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Editorial: Salvaging failed radiation therapy: does the tumour location permit a less toxic approach?

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In the introduction to their manuscript in this issue of the BJUI, Meeks et al. outline a significant challenge for physicians managing prostate cancer: from the estimated 240 000 diagnosed annually (USA) to the 120 000 choosing radiation, to the 40 000 estimated biochemical failures in the first 5 years who may benefit from additional local therapy to avoid local and/or systemic progression. The basis of these calculations was from conventional beam radiation, and although we expect dose-escalation strategies to perform better, the ideal management strategy remains to be identified. Indeed, Zelefsky et al. showed that there was a higher risk of metastatic disease with external beam radiation therapy than with surgery for high-risk prostate cancer, although there was some confounding of the results due to the differences in salvage treatment. This confounding may be the key point: more acceptable salvage options may promote optimal local control and fewer progressions.

Certainly, the concern with salvage therapy after failed radiation is the toxicity, and the concept of achieving less urinary incontinence with cryotherapy or even focal cyrotherapy is attractive, as outlined by de Castro Abreu et al. in this issue. In their parallel cohorts of total and focal salvage cryotherapy, urinary incontinence occurred in three (13%) of the 25 salvage total and zero of the 25 salvage focal therapies, and there was only one fistula in either series. However, the cancer control outcomes are different among these non-randomised and non-comparable cohorts: 87% disease-free survival for patients with bilateral disease treated with total cryotherapy and 54% disease-free survival for patients with unilateral disease treated with focal cryotherapy. These comparisons are limited, but one could hypothesise that salvage total therapy has improved disease control over salvage focal therapy.

Returning to the Meeks et al. study, a cohort of 198 patients with biopsy confirmed radiation recurrence underwent a salvage prostatectomy at a single institution. Pre-treatment biopsies showed 48% and 13% Gleason sums 7 and 8–10, respectively, and multifocal location in 61% (92/151 patients). Salvage prostatectomies showed 56% advanced pathological stage and 35% Gleason 8–10, and multifocal location in 57%. In comparing specific biopsy locations to radical prostatectomy mapping, undetected cancers from biopsy ranged from 12% to 26%, and 58% upgrading. In patients with unilaterally localised biopsies, final pathology was unilateral in only half – a statistic that matches the PSA failure rate from focal therapy in the de Castro Abreu et al.’s study. The authors point to a non-radiated biopsy-to-prostatectomy study and by comparison conclude that the accuracy of biopsy in radiated prostates is actually greater, perhaps due to the smaller radiated gland. But let’s be clear – both groups had significant rates of multifocal disease and inaccuracies between biopsy and radical prostatectomy.

These two BJUI studies provide a developing agenda of what we know and do not know about salvage therapy for failed radiation:

  • Local failure after radiation selects patients who probably have significant disease in terms of volume, stage, and grade, and should not be confused with the over-detection of low-volume, low-grade disease seen in primary treatments for PSA-screened disease.
  • Salvage focal therapy for unilateral disease by biopsy may be less morbid but may be only 50% effective.
  • The link between metastatic progression and PSA failure after failed salvage focal therapy is unknown, and completion treatment of the other side could be studied.
  • The additive accuracy of post-radiation biopsy plus imaging is not established.
  • We are basing most of our treatment recommendations on tumour morphology (histopathology, location, size) and surrogates (PSA failure definitions) rather than biology and survival.
  • The current management of post-radiation local failure should consider total gland treatments as the standard and focal therapies as experimental.

John W. Davis and Seungtaek Choi*
Departments of Urology and *Radiation Oncology, UT MD Anderson Cancer Center, Houston, TX, USA

Article by Meeks et al.
Article by de Castro Abreu et al.

Video: Cryoablation after failed primary radiotherapy: study finds encouraging results

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Salvage focal and salvage total cryoablation for locally recurrent prostate cancer after primary radiation therapy

Andre Luis de Castro Abreu*, Duke Bahn*†, Scott Leslie*, Sunao Shoji*, Paul Silverman†, Mihir M. Desai*, Inderbir S. Gill* and Osamu Ukimura*

*USC Institute of Urology, Hillard and Roclyn Herzog Center for Prostate Cancer Focal Therapy, Keck School of Medicine, University of Southern California, Los Angeles, and †Prostate Institute of America, Community Memorial Hospital, Ventura, CA, USA

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OBJECTIVES

• To present the oncological and functional outcomes of salvage focal (SFC) and salvage total (STC) cryoablation for recurrent prostate cancer (PCa) after failed primary radiotherapy.

PATIENTS AND METHODS

• From March 2003 to August 2010, 50 men with biopsy-proven unilateral (n = 25) or bilateral (n = 25) radio-recurrent PCa underwent SFC or STC, respectively.

• Patients were assessed after treatment by prostate-specific antigen (PSA) testing, transrectal ultrasonography, biopsy and questionnaires. Biochemical failure (BF) was defined using the Phoenix criteria (PSA nadir + 2 mg/mL).

• Data were prospectively collected and retrospectively analysed.

RESULTS

• The median pre-cryoablation PSA level and Gleason score were, respectively, 2.8 ng/mL and 7 for SFC, and 3.9 ng/mL and 7 for STC. The median follow-up was 31 and 53 months (P = 0.004) for SFC and STC, respectively.

• Oncological outcomes were as follows: no patient died; one patient who underwent STC developed bone metastases; eight patients who underwent SFC and three who underwent STC had BF and the 5-year BF-free survival rates were 54 and 86%, respectively. In those patients without BF, the mean PSA decreased by 86% for SFC and 90% for STC within the first year and remained stable.

• Functional outcomes were as follows: new onset urinary incontinence occurred in three (13%) patients in the STC group, whereas no patient in the SFC group developed incontinence (P = 0.10); Two of seven patients in the SFC group retained postoperative potency, but none of the four potent patients in the STC group recovered potency postoperatively (P = 0.48); one (4%) patient in the STC group developed a recto-urethral fistula, but none occurred in the SFC group (P = 0.48).

CONCLUSIONS

• SFC and STC are feasible and safe with acceptable mid-term oncological outcomes. For carefully selected patients, SFC is an option that could be associated with lower treatment-related morbidity compared with STC.

• Although longer follow-up and more patient numbers are needed, our initial oncological and functional outcomes of SFC and STC are encouraging.

Article of the week: Smaller is better? Microperc comes of age

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Micropercutaneous nephrolithotomy (microperc) vs retrograde intrarenal surgery for the management of small renal calculi: a randomized controlled trial

Ravindra B. Sabnis, Raguram Ganesamoni, Amit Doshi, Arvind P. Ganpule, Jitendra Jagtap and Mahesh R. Desai

Department of Urology, Muljibhai Patel Urological Hospital, Nadiad, Gujarat, India

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OBJECTIVE

• To compare micropercutaneous nephrolithotomy (microperc) and retrograde intrarenal surgery (RIRS) for the management of renal calculi <1.5 cm with regard to stone clearance rates and surgical characteristics, complications and postoperative recovery.

PATIENTS AND METHODS

• Seventy patients presenting with renal calculi <1.5 cm were equally randomized to a microperc or a RIRS group between February 2011 and August 2012 in this randomized controlled trial. Randomization was based on centralized computer-generated numbers. Patients and authors assessing the outcomes were not blinded to the procedure.

• Microperc was performed using a 4.85-F (16-gauge) needle with a 272-μm laser fibre. RIRS was performed using a uretero-renoscope.

• Variables studied were stone clearance rates, operating time, need for JJ stenting, intra-operative and postoperative complications (according to the Clavien–Dindo classification system), surgeon discomfort score, postoperative pain score, analgesic requirement and hospital stay.

• Stone clearance was assessed using ultrasonography and X-ray plain abdominal film of kidney, ureter and bladder at 3 months.

RESULTS

• There were 35 patients in each group. All the patients were included in the final analysis.

• The stone clearance rates in the microperc and RIRS groups were similar (97.1 vs 94.1%, P = 1.0).

• The mean [sd] operating time was similar between the groups (51.6 [18.5] vs 47.1 [17.5], P = 0.295). JJ stenting was required in a lower proportion of patients in the microperc group (20 vs 62.8%, P < 0.001). Intra-operative complications were a minor pelvic perforation in one patient and transient haematuria in two patients, all in the microperc group. One patient in each group required conversion to miniperc.

• One patient in the microperc group needed RIRS for small residual calculi 1 day after surgery. The decrease in haemoglobin was greater in the microperc group (0.96 vs 0.56 g/dL, P < 0.001). The incidence of postoperative fever (Clavien I) was similar in the two groups (8.6 vs 11.4%, P = 1.0). None of the patients in the study required blood transfusion.

 

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Editorial: Micro-PNL vs RIRS: dealer’s choice? The devil is in the details

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Advances in minimally invasive endourological techniques continue to provide the Urologist a myriad of options for the management of symptomatic renal calculi. Previously, shock wave lithotripsy (SWL) or standard percutaneous nephrolithotomy (PNL) were the only two endourological options available. Yet, limitations of these two ‘standard’ techniques result from hard or dependent stones (for SWL) or the potential of increased morbidity during the treatment of small renal calculi (for PNL). Now the introduction of smaller fibre-optic needle-scopes combined with laser stone fragmentation (micro-PNL or ‘microperc’) provides access to difficult-to-reach renal calculi with minimal patient morbidity. Moreover, newer flexible ureteroscopes, along with nitinol baskets and graspers (retrograde intra-renal surgery or ‘RIRS’) allow another minimally invasive option for hard-to-reach renal calculi.

In the present issue of BJUI, Sabnis et al. present a well performed, randomised, prospective trial comparing microperc to RIRS for the management of renal calculi of <1.5 cm in diameter. They determined that both procedures were essentially identical in their ability to remove small-to-moderate sized renal stones with minimal patient morbidity/complications. Yet, both of these procedures have inherent limitations that are unique to the instrumentation used for each technique. Microperc has limited applicability for stones located anteriorly within the kidney, while RIRS is an ideal technique to access symptomatic renal stones within an anterior calyx. RIRS may not be able to target lower pole calculi in those patients with an acute infundibular angle or stones in a calyceal diverticulum, whereas a microperc can be used to reach hard-to-access calculi.

One must accept that both of these innovative procedures are inefficient in their ability for removal of large volume stones and neither technique offers an efficient method of clearing multiple stone fragments. Ideally, both microperc and RIRS should only be used for small volume renal calculi.

I would offer that both procedures are safe and effective alternatives for the management of small renal calculi. Yet, we must be realistic in offering these techniques to our patients, pairing each procedure with the most appropriate situation. Even in 2013, large volume renal calculi are best managed by standard or mini-PNL, where devices such as ultrasonic lithotripsy or dual ultrasonic/pneumatic lithotripsy offer efficient methods of stone removal. SWL is still a reasonable option for the treatment of renal calculi of ≤1 cm in diameter.

Now RIRS and microperc can be added to the list of treatment options for managing symptomatic renal calculi. In patients with large renal calculi, along with multiple medical comorbidities or bleeding diatheses/on anti-coagulation, RIRS provides another, yet inefficient, alternative for stone removal, often requiring multiple procedures to clear the stone. In those situations where the flexible ureteroscope cannot target a renal calculus of <1.5 cm, microperc provides the option of accessing the calculus, yet offers no method of efficiently clearing stone fragments. If we set reasonable expectations for the use of these two minimally invasive endourological techniques, our patients will surely benefit.

Glenn M. Preminger
Duke University Medical Center, Durham, NC, USA

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Video: Small renal calculi can be effectively managed with microperc

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Micropercutaneous nephrolithotomy (microperc) vs retrograde intrarenal surgery for the management of small renal calculi: a randomized controlled trial

Ravindra B. Sabnis, Raguram Ganesamoni, Amit Doshi, Arvind P. Ganpule, Jitendra Jagtap and Mahesh R. Desai

Department of Urology, Muljibhai Patel Urological Hospital, Nadiad, Gujarat, India

Read the full article
OBJECTIVE

• To compare micropercutaneous nephrolithotomy (microperc) and retrograde intrarenal surgery (RIRS) for the management of renal calculi <1.5 cm with regard to stone clearance rates and surgical characteristics, complications and postoperative recovery.

PATIENTS AND METHODS

• Seventy patients presenting with renal calculi <1.5 cm were equally randomized to a microperc or a RIRS group between February 2011 and August 2012 in this randomized controlled trial. Randomization was based on centralized computer-generated numbers. Patients and authors assessing the outcomes were not blinded to the procedure.

• Microperc was performed using a 4.85-F (16-gauge) needle with a 272-μm laser fibre. RIRS was performed using a uretero-renoscope.

• Variables studied were stone clearance rates, operating time, need for JJ stenting, intra-operative and postoperative complications (according to the Clavien–Dindo classification system), surgeon discomfort score, postoperative pain score, analgesic requirement and hospital stay.

• Stone clearance was assessed using ultrasonography and X-ray plain abdominal film of kidney, ureter and bladder at 3 months.

RESULTS

• There were 35 patients in each group. All the patients were included in the final analysis.

• The stone clearance rates in the microperc and RIRS groups were similar (97.1 vs 94.1%, P = 1.0).

• The mean [sd] operating time was similar between the groups (51.6 [18.5] vs 47.1 [17.5], P = 0.295). JJ stenting was required in a lower proportion of patients in the microperc group (20 vs 62.8%, P < 0.001). Intra-operative complications were a minor pelvic perforation in one patient and transient haematuria in two patients, all in the microperc group. One patient in each group required conversion to miniperc.

• One patient in the microperc group needed RIRS for small residual calculi 1 day after surgery. The decrease in haemoglobin was greater in the microperc group (0.96 vs 0.56 g/dL, P < 0.001). The incidence of postoperative fever (Clavien I) was similar in the two groups (8.6 vs 11.4%, P = 1.0). None of the patients in the study required blood transfusion.

• The mean [sd] postoperative pain score at 24 h was slightly higher in the microperc group (1.9 [1.2] vs 1.6 [0.8], P = 0.045). The mean [sd] analgesic requirement was higher in the microperc group (90 [72] vs 40 [41] mg tramadol, P < 0.001). The mean [sd] hospital stay was similar in the two groups (57 [22] vs 48 [18] h, P = 0.08).

CONCLUSIONS

• Microperc is a safe and effective alternative to RIRS for the management of small renal calculi and has similar stone clearance and complication rates when compared to RIRS.

• Microperc is associated with higher haemoglobin loss, increased pain and higher analgesic requirements, while RIRS is associated with a higher requirement for JJ stenting.

Article of the week: Long-term study finds excellent outcomes after RARP

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Every week the Editor-in-Chief selects the 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 week, it should be this one.

Long-term evaluation of survival, continence and potency (SCP) outcomes after robot-assisted radical prostatectomy (RARP)

Vincenzo Ficarra*†, Marco Borghesi*‡, Nazareno Suardi§, Geert De Naeyer*, Giacomo Novara†, Peter Schatteman*, Ruben De Groote*, Paul Carpentier* and Alexander Mottrie*

*OLV Robotic Surgery Institute, Aalst, Belgium, †University of Padova, Padova, ‡University of Bologna, Bologna, and §Vita-Salute University San Raffaele, Milan, Italy

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OBJECTIVE

• To report combined oncological and functional outcome in a series of patients who underwent robot-assisted radical prostatectomy (RARP) for clinically localised prostate cancer in a single European centre after 5-year minimum follow-up according to survival, continence and potency (SCP) outcomes.

PATIENTS AND METHODS

• We extracted from our prostate cancer database all consecutive patients with a minimum follow-up of 5 years after RARP. Biochemical failure was defined as a confirmed PSA concentration of >0.2 ng/mL.

• All patients alive at the last follow-up were evaluated for functional outcomes using the Expanded Prostate Cancer Index Composite (EPIC) and Sexual Health Inventory for Men (SHIM) questionnaires.

• Oncological and functional outcomes were reported according to the SCP system. Specifically, patients were classified as using no pad (C0), using one pad for security (C1), and using ≥1 pad (C2) (not including the prior definition).

• Patients potent (SHIM score of >17) without any aids were classified as P0 category; patients potent (SHIM score of >17) with use of phosphodiesterase type 5 inhibitorsas P1; and patients with erectile dysfunction (SHIM score of <17) as P2 category. Patients who did not undergo a nerve-sparing technique, who were not potent preoperatively, who were not interested in erections, or who did not have sexual partners were classified as Px category.

RESULTS

• The 3-, 5- and 7-year biochemical recurrence-free survival rates were 96.3%; 89.6% and 88.3%, respectively.

• At follow-up, 146 (79.8%) were fully continent (C0), 20 (10.9%) still used a safety pad (C1) and 17 (9.3%) were incontinent using ≥1 pad (C2).

• Excluding Px patients, 52 patients (47.3%) were classified as P0; 41 patients (37.3%) were classified as P1 and 17 patients (15.5%) were P2.

• In patients preoperatively continent and potent, who received a nerve-sparing technique and did not require any adjuvant therapy, oncological and functional success was attained by 77 (80.2%) patients.

• In the subgroup of 67 patients not evaluable for potency recovery (Px), oncological and continence outcomes were attained in 46 patients (68.7%).

CONCLUSIONS

• Oncological and functional success was attained in a high percentage of patients who underwent RARP at ≥5 years follow-up.

• Interestingly, this study confirmed that excellent oncological and functional outcomes can be obtained in the ‘best’ category of patients, i.e. those preoperatively continent and potent and with tumour characteristics suitable for a nerve-sparing technique.

 

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Editorial: Time to raise the bar in localised prostate cancer

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In this issue of BJUI, Ficarra et al. present the long-term (mean 81.3 months) follow-up of a case series of 183 men that underwent robot-assisted radical prostatectomy (RARP) at a single academic medical centre in Europe. To the authors’ credit, they report both cancer control and patient-reported outcomes, using well-known validated and reliable instruments to assess both urinary and sexual function. Like others before them, Ficarra et al. demonstrate that RARP is a safe and effective way to treat localised prostate cancer.

However, the question the study raises is not so much about the operation’s success rate but rather how success is defined in the first place. Throughout the prostate cancer literature, we have loosened definitions of successful urinary and sexual function to make RP more palatable to patients. In the present study, potency is effectively defined as a Sexual Health Inventory for Men (SHIM) score of >17 with or without the use of a phosphodiesterase type 5 (PDE5) inhibitor. Similarly, continence is defined as either no pad use or the use of a single pad ‘for security’. This approach certainly has face validity to us as clinicians. After all, PDE5 inhibitors are effective therapies for erectile dysfunction and the use of a single urinary liner certainly does not seem like a big deal. However, we need to consider this from the patient’s perspective. Both urinary pads and PDE5 inhibitors are costly to the patient and may represent an inconvenience and a potential embarrassment to many men. Is it really fair to tell men that they will be potent and/or continent after the operation, if they are going to require these additional interventions to achieve the desired state? I think not.

Going forward, we must set the bar higher if we are to be truly honest with our patients and optimise outcomes after RP. We must effectively ‘leave patients the way we found them’ with the critical difference being that they are now cancer-free. In other words, if a man was able to achieve an erection sufficient for intercourse preoperatively without the use of PDE5 inhibitors, he should only be considered potent postoperatively if he is in the same state, i.e. able to achieve an erection sufficient for intercourse without the use of a PDE5 inhibitor. The same holds true for urinary continence and the use of urinary liners. This will certainly make it more difficult to achieve the ‘trifecta’ but the reader should remember that the term is meant to imply ‘triple perfection’ and needing to use a PD5 inhibitor for sexual activity or having to wear a urinary pad, while acceptable to many patients, is certainly not perfect.

Some will say that I am insisting that the bar be set too high, that patients are willing to accept these reasonable but less than perfect definitions of success to be cured of their cancer. I acknowledge that there may be some validity to this argument in men with higher risk disease, where we know that cancer control and cure is necessary. However, I do not think the argument holds up in the case of men with low-risk disease, many of whom will never experience any symptoms of prostate cancer in their lifetimes and will not die of their disease if it were left untreated. In these patients, setting the bar higher would not only be more honest but it would probably increase the uptake of active surveillance and decrease overtreatment. In summary, while the use of more stringent definitions of success after RP may make our operations look ‘worse’, it will help our patients to set more realistic expectations, make more informed choices about treatment and ultimately to have better outcomes.

David F. Penson
Department of Urologic Surgery, Vanderbilt University, 2525 West End Avenue, Suite 1200, Nashville, TN, 37203, USA

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Article of the week: Both men and women with OAB find better relief with fesoterodine

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Every week the Editor-in-Chief selects the 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.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video by Dr. Ginsberg and colleagues.

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

Efficacy of fesoterodine compared with extended-release tolterodine in men and women with overactive bladder

David Ginsberg, Tim Schneider*, Con Kelleher†, Philip Van Kerrebroeck‡, Steven Swift§, Dana Creanga and Diane L. Martire**

Department of Urology, University of Southern California, Los Angeles, CA, §Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, SC, Consultant to Pfizer Inc, **Pfizer Inc, New York, NY, USA, *Praxisklinik Urologie Rhein/Ruhr, Mülheim, Germany, †St. Thomas’ Hospital, London, UK, and ‡Department of Urology, Maastricht University Medical Center, Maastricht, The Netherlands

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OBJECTIVE

• To assess the efficacy of fesoterodine 8 mg vs extended-release (ER) tolterodine 4 mg for overactive bladder (OAB) symptoms in terms of patient-reported outcomes in women and in men.

SUBJECTS AND METHODS

•  Pooled data from two 12-week, randomized, double-blind, double-dummy studies were analysed.

• Participants eligible for the studies were ≥18 years old, had self-reported OAB symptoms for ≥3 months in 3-day baseline diaries and had ≥8 micturitions and ≥1 urgency urinary incontinence (UUI) episode per 24 h.

• Individuals were randomized to fesoterodine (4 mg for 1 week then 8 mg for 11 weeks), ER tolterodine (4 mg), or placebo.

• Changes from baseline in 3-day bladder diary variables and scores from the Patient Perception of Bladder Condition (PPBC), Urgency Perception Scale (UPS), and Overactive Bladder Questionnaire (OAB-q), were assessed, as was the ‘diary-dry’ rate (the proportion of subjects with >0 UUI episodes according to baseline diary and no UUI episodes according to post-baseline diary).

• The primary endpoint was the change from baseline to week 12 in UUI episodes.

RESULTS

• At week 12, women showed significantly greater improvement with fesoterodine 8 mg (n = 1374) than with ER tolterodine 4 mg (n= 1382) and placebo (n = 679) in UUI episodes (primary endpoint), micturition frequency, urgency episodes, and all other diary endpoints (except nocturnal micturitions versus ER tolterodine), and also in scores on the PPBC, UPS, and all OAB-q scales and domains (all P < 0.005).

• Diary-dry rates in women were significantly greater with fesoterodine (63%) than with tolterodine (57%; P = 0.002) or placebo (48%; P < 0.0001).

• In men, there were no significant differences in improvement in UUI episodes between any treatment groups at week 12. Improvements in men were significantly greater with fesoterodine 8 mg (n = 265) than with ER tolterodine (n = 275) for severe urgency and the OAB-q Symptom Bother domain and were also significantly greater with fesoterodine than with placebo (n = 133) for micturition frequency, urgency episodes, severe urgency episodes, PPBC responses and scores on all OAB-q scales and domains at week 12 (all P < 0.04).

• The most frequently reported treatment-emergent adverse events in both genders were dry mouth (women: fesoterodine, 29%; ER tolterodine, 15%; placebo, 6%; men: fesoterodine, 21%; ER tolterodine, 13%; placebo, 5%) and constipation (women: fesoterodine, 5%; ER tolterodine, 4%; placebo, 2%; men: fesoterodine, 5%; ER tolterodine, 3%; placebo, 1%).

• Urinary retention rates were low in women (fesoterodine, <1%; ER tolterodine, <1%; placebo, 0%) and men (fesoterodine, 2%; ER tolterodine <1%; placebo, 2%).

CONCLUSION

• This analysis supports the superiority of fesoterodine 8 mg over ER tolterodine 4 mg on diary endpoints, including UUI, symptom bother and health-related quality of life in women.

• In men, fesoterodine 8 mg was superior to ER tolterodine 4 mg for improving severe urgency and symptom bother.

 

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Editorial: Fesoterodine is superior to extended-release tolterodine for OAB

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The treatment of overactive bladder (OAB) is still based on antimuscarinics, although the recent introduction of β3 agonists and botulinum toxin A has opened a window of new opportunities, the range of which is yet to be defined.

The clinical development of fesoterodine has taken the Urological community by surprise and raised levels of expectation. From a pharmacological standpoint fesoterodine is just a ‘smart drug’ because it is the pro-drug of 5-hydroxymethyl tolterodine (5-HMT) the active metabolite of tolterodine that is metabolised into 5-HMT by cytochrome P450 (CYP) enzymes, the activity of which is known to suffer significant genetic variability. Fesoterodine is transformed into 5-HMT by nonspecific esterase pathways. Pharmacokinetic studies of fesoterodine have shown highly predictable plasma levels of the 5-HMT after fesoterodine administration. Whether or not the better bioavailability offered by the esterase-related activation pathway translates into a larger clinic benefit for our patients with OAB was initially unclear. A phase II study showed a good safety profile and suggested that two different doses of fesoterodine could be proposed with a good balance between efficacy and adverse events. Results of the pivotal phase III study confirmed how the two different doses: 4 and 8 mg, tended to separate with a larger benefit observed with the larger dose, although a slightly larger incidence of adverse events was observed. As long as the comparison between 4 and 8 mg of fesoterodine was not part of the pre-planned analysis, the results of thepost hoc analysis had to be confirmed in a properly design prospective randomised trial.

The assumption that a higher drug dose brings a larger therapeutic effect is very often just wishful thinking and clinical pharmacology has often disproved such a belief. What is instead clear, from the paper of David Ginsberg et al., which pools data from two randomised trials (BJU Int 2010, BJU Int 2011), is that the flexible dosage available with fesoterodine brings a clinically relevant advantage in our daily practice.

The question is whether there is a real need for dose flexibility in the management of OAB. After a couple of decades in this area, I strongly believe that flexible dosing is crucial, in general, and even more so in functional urology. This is in fact an area where storage and voiding function needs to be rebalanced; a too weak or too strong effect may easily lead to a therapeutic failure. Reaching the right balance between therapeutic effect and adverse events is crucial while using antimuscarinics. If 40% of patients who withdraw from anticholinergic medications do so because of insufficient benefit, another large proportion (22%) discontinues treatment because of side-effects.

The question in real-life practice, provided treatment should be initiated with a 4 mg dose because of regulatory issues, is whether the dose should be upgraded and when, should this be left to the individual patient’s decision or should it be guided by the treating physician? There is no ‘golden’ rule and in my opinion is a matter of patient expectations. Most patients expect drugs to cure the conditions they are prescribed for, although we know this is rarely the case. When patients are properly informed about the effect of antimuscarinics treatment they will often choose their goal, some patients will look for reducing OAB symptoms while avoiding dry mouth and constipation as much as possible, others will want to become dry and accept higher levels of adverse events. Furthermore, because of body distribution, different doses of drugs may be required in a 45 kg lady and in a 90 kg man, although this may depend on the drug bioavailability at the target organ. The same applies to patients with normal detrusor contractility and patients with a weak bladder, such as patients with multiple sclerosis. The ‘one dose fits all’ approach does not seem to be the way to go.

The larger therapeutic effect achieved in the 8 mg fesoterodine group is obtained at the expense of almost doubling the incidence of dry mouth (from 15% to 28%), although the increase in the constipation rate is just 1%. Whether or not the observed differential improvement between tolterodine 4 mg and fesoterodine 8 mg is clinically relevant is matter for discussion for the investigators but looking at the parallel improvement in all patients reported outcomes, the difference seems to be of importance from the patient perspective.

The therapeutic area of storage disorders, e.g. OAB, is experiencing a number of paradigm changes, including the availability of flexible dosing of antimuscarinics, β3 agonists and botulinum toxin A. What once used to be a neglected area of functional urology is now an exciting area of basic and clinical research.

Andrea Tubaro and Cosimo De Nunzio*
Urology Unit, Department of Clinical and Molecular Medicine, Faculty of Health Sciences, Sapienza University, and *Urology Unit, Sant’Andrea Hospital, Rome, Italy

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Video: Fesoterodine vs tolterodine in men and women with OAB

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Efficacy of fesoterodine compared with extended-release tolterodine in men and women with overactive bladder

David Ginsberg, Tim Schneider*, Con Kelleher†, Philip Van Kerrebroeck‡, Steven Swift§, Dana Creanga and Diane L. Martire**

Department of Urology, University of Southern California, Los Angeles, CA, §Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, SC, Consultant to Pfizer Inc, **Pfizer Inc, New York, NY, USA, *Praxisklinik Urologie Rhein/Ruhr, Mülheim, Germany, †St. Thomas’ Hospital, London, UK, and ‡Department of Urology, Maastricht University Medical Center, Maastricht, The Netherlands

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OBJECTIVE

• To assess the efficacy of fesoterodine 8 mg vs extended-release (ER) tolterodine 4 mg for overactive bladder (OAB) symptoms in terms of patient-reported outcomes in women and in men.

SUBJECTS AND METHODS

•  Pooled data from two 12-week, randomized, double-blind, double-dummy studies were analysed.

• Participants eligible for the studies were ≥18 years old, had self-reported OAB symptoms for ≥3 months in 3-day baseline diaries and had ≥8 micturitions and ≥1 urgency urinary incontinence (UUI) episode per 24 h.

• Individuals were randomized to fesoterodine (4 mg for 1 week then 8 mg for 11 weeks), ER tolterodine (4 mg), or placebo.

• Changes from baseline in 3-day bladder diary variables and scores from the Patient Perception of Bladder Condition (PPBC), Urgency Perception Scale (UPS), and Overactive Bladder Questionnaire (OAB-q), were assessed, as was the ‘diary-dry’ rate (the proportion of subjects with >0 UUI episodes according to baseline diary and no UUI episodes according to post-baseline diary).

• The primary endpoint was the change from baseline to week 12 in UUI episodes.

RESULTS

• At week 12, women showed significantly greater improvement with fesoterodine 8 mg (n = 1374) than with ER tolterodine 4 mg (n= 1382) and placebo (n = 679) in UUI episodes (primary endpoint), micturition frequency, urgency episodes, and all other diary endpoints (except nocturnal micturitions versus ER tolterodine), and also in scores on the PPBC, UPS, and all OAB-q scales and domains (all P < 0.005).

• Diary-dry rates in women were significantly greater with fesoterodine (63%) than with tolterodine (57%; P = 0.002) or placebo (48%; P < 0.0001).

• In men, there were no significant differences in improvement in UUI episodes between any treatment groups at week 12. Improvements in men were significantly greater with fesoterodine 8 mg (n = 265) than with ER tolterodine (n = 275) for severe urgency and the OAB-q Symptom Bother domain and were also significantly greater with fesoterodine than with placebo (n = 133) for micturition frequency, urgency episodes, severe urgency episodes, PPBC responses and scores on all OAB-q scales and domains at week 12 (all P < 0.04).

• The most frequently reported treatment-emergent adverse events in both genders were dry mouth (women: fesoterodine, 29%; ER tolterodine, 15%; placebo, 6%; men: fesoterodine, 21%; ER tolterodine, 13%; placebo, 5%) and constipation (women: fesoterodine, 5%; ER tolterodine, 4%; placebo, 2%; men: fesoterodine, 5%; ER tolterodine, 3%; placebo, 1%).

• Urinary retention rates were low in women (fesoterodine, <1%; ER tolterodine, <1%; placebo, 0%) and men (fesoterodine, 2%; ER tolterodine <1%; placebo, 2%).

CONCLUSION

• This analysis supports the superiority of fesoterodine 8 mg over ER tolterodine 4 mg on diary endpoints, including UUI, symptom bother and health-related quality of life in women.

• In men, fesoterodine 8 mg was superior to ER tolterodine 4 mg for improving severe urgency and symptom bother.

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