum of Intermediate Risk Nonmuscle Invasive Bladder Cancer.  J Urol. 2014 Aug;192(2):305-315. Review.

Non-muscle Invasive Urothelial Cancers of the Bladder (NMIUC)

Low-Risk 

Definition: Solitary, primary low-grade papillary Ta tumor
Well-agreed upon definition
Treatment Options:
Transurethral Resection of Bladder Tumor (TURBT)
Single, immediate post-operative chemotherapy (mitomycin C) - [Evidence: 5,6]
Office Fulguration
Active surveillance with serial cystoscopy
Cancer Outcomes:
Recurrence: 50-70%
Progression:  5-10%
Deaths: 1-5%

Intermediate-Risk 

Definition: Multiple or recurrent low-grade Ta tumors***

The following risk factors stratify intermediate-risk patients:

• Multiple tumors
• Tumor size >3cm
• Early recurrence (<1 year)
• Frequent recurrences (>1 per year)

Those patients with no risk factors should be considered as Low-Risk NMIUC (see above).

Those patients with 1-2 risk factors should be considered as Intermediate-Risk NMIUC.

Those patients with 3 or more risk factors should be considered High-Risk NMIUC (see below).

***Not well-agreed upon definition (recently proposed by the IBCG)

Treatment Options:
Transurethral Resection of Bladder Tumor (TURBT)
Adjuvant intravesical treatment (BCG with maintenance for at least 1 year > chemotherapy)
     If recurrence while receiving chemotherapy, consider BCG induction and maintenance
     If recurrence while receiving BCG, consider maintenance therapy or alternative chemotherapy
Cancer Outcomes: [3,7]
Recurrence: 78%
Progression:  17%
Deaths: 10-25%

Evidence: A number of well-organized studies and meta-analyses demonstrate improvement in recurrence rates and other oncologic parameters for patients with intermediate-risk NMIUC receiving intravesical treatments.  BCG is superior to chemotherapeutic agents (epirubicin, mitomycin c) with regard to recurrence in nearly all studies, however progression and survival rates are often indeterminate.  Some of the important studies are highlighted:

• Meta-analysis: reduced recurrence rates for BCG maintenance > mitomycin C, no difference in progression or death between groups. [8]
• EORTC30911: Time to recurrence, time to distant metastases, disease-specific and overall survival improved with BCG > Epirubicin.[9]
• FinnBladder I: reduced recurrence rate with BCG maintenance > mitomycin C; trend toward decreased progression and death rates with BCG.[10]
• EORTC30962: full-dose BCG for 1 year associated with the best outcomes [11]

High-Risk 

Definition: Any T1 or high-grade tumor, and/or carcinoma in situ
Well-agreed upon definition
Treatment Options:
Transurethral Resection of Bladder Tumor (TURBT)
BCG maintenance
Consider early cystectomy
Cancer Outcomes:
Recurrence: >80%
Progression:  50% within 3 years
Deaths: 33%


While this journal article highlights a deficiency in our understanding of bladder cancer and offers a framework to better classify and treat patients, it should be clearly stated that this is not standard of care nor is it an endorsement from the Brady Urological Institute. This is merely a blog where we share important work from other contributors in the field.



[1] American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.
[2] Heney NM, Ahmed S, Flanagan MJ, Frable W, Corder MP, Hafermann MD et al: Superficial bladder cancer: progression and recurrence. J Urol 1983; 130: 1083.
[3] Jones SJ and Larchian WA.  Non–Muscle-Invasive Bladder Cancer (Ta, T1, and CIS). In: Campbell-Walsh Urology, 10th ed. Edited by AJ Wein, LR Kavoussi, AC Novick, AW Partin, CA Peters. Philadelphia: W. B. Saunders 2012; chapt 81, pp 2335-54.
[4] Kamat AM, Witjes JA, Brausi M, Soloway M, Lamm D, Persad R, Buckley R, Böhle A, Colombel M, Palou J.  Defining and Treating the Spectrum of Intermediate Risk Nonmuscle Invasive Bladder Cancer.  J Urol. 2014 Aug;192(2):305-315. doi: 10.1016/j.juro.2014.02.2573. Epub 2014 Mar 25. Review.
[5] Gudjónsson, S., Adell, L., Merdasa, F. et al. Should all patients with non-muscle-invasive bladder cancer receive early intravesical chemotherapy after transurethral resection? The results of a prospective randomised multicentre study. Eur Urol. 2009; 55: 773
[6] Dobruch, J. and Herr, H. Should all patients receive single chemotherapeutic agent instillation after bladder tumour resection?. BJU Int. 2009; 104: 170
[7] Sylvester, R.J., van der Meijden, A.P., Oosterlinck, W. et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006; 49: 466
[8] Malmström, P.U., Sylvester, R.J., Crawford, D.E. et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guérin for non-muscle-invasive bladder cancer. Eur Urol. 2009; 56: 247
[9] Sylvester, R.J., Brausi, M.A., Kirkels, W.J. et al. Long-term efficacy results of EORTC Genito-Urinary Group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guérin and bacillus Calmette-Guérin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010; 57: 766
[10] Jӓrvinen, R., Kaasinen, E., Sankila, A. et al. Long-term efficacy of maintenance bacillus Calmette-Guérin versus maintenance mitomycin C instillation therapy in frequently recurrent TaT1 tumours without carcinoma in situ: a subgroup analysis of the prospective, randomised FinnBladder I study with a 20-year follow-up. Eur Urol. 2009; 56: 260
[11] Oddens, J., Brausi, M., Sylvester, R. et al. Final results of an EORTC-GU Cancer Group randomized study of maintenance bacillus Calmette-Guérin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol. 2013; 63: 462