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Article of the Week: Impact of dutasteride/tamsulosin combination therapy on sexual function in men with LUTS secondary to BPH

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Every Week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this month, it should be this one.

A prospective randomised placebo‐controlled study of the impact of dutasteride/tamsulosin combination therapy on sexual function domains in sexually active men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH)

 

Claus G. Roehrborn*, Michael J. Manyak†, Juan Manuel Palacios-Moreno‡, Timothy H. Wilson§, Erik P.M. Roos, Javier Cambronero Santos**, Dimitrios Karanastasis††, Janet Plastino‡‡, Francois Giuliano§§ and Raymond C. Rosen¶¶

 

*Department of Urology, University of Texas (UT) Southwestern Medical Center, Dallas, TX, USA, †GlaxoSmithKline (GSK), Washington, DC, USA, ‡GSK, Madrid, Spain, §PAREXEL International, Durham, NC, USA, Antonius Ziekenhuis Sneek, Sneek, The Netherlands, **Hospital Universitario Infanta Leonor, Madrid, Spain, ††Urologic Clinic, General Hospital of Athens ‘Elpis’, Athens, Greece, ‡‡GSK, Collegeville, PA,USA, §§Neuro-Urology R. Poincare Hospital AP-HP, Garches, UMR1179 Inserm-UVSQ-Paris Saclay University, Paris, France, France, and ¶¶New England Research Institutes,nWatertown, MA, USA

 

Abstract

Objective

To prospectively assess the impact of the fixed‐dose combination (FDC) of the 5α‐reductase inhibitor (5ARI), dutasteride 0.5 mg and the α1‐adrenoceptor antagonist, tamsulosin 0.4 mg (DUT‐TAM FDC) therapy on sexual function domain scores in sexually active men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), using the Men’s Sexual Health Questionnaire (MSHQ).

Patients and Methods

This European and Australian double‐blind, placebo‐controlled, parallel‐group study was conducted at 51 centres. Inclusion criteria: age ≥50 years, International Prostate Symptom Score ≥12, prostate volume ≥30 cc, prostate‐specific antigen 1.5–10 ng/mL. Patients were randomised 1:1 to DUT‐TAM FDC therapy or placebo for 12 months. The change from baseline to Month 12 on the total MSHQ (primary endpoint) and MSHQ erection, ejaculation and satisfaction domains (secondary outcome) was assessed, using a mixed model repeated measures analysis. Safety was evaluated.

Results

The intention‐to‐treat population included 489 patients (243 DUT‐TAM FDC therapy; 246 placebo). A significant decrease (worsening) was observed with DUT‐TAM FDC therapy versus placebo on the total MSHQ score (−8.7 vs −0.7; standard error [se]: 0.81, 0.78; P < 0.001), and the ejaculation (−7.5 vs −0.6; se: 0.56, 0.55; P < 0.001) and satisfaction (−0.6 vs +0.3; se: 0.3, 0.29, P = 0.047) domains, but not the erection domain (−1.0 vs −0.5; se: 0.19, 0.19, P = 0.091).

Conclusion

This is the first domain‐specific quantitative evaluation of DUT‐TAM FDC therapy on sexual function in men with LUTS secondary to BPH. The observed changes in the MSHQ with DUT‐TAM FDC therapy were mainly driven by changes in the ejaculation domain. These findings will help give context to erectile and ejaculatory dysfunction AEs reported spontaneously in earlier 5ARI studies.

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Editorial: Sexual function in patients undergoing combination treatment with α1‐adrenoceptor antagonists and 5α‐reductase inhibitors – a step forward in a still‐open debate

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Combination treatment with α1‐adrenoceptor antagonists and 5α‐reductase inhibitors (5ARIs) is recommended in men with moderate‐to‐severe LUTS and risk of disease progression 1, 2. These drugs can improve symptoms as well as urodynamic markers of BOO 3, 4. Despite the clinical benefits, the potential negative impact of these drugs on sexual function is of major concern, and may be cause for treatment discontinuation. Additionally, in everyday clinical practice, the incidence of sexually‐related adverse events is often perceived to be higher than that reported in clinical trials, and clinicians may consequently be reluctant to prescribe these drugs in younger, sexually active patients 5. Evidence from the literature in this area, however, is low‐level, controversial and inconclusive. Notably, in most clinical studies on combination treatment, assessment of sexual function is based only on the reported incidence of sexually‐related adverse events; a non‐quantitative method that can be biased by the subjective burden of suffering, by a patient’s misinterpretation of symptoms and his propensity to mention them during follow‐up visits.

Roehrborn et al. 1 investigated the impact of a fixed‐dose combination of the 5ARI dutasteride 0.5 mg and the α1‐adrenoceptor antagonist tamsulosin 0.4 mg therapy on sexual function in sexually active men with LUTS, secondary to BPH 1. The authors designed a prospective, randomized, placebo‐controlled study and adopted, for the first time in this setting, the Men’s Sexual Health Questionnaire (MSHQ). Overall, 489 patients, with a mean age of 65.5 years, an IPSS ≥12 and a prostate volume ≥30 mL were randomized to receive combination therapy (n = 243) or placebo (n = 246) for 12 months. Change in sexual function from baseline to month 12, as measured by a change in total MSHQ score, was the primary endpoint of the study. Change from baseline in the MSHQ erection, ejaculation and satisfaction domain scores were among the secondary endpoints. The authors found a statistically significant decrease in the total MSHQ score in the active treatment group compared with placebo at all post‐treatment visits (months 1,3, 6, 9 and 12), indicating a worsening of sexual function 1. The magnitude of the total MSHQ reduction was greater at month 6 and remained substantially unchanged beyond this time point. This change was driven largely by the change in the score for the ejaculatory domain, which showed a similar temporal trend. Changes in terms of the overall satisfaction domain, although statistically significant, were judged to be numerically small and therefore unlikely to be clinically relevant. Changes in terms of erectile domain score were not statistically significant.

The major methodological strength of this study was the adoption of the MSHQ, a clinically validated questionnaire designed to assess quantitatively multiple domains of sexual function, namely erectile function, ejaculatory function and sexual satisfaction. Findings are relevant from both a pathophysiological and clinical viewpoint. Indeed, the temporal trend that characterizes the deterioration of ejaculatory function and therefore the total MSHQ score implies the involvement of both drugs in this process. From a clinical point of view the study provides additional data to counsel patients requiring combination therapy about the deleterious effects on sexual function and particularly on ejaculatory function. The main limitations of the study, as acknowledged by the authors, is the lack of long‐term follow‐up. Indeed, a recent meta‐analysis showed a positive correlation between duration of therapy with 5ARIs and incidence of sexual dysfunction, with long‐term exposure (≥1 year) being associated with a significantly higher risk 6. Consequently, conclusive data about erectile function cannot be drawn based on the results from the present 1‐year‐long study. Additionally, the authors do not report on possible changes in sexual desire. This aspect deserves future investigation as the risk of decreased libido has been reported to be statistically significant in patients assuming therapy with 5ARIs 6. Finally, results from clinical trials do not always correspond to everyday clinical practice, as patient selection for therapies in the real world is often different with respect to inclusion criteria adopted in clinical trials. Specifically, patients who receive therapy with 5ARIs (alone or in combination) in everyday clinical practice are often older than the patients who were enrolled in the present study and in other clinical trials and therefore may have comorbidities that could contribute to the development of sexual side effects during treatment 5.

Ferdinando Fusco and Massimiliano Creta
Department of Neurosciences, Human Reproduction and Odontostomatology, University of Naples Federico II, Naples, Italy

 

References

 

  • 1 Roehrborn CG, Manyak MJ, Palacios‐Moreno JM et al. A prospective randomised placebo‐controlled study of the impact of dutasteride/tamsulosin combination therapy on sexual function domains in sexually active men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). BJU Int 2018; 121: 647–58

 

  • 2 Gratzke C, Bachmann A, Descazeaud A et al. EAU guidelines on the assessment of non‐neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol2015; 67: 1099–109

 

  • 3 Fusco F, Creta M, Imperatore V et al. Benign prostatic obstruction relief in patients with lower urinary tract symptoms suggestive of benign prostatic enlargement undergoing endoscopic surgical procedures or therapy with alpha‐blockers: a review of urodynamic studies. Adv Ther2017; 34: 773–83

 

  • 4 Matsukawa Y, Takai S, Funahashi Y et al. Effects of withdrawing α1‐blocker from combination therapy with α1‐blocker and 5α‐reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a prospective and comparative trial using urodynamics. J Urol 2017; 198: 905–12

 

  • 5 Fusco F, Arcaniolo D, Creta M et al. Demographic and comorbidity profile of patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia in a real‐life clinical setting: Are 5‐alpha‐reductase inhibitor consumers different? World J Urol 2015; 33: 685–9

 

  • 6 Liu L, Zhao S, Li F et al. Effect of 5α‐reductase inhibitors on sexual function: a meta‐analysis and systematic review of randomized controlled trials. J Sex Med 2016; 13: 1297–310

 

Article of the Month: MEAL Study – Effects of Diet in PCa Patients on AS

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Every Month, the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this month, it should be this one.

Men’s Eating and Living (MEAL) study (CALGB 70807 [Alliance]): recruitment feasibility and baseline demographics of a randomized trial of diet in men on active surveillance for prostate cancer

J. Kellogg Parsons*†‡ , John P. Pierce§, James Mohler¶, Electra Paskett**, Sin-Ho Jung††, Michael J. Morris‡‡, Eric Small§§, Olwen Hahn¶¶, Peter Humphrey***, John Taylor††† and James Marshall†††

*Division of Urologic Oncology, UC San Diego Moores Comprehensive Cancer Center, La Jolla, CA, USA, †Department of Urology, UC San Diego Health System, La Jolla, CA, USA, ‡VA San Diego Healthcare System, La Jolla, CA, USA, §Department of Family Medicine and Public Health and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA, ¶Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA, **Department of Medicine, College of Medicine, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA, ††Alliance Statistics and Data Center, Duke University, Durham, NC, USA, ‡‡Memorial Sloan Kettering Cancer Center, New York, NY, USA, §§UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA, ¶¶Alliance Central Protocol Operations, University of Chicago, Chicago, IL, USA, ***Department of Pathology, Yale University Medical School, New Haven, CT, USA, and †††Department of Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, NY, USA J. Protocol Operations, University of Chicago, Chicago, IL, USA, ***Department of Pathology, Yale University Medical School, New Haven, CT, USA, and †††Department of Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, NY, USA

 

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Abstract

Objective

To assess the most recommended books on keto and the feasibility of performing national, randomized trials of dietary interventions for localized prostate cancer.

Methods

The Men’s Eating and Living (MEAL) study (CALGB 70807 [Alliance]) is a phase III clinical trial testing the efficacy of a high‐vegetable diet to prevent progression in patients with prostate cancer on active surveillance (AS). Participants were randomized to a validated diet counselling intervention or to a control condition. Chi‐squared and Kruskal–Wallis analyses were used to assess between‐group differences at baseline.

Results

Between 2011 and 2015, 478 (103%) of a targeted 464 patients were randomized at 91 study sites. At baseline, the mean (sd) age was 64 (6) years and mean (sd) PSA concentration was 4.9 (2.1) ng/mL. Fifty‐six (12%) participants were African‐American, 17 (4%) were Hispanic/Latino, and 16 (3%) were Asian‐American. There were no significant between‐group differences for age (P = 0.98), race/ethnicity (P = 0.52), geographic region (P = 0.60), time since prostate cancer diagnosis (P = 0.85), PSA concentration (P = 0.96), clinical stage (T1c or T2a; P = 0.27), or Gleason sum (Gleason 6 or 3+4 = 7; P = 0.76). In a pre‐planned analysis, the baseline prostate biopsy samples of the first 50 participants underwent central pathology review to confirm eligibility, with an expectation that <10% would become ineligible. One of 50 participants (2%) became ineligible.

Conclusion

The MEAL study shows the feasibility of implementing national, multi‐institutional phase III clinical trials of diet for prostate cancer and of testing interventions to prevent disease progression in AS.

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Editorial: PCa Prevention – Proof is Elusive

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Prevention is so much better than cure because it saves the labor of being sick. Thomas Adams, 1618

Inferior doctors treat the full blown disease; mediocre doctors treat the disease before evident; superior doctors prevent disease.   Nai Ching, 1st Chinese Medical Text, 2600 BC. 

Enthusiasm for prevention is hundreds, even thousands of years old.  In the field of prostate cancer, profound differences in the regional variation of prostate cancer around the world (highest in Americans and Scandinavians, lowest in Asians) despite the similar incidence of histologic occult prostate cancer, and shifts in the incidence in mortality amongst immigrant populations moving from low to high prostate cancer regions, led to a firm belief that clinical disease was preventable.   This belief was supported by the known long initiation phase for prostate cancer, providing an opportunity over decades for diet and micronutrient intake to influence the likelihood of disease progression.

In addition, many epidemiologic studies pointed to the benefits of fruits and vegetable intake high in Vitamin E, Selenium, Beta Carotene, Lycopene, and other micronutrients, and a diet low in animal fat.

However, recently several pivotal studies have taken the bloom off the rose of prevention.  In particular, the SELECT study demonstrated a 17% increased rate of prostate cancer in men on Vitamin E, and an increase in DM in men on Selenium (1).  The study was resoundingly negative.  In addition, both high intake of multivitamins, and high dairy and calcium intake, have been associated with an increased risk of fatal prostate cancer (2).   Folic acid intake results in an increased incidence of prostate cancer.  Despite the positive PCPC and Reduce trials, the 5 ARIs were not approved for prevention by the FDA due to concerns about an increased risk of high grade prostate cancer, despite the reduction in positive biopsies in men on the drug (mostly due to  a decrease in low grade cancer).

Further, studies of the association between dietary intake of fruits and vegetables and PCa are inconsistent.  For example, one large study of 130,544 men found no significant association between fruit or vegetable intake, including cruciferous vegetables, and prostate cancer. (3)  Another study showed dietary modification, reducing fat and increasing fruits, vegetables, and fiber, had no impact on PSA.  (4).

And yet, despite the negative intervention studies, a lingering spark of hope exists that the many positive population, epidemiologic, and pre- clinical studies supporting dietary prevention will be vindicated.  The study in the current issue of BJU Int on the MEAL study is therefore a laudable and ambitious initiative (5).   Remarkably, 478 men have been randomized to validated dietary counseling intervention vs no intervention.  This paper reports the initial demographics and eligibility data.  It is undoubtedly the first of many publications that will arise from this important trial.

Will this study prove its’ ambitious goal, to demonstrate that prostate cancer progression can be influenced by dietary modification?   While the initiative is laudable, I suspect the hurdles are insurmountable given the sample size and conceptual basis for the study.  The study is being performed in men on active surveillance, and the primary end point will be the risk of disease ‘progression’.  The study references the Redeem study, which showed a 44% reduction in disease ‘progression’ with dutasteride compared to placebo (6).

What we have learned since the Redeem study was initiated more than a decade ago was that the major limitation of conservative management in men diagnosed with low grade prostate cancer on systematic biopsy is not disease progression as it is usually defined (ie, developing worse disease over time); it is grade misattribution, based on sampling and pathologic miss of co-existent higher grade cancer (7).  Higher grade cancer is present in about 30% of men with Gleason 6 cancer on systematic biopsy.  Finding this on subsequent systematic biopsy is largely a matter of luck, location of the cancer, and biopsy strategy and number.    In contrast, true grade progression (from Gleason pattern 3 to pattern 4 or 5) is uncommon, estimated to occur in only 1-2% of patients per year (8).  The adoption of MRI and targeted biopsy into the surveillance algorithm has reduced the misattribution problem.   Thus, the true ‘event rate’ (exclusive of misattribution) is likely to be in the 15% range at 10 years.   A study with the power to detect a 20% relative difference in these events, ie a 3% absolute difference, would require more than a thousand patients followed for 10 years.

In the Redeem study, the reduction in ‘progression’ was entirely related to a decrease in the volume of low grade cancer.  Indeed, the rate of upgrading was 13% in both arms in Redeem.  Therefore the decrease in progression in that study likely reflected the cytoreduction effect of 5 ARIs, and not a real biological effect on cancer progression.

Thus, to be meaningful, prevention studies in men on surveillance should identify, at the very least, a real reduction in grade progression, based on state of the art evaluation at baseline with MRI and targeted biopsies as warranted, and long term follow up.    A decrease in the rate of volume progression of Gleason 6, a major end point of this study, is not meaningful.   In the study as described, which does not explicitly incorporate MRI, an imbalance in the number of patients having off protocol MRI and targeted biopsies between the two arms could significantly bias the outcome.

A further problem with long term studies of dietary intervention relates to the well-known methodological limitations in this area—ensuring long term compliance, recall bias of food intake, and contamination of the control arm.

Nonetheless, the authors deserve strong congratulations for pursuing this major initiative.  We will follow the course of this study with interest.

 

Dr. Laurence Klotz C.M.

Division of Urology, Sunnybrook Health Sciences Centre, 2075 Bayview Ave. #MG408 

Toronto, Ontario M4N 3M5

 

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References

  1. Klein EA, Thompson IM Jr, Tangen CM, et al.: Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306 (14): 1549-56, 2011
  2. Lawson KA, Wright ME, Subar A, et al.: Multivitamin use and risk of prostate cancer in the National Institutes of Health-AARP Diet and Health Study. J Natl Cancer Inst 99 (10): 754-64, 2007
  3. Key TJ, Allen N, Appleby P, et al.: Fruits and vegetables and prostate cancer: no association among 1104 cases in a prospective study of 130544 men in the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 109 (1): 119-24, 2004
  4. Shike M, Latkany L, Riedel E, et al.: Lack of effect of a low-fat, high-fruit, -vegetable, and -fiber diet on serum prostate-specific antigen of men without prostate cancer: results from a randomized trial. J Clin Oncol 20 (17): 3592-8, 2002.
  5. BJU-2016-1793.R2 – The Men’s Eating and Living (MEAL) Study (CALGB 70807 [Alliance]): Recruitment Feasibility and Baseline Demographics of a Randomized Trial of Diet in Men on Active Surveillance for Prostate Cancer
  6. Fleshner NE, Lucia MS, Egerdie B, et al. Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial. 2012;379(9821):1103-1111.
  7. Cooperberg MR, Carroll PR, Klotz L: Active surveillance for prostate cancer: progress and promise. J Clin Oncol 29 (27): 3669-76, 2011. [PubMed]
  8. Lurdes Y.T. Inoue, Bruce J. Trock, Alan W. Partin, H. Ballentine Carter, Ruth Etzioni Modeling Grade Progression In An Active Surveillance Study Stat Med. Author manuscript; available in PMC 2015 Mar 15. Published in final edited form as: Stat Med. 2014 Mar 15; 33(6): 930–939.

 

Article of the Week: Chitosan membranes applied on the prostatic neurovascular bundles after nerve‐sparing robot‐assisted radical prostatectomy: a phase II study

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Every Week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this month, it should be this one.

Chitosan membranes applied on the prostatic neurovascular bundles after nerve‐sparing robot‐assisted radical prostatectomy: a phase II study

Francesco Porpiglia* , Riccardo Bertolo*, Cristian Fiori*, Matteo Manfredi*, Sabrina De Cillis* and Stefano Geuna†

 

*Division of Urology, Department of Oncology, and †Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy

 

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Abstract

Objective

To evaluate the feasibility and the safety of applying chitosan membrane (ChiMe) on the neurovascular bundles (NVBs) after nerve‐sparing robot‐assisted radical prostatectomy (NS‐RARP). The secondary aim of the study was to report preliminary data and in particular potency recovery data.

Patients and Methods

This was a single‐centre, single‐arm prospective study, enrolling all patients with localised prostate cancer scheduled for RARP with five‐item version of the International Index of Erectile Function scores of >17, from July 2015 to September 2016. All patients underwent NS‐RARP with ChiMe applied on the NVBs. The demographics, perioperative, postoperative and complications data were evaluated. Potency recovery data were evaluated in particular and any sign/symptom of local allergy/intolerance to the ChiMe was recorded and evaluated.

Results

In all, 140 patients underwent NS‐RARP with ChiMe applied on the NVBs. Applying the ChiMe was easy in almost all the cases, and did not compromise the safety of the procedure. None of the patients reported signs of intolerance/allergy attributable to the ChiMe and potency recovery data were encouraging.

Conclusion

In our experience, ChiMe applied on the NVBs after NS‐RARP was feasible and safe, without compromising the duration, difficulty or complication rate of the ‘standard’ procedure. No patients had signs of intolerance/allergy attributable to the ChiMe and potency recovery data were encouraging. A comparative cohort would have added value to the study. The present paper was performed before Conformité Européene (CE)‐mark achievement.

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Editorial: Nerve wrapping with biomaterials during radical prostatectomy to improve potency recovery

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Radical prostatectomy is one of the standard treatment options for localized prostate cancer. The functional outcomes of radical prostatectomy are steadily improving along with better understanding of the surgical anatomy involved. Technological and technical advancements have helped improve continence outcomes significantly. High‐volume centres have consistently reported continence rates of >95% 1; however, potency recovery is the major limiting factor in achieving trifecta, even with full nerve‐sparing. Neuropraxia secondary to surgical dissection is one of the factors delaying potency recovery. We were the first to introduce the concept of protecting the neurovascular bundle using a wrap. In 2015, we first published our work on dehydrated human amnion‐chorion membrane (dHACM) nerve wrapping, a potential means of improving functional outcomes after radical prostatectomy 2.

Clinical applications of biomaterials are increasingly being explored. Their biological and physiochemical properties influence their role in peripheral nervous system regenerative therapy 3. Amniotic membrane graft has multiple growth factors including epidermal growth factor, vascular endothelial growth factor and anti‐inflammatory chemokines and cytokines including interleukin (IL)‐1, IL‐10 and IL‐1ra. In vitro and in vivo studies have reported that dHACM minimizes the surgical trauma‐induced inflammation and peri‐neural adhesions. These membranes are commercially available in various sizes for clinical use.

Porpiglia et al. 4 have reported their work on chitosan membrane application on the prostatic neurovascular bundle. Their phase II study is a step towards finding an ideal biomaterial favouring peripheral nerve healing. Chitosan is another potential biomaterial made of glucosamine and N‐acetyl glucosamine polymer which are natural components of mammalian tissues 5. Chitosan is hypoallergenic and only transiently stimulates the immune system and ultimately becomes bio‐tolerated and metabolized. It is not possible to develop specific antibodies against it because there are no proteins and lipids in its structure. Chitosan has inherent antimicrobial activity as its positive loads destabilize the membrane integrity of microorganisms. The inherent haemostatic and antimicrobial action of chitosan favour its application in wound healing. Chitosan has been extensively researched as a carrier molecule for biologically active particles and a scaffold in tissue engineering. Porpiglia et al. 4 have reported the safety and feasibility of its application for neurovascular bundle wrap during radical prostatectomy. In their non‐comparative study, they observed 96.4% continence and 68.6% potency recovery within 6 months. Comparative clinical trials are recommended to study its advantages in both partial and full nerve‐sparing settings. Membranes were manufactured from chitosan solution and sterilized for the purposes of the study. Pending approval by the regulators, study in other centres using chitosan membrane may be challenging.

The urological community has long been searching for ways to optimize functional outcomes after radical prostatectomy. Even for an ideal candidate with full nerve‐sparing, potency recovery is not assured. Several technical and technological modifications are being explored to address this concern. Bio-materials hold potential, and further exploration is warranted in the form of multicentre and randomized trials.

Hariharan Palayapalayam Ganapathi, Fikret Onol, Travis Rogers and Vipul Patel
Global Robotics Institute at Florida Hospital, University of Central Florida College of Medicine, Celebration, FL, USA

 

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References

 

  • 1 Patel VR, Abdul‐Muhsin HM, Schatloff O et al.Critical review of ‘pentafecta’ outcomes after robot‐assisted laparoscopic prostatectomy in high‐volume centres. BJU Int2011; 108: 1007–17

 

  • 2 Patel VR, Samavedi S, Bates AS et al.Dehydrated Human Amnion/Chorion membrane allograft nerve wrap around the prostatic neurovascular bundle accelerates early return to continence and potency following robot‐assisted radical prostatectomy: propensity score‐matched analysis. Eur Urol2015; 67: 977–80

 

  • 3 Dalamagkas K, Tsintou M, Seifalian A. Advances in peripheral nervous system regenerative therapeutic strategies: a biomaterials approach. Mater Sci Eng C Mater Biol Appl2016; 65: 425–32

 

  • 4 Porpiglia F, Bertolo R, Fiori C, Manfredi M, De Cillis S, Geuna S. Chitosan membranes applied on the prostatic neurovascular bundles after nerve‐sparing robot‐assisted radical prostatectomy: a phase II study. BJU Int2018; 121: 473–9

 

  • 5 Rodríguez‐Vázquez M, Vega‐Ruiz B, Ramos‐Zúñiga R, Saldaña‐Koppel DA, Quiñones‐Olvera LF. Chitosan and its potential use as a scaffold for tissue engineering in regenerative medicine. Biomed Res Int2015; 2015: 821279

 

Video: Chitosan membranes applied on the prostatic neurovascular bundles after nerve‐sparing robot‐assisted radical prostatectomy: a phase II study

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Chitosan membranes applied on the prostatic neurovascular bundles after nerve‐sparing robot‐assisted radical prostatectomy: a phase II study

 

Read the full article

Abstract

Objective

To evaluate the feasibility and the safety of applying chitosan membrane (ChiMe) on the neurovascular bundles (NVBs) after nerve‐sparing robot‐assisted radical prostatectomy (NS‐RARP). The secondary aim of the study was to report preliminary data and in particular potency recovery data.

Patients and Methods

This was a single‐centre, single‐arm prospective study, enrolling all patients with localised prostate cancer scheduled for RARP with five‐item version of the International Index of Erectile Function scores of >17, from July 2015 to September 2016. All patients underwent NS‐RARP with ChiMe applied on the NVBs. The demographics, perioperative, postoperative and complications data were evaluated. Potency recovery data were evaluated in particular and any sign/symptom of local allergy/intolerance to the ChiMe was recorded and evaluated.

Results

In all, 140 patients underwent NS‐RARP with ChiMe applied on the NVBs. Applying the ChiMe was easy in almost all the cases, and did not compromise the safety of the procedure. None of the patients reported signs of intolerance/allergy attributable to the ChiMe and potency recovery data were encouraging.

Conclusion

In our experience, ChiMe applied on the NVBs after NS‐RARP was feasible and safe, without compromising the duration, difficulty or complication rate of the ‘standard’ procedure. No patients had signs of intolerance/allergy attributable to the ChiMe and potency recovery data were encouraging. A comparative cohort would have added value to the study. The present paper was performed before Conformité Européene (CE)‐mark achievement.

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Article of the Week: Prospective randomised non-inferiority trial of PD placement vs ND placement after RARP

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Every Week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this month, it should be this one.

Prospective randomised non-inferiority trial of pelvic drain placement vs no pelvic drain placement after robot-assisted radical prostatectomy

Avinash Chenam* , Bertram Yuh*, Ali Zhumkhawala*, Nora Ruel†, William Chu*, Clayton Lau*, Kevin Chan*, Timothy Wilson* and Jonathan Yamzon*

 

*Department of Surgery, Division of Urology and Urologic Oncology , and †Department of Biostatistics, City of Hope National Medical Center, Duarte, CA, USA

 

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Abstract

Objective

To determine if eliminating the prophylactic placement of a pelvic drain (PD) after robot-assisted radical prostatectomy (RARP) affects the incidence of early (90-day) postoperative adverse events.

Patients and Methods

In this parallel-group, blinded, non-inferiority trial, we randomised patients planning to undergo RARP to one of two arms: no drain placement (ND) or PD placement. Patients with demonstrable intraoperative leakage upon bladder irrigation were excluded. Randomisation sequence was determined a priori using a computer algorithm, and included a stratified design with respect to low vs intermediate/high D’Amico risk classifications. Surgeons remained blinded to the randomisation arm until final eligibility was verified at the end of the RARP. The primary endpoint was overall incidence of 90-day complications which, based on our standard treatment using PD retrospectively, was estimated at 13%. The non-inferiority margin was set at 10%, and the planned sample size was 312. An interim analysis was planned and conducted when one-third of the planned accrual and follow-up was completed, to rule out futility if the delta margin was in excess of 0.1389.

Results

From 2012 to 2016, 189 patients were accrued to the study, with 92 patients allocated to the ND group and 97 to the PD group. Due to lower than expected accrual rates, accrual to the study was halted by regulatory entities, and we did not reach the intended accrual goal. The ND and PD groups were comparable for median PSA level (6.2 vs 5.8 ng/mL, P = 0.5), clinical stage (P = 0.8), D’Amico risk classification (P = 0.4), median lymph nodes dissected (17 vs 18, P = 0.2), and proportion of patients receiving an extended pelvic lymph node dissection (70.7% vs 79.4%, P = 0.3). Incidence of 90-day overall and major (Clavien–Dindo grade >III) complications in the ND group (17.4% and 5.4%, respectively) was not inferior to the PD group (26.8% and 5.2%, respectively; P < 0.001 and P = 0.007 for difference of proportions <10%, respectively). Symptomatic lymphocoele rates (2.2% in the ND group, 4.1% in the PD group) were comparable between the two arms (P = 0.7).

Conclusions

Incidence of adverse events in the ND group was not inferior to the group who received a PD. In properly selected patients, PD placement after RARP can be safely withheld without significant additional morbidity.

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Editorial: To drain or not to drain after RARP? That is the question

/1 Comment/by

In the current issue of BJUI, the article by Chenam et al. [1] from the City of Hope Hospital clarifies an important surgical issue that most major uro-oncology centres face every day, but it also raises several other important surgical issues. The objective of the study was to determine if eliminating the routine placement of a pelvic drain after robot-assisted radical prostatectomy (RARP) affects the incidence of early (90-day) postoperative adverse events. RARP has become the new ‘gold standard’ approach for the surgical treatment of localized prostate cancer, and now comprises the majority of radical prostatectomies performed in the USA and the UK, with >80% of cases using this technique [2].

In this parallel-group, blinded, non-inferiority trial, patients who were planned to undergo RARP were randomized to one of two arms: no drain placement or pelvic drain placement. The primary endpoint was incidence of 90-day complications which, based on standard treatment using pelvic drain retrospectively, was estimated at 13%. The non-inferiority margin was set at 10%, and the planned sample size was 312. Despite stopping short of the intended number of patients to reach the accrual goal, it was impressive to read that the study was still well conducted, with robust statistical evidence that the no drain placement group was not inferior to the pelvic drain group. As a result, the authors conclude that pelvic drain can be safely omitted based on a clinical decision according to the surgeon’s discretion.

It has previously been demonstrated that the need for pelvic drain placement in RARP may be significantly less than in open prostatectomy techniques [3], and the concept of omitting the drain was initially presented more than 10 years ago [4]. But in any radical prostatectomy the rationale for placing a pelvic drain is potentially complex. Firstly, an anastomotic urine leak and subsequent urinoma or urinary peritonitis are the key historical concerns. The current reliable continuous running anastomosis now routinely possible with the robotic approach is far superior to the five to seven interrupted sutures inserted with the open or laparoscopic techniques, and hence the integrity is far more robust. Anastomotic leak rate is therefore generally very low at ~0.5–1% [2], and other non-randomized studies have previously shown that omission of pelvic drains is potentially safe [5].

Secondly, a drain may also assist with drainage of lymphatic leak after pelvic lymphadenectomy, preventing symptomatic lymphocele. The incidence of symptomatic lymphocele is ~2.5% in those undergoing RARP and extended pelvic lymph node dissection, as most lymphoceles are asymptomatic, but those that present late may be more at risk of infection in people with diabetes [6]. Another aspect that a small randomized controlled trial will not evaluate is the impact of the very occasional disaster, such as significant anastomotic disruption by a pelvic haematoma or a postoperative haemorrhage, and how that might be adverted by prior placement of a pelvic drain.

One of the few relevant problems with small randomized controlled trials in single centres is generalizability; results potentially only relate to very similar patient populations, i.e. those treated at high-volume and experienced centres, and cannot necessarily be extrapolated to other situations, such as RARPs performed by surgeons early on their learning curve or by those on fellowship/training programmes, or complex cases such as salvage RARP or when the anastomosis is technically challenging. This may include cases with significant bladder neck reconstruction, RARPs performed after TURP, or even cases with patients on steroids or other immunosuppressants. How necessary a pelvic drain is to the rapidly emerging Retzius-sparing RARPs remains to be seen, but judicious placement initially during the learning curve at least seems very sensible. Thus it would be wrong to conclude from the present study that pelvic drains are never indicated, as the authors also specify. Perhaps future larger studies may indicate more clearly those populations which do require pelvic drains in the form of an algorithm or decision-making tool.

It is clear that, as the emphasis shifts to enhanced recovery in the RARP population, pelvic drain placement may delay discharge and have a negative impact on the patient, such as increased anxiety and potential morbidity. In a public healthcare system such as the NHS, in which length of stay is an important cost variable, the present study empowers urologists to dispense with drains in the majority of cases. We believe the study was very well conducted and raises an important and a controversial topic. Overall, as we are all so much more familiar with standard RARP, it seems the time has come to omit the routine pelvic drain.

Salma Ghanem, Benjamin Namdarian and Ben Challacombe
Urology Centre, Guy’s Hospital, London, UK

 

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References

 

1 Chenam A, Yuh B, Zhumkhawala A et al. Prospective randomized non-inferiority trial of pelvic drain placement vs no pelvic drain placement after robot-assisted radical prostatectomy. BJU Int 2018; 121: 358–65

 

2 BAUS UK Radical Prostatectomy Audit 2016. Available at: https:// www.baus.org.uk/_userfiles/pages/files/Publications/Audit/Radical% 20Prostatectomy%202016%20final%20analysis.pdf. Accessed November 2017

 

3 Danuser H, Di Pierro GB, Stucki P, Mattei A. Extended pelvic lymphadenectomy and various radical prostatectomy techniques: is pelvic drainage necessary? BJU Int 2013; 111: 963–9

 

4 Sharma S, Kim HL, Mohler JL. Routine pelvic drainage not required after open or robotic radical prostatectomy. Urology 2007; 69: 330–3

 

5 Musser JE, Assel M, Guglielmetti GB et al. Impact of routine use of surgical drains on incidence of complications with robot-assisted radical prostatectomy. J Endourol 2014;28:1333–7

 

6 Keskin MS, Argun OB, Obek C et al. The incidence and sequela of lymphocele formation after robot-assisted extended pelvic lymph node dissection. BJU Int 2016; 118: 127–31

 

Article of the Week: Natural history of ‘second’ biochemical failure after SRT for PCa

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Every Week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this month, it should be this one.Follow us rothwelldouglas for more articles like this one.

Natural history of ‘second’ biochemical failure after salvage radiation therapy for prostate cancer: a multi-institution study

 

Vasu Tumati*, William C. Jackson†, Ahmed E. Abugharib†, Ganesh Raj‡, Claus Roehrborn‡, Yair Lotan‡ ,Kevin Courtney§, Aditya Bagrodia‡, Jeffrey C. Gahan‡, Zachary S. Zumsteg**, Michael R. Folkert*, Aaron M. Laine*, Raquibul Hannan*, Daniel E. Spratt† and Neil B. Desai* 

 

Departments of *Radiation Oncology, ‡Urology, §Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA, Department of †Radiation Oncology, University of Michigan, Ann Arbor, MI, USA, and **Department of Radiation Oncology Cedars-Sinai Medical Center, Los Angeles, CA, USA

 

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Abstract

Objectives

To describe the natural history of prostate cancer in men who experience a second biochemical recurrence (BCR) after salvage radiotherapy (SRT) after prostatectomy.

Patients and Methods

After undergoing SRT at one of two institutions between 1986 and 2013, 286 patients experienced a second BCR, defined as two rises in prostate-specific antigen (PSA) of ≥0.2 ng/mL above nadir. Event rates for distant metastasis (DM) or freedom from DM (FFDM), castration-resistant prostate cancer (CRPC), prostate cancer-specific survival (PCSS), and overall survival (OS) were estimated using the Kaplan–Meier method. Cox regression was used for comparative analyses.

Results

At a median of 6.1 years after second BCR, DM, CRPC, PCSS and OS rates were 41%, 27%, 83% and 73%, respectively. On multivariable analysis, interval to second BCR <1 year (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.71–4.14; P < 0.001], Gleason score 8–10 (HR 1.65, 95% CI 1.07–2.54; P = 0.022), and concurrent ADT during SRT (HR 1.76, 95% CI 1.08–2.88; P = 0.024) were associated with FFDM, while PCSS was associated with interval to second BCR <1 year (HR 3.00, 95% CI 1.69–5.32; P < 0.001) and concurrent ADT during SRT (HR 2.15, CI 1.13–4.08; P = 0.019). These risk factors were used to stratify patients into three groups, with 6-year FFDM rates of 71%, 59% and 33%, and PCSS rates of 89%, 79%, and 65%, respectively.

Conclusion

Following second BCR after SRT, clinical progression is enriched in a subgroup of patients with prostate cancer, while others remain without DM for long intervals. Stratifying patients into risk groups using prognostic factors may aid counselling and future trial design.

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