A 59-year-old healthy Caucasian male had a perineal prostatectomy for Gleason 3+3 adenocarcinoma of the prostate. He had a mild degree of hypospadias, no meatal stenosis, and a 30 cc gland on magnetic resonance imaging (MRI).

At induction, a lumbar epidural catheter was placed at L3-L4 for analgesia. A 10 ml bolus of .25% bupivacaine was injected epidurally at induction. Intraoperatively, 30 mins following the first bolus dose, a further bolus of 5 mls of .25% bupivacaine and 50 mcgs of fentanyl were administered epidurally. Penile erection was first noticed while performing the incision and persisted throughout the procedure. Postoperatively, epidural infusion of .1% bupivacaine with 2 mcg/ml of fentanyl was commenced at an infusion rate of 10 ml/h. Due to the persistence of painless penile erection, patient was advised to sit up. Detumescence commenced within 7 minutes of postural change; complete detumescence was achieved within 45 minutes. This simple maneuver of sitting the patient up seemed to have achieved complete detumescence without the need for any further invasive procedures, while continuing the epidural for adequate postoperative analgesia.

DISCUSSION

Priapism is an uncommon pathological condition described as a prolonged, painful, penile erection usually unrelated to sexual stimulation. Our understanding of the pathophysiology of the condition owes much to the concept of low-flow (ischemic, anoxic) and high-flow (nonischemic, arteriogenic) priapism,¹ the introduction of intracavernous pharmacotherapy for the treatment of erectile dysfunction^{2, 3} and the need to reverse the prolonged erections that were induced.⁴ Low-flow priapism is associated with vascular stasis due to reduced venous outflow that, in turn, causes tissue hypoxia and acidosis. High flow priapism, the rare form resulting from the increased arterial inflow into the penile sinusoids is usually a result of penile or perineal trauma.⁵ Priapism has been associated with spinal or epidural anesthesia especially in those urological procedures involving genital manipulations.^{6, 7} Priapism due to epidural opioid has been rarely seen. There have, in fact, been only three cases of priapism reported following epidural morphine,^8–10 one case following a combination of epidural bupivacaine and clonidine¹¹ and one case following epidural bupivacaine¹² in the past. We report the second case of priapism following epidural bupivacaine. The underlying mechanism is, however, uncertain.

In our patient, we presume that this event may have occurred due to an imbalance between the sympathetic and parasympathetic blockade by the epidural bupivacaine. Due to a relatively short period between the injection of the first bolus of epidural bupivacaine and positioning the patient in the extended lithotomy position required for perineal prostatectomy (Figure 1, Figure 2), it is likely that the bupivacaine might have accumulated around the lumbar sympathetics, thus blocking the sympathetic outflow that is normally responsible for detumescence. The sacral parasympathetics, which are normally responsible for tumescence, may have been less affected by the epidural bupivacaine due to the gravitational effect in the extended lithotomy position, hence accounting for sustained and uninhibited penile erection. Sitting the patient up could have facilitated the epidural bupivacaine to gravitate down and block the sacral parasympathetics, hence resulting in spontaneous detumescence, without requiring further invasive interventions. Sustained penile erection in our patient cannot be attributed to the epidural fentanyl, as this was administered after the onset of the erection. Patient position on the operating table and the resulting epidural pressure determines the distribution of the anesthetic in the epidural space. Position may also influence the orientation of the epidural catheter and this would be an alternative explanation. It is possible that the epidural catheter might have migrated during extended lithotomy position and caused irritation to sacral nerve roots, thus resulting in priaprism. Spontaneous resolution, however, did not occur when the patient was repositioned in supine posture at the end of the procedure. The lack of a temporal relationship between taking the legs down from lithotomy and early resolution, and the absence of evidence of symptomatic irritation in the recovery room suggests that nerve irritation from an epidural catheter is unlikely to be the precipitating factor for the prolonged erection. The patient's priapism persisted for over 30 minutes despite being placed in the supine position. It was only after the patient was sat up on the ward and further local anesthetic administered that detumescence occurred, thus supporting our hypothesis that this event may have occurred due to an imbalance between the sympathetic and parasympathetic blockade by the epidural bupivacaine in extended lithotomy position.

In retrospect, the authors postulate that allowing adequate time between the injection of epidural analgesia and positioning the patient in extended lithotomy may result in an even distribution of the analgesic in the epidural space resulting in simultaneous blockade of the lumbar sympathetics and parasympathetics, thus avoiding an uninhibited penile erection.

Disclosure: The authors declare that there are no conflicts of interest.

Keywords

Epidural, extended lithotomy, priapism

REFERENCES

1. Hauri D, Spycher M, Brühlmann W. Erection and priapism: a new physiopathological concept. Urol Int. 1983;38:138–145.
2. Virag R. Intracavernous injection of papaverine for erectile failure. Lancet. 1982;2(8304):938.
3. Brindley GS. Cavernosal alpha blockade: a new technique for investigating and treating erectile impotence. Br J Psychiatry. 1983;143:332–337.
4. Brindley GS. New treatment for priapism. Lancet. 1984;28:220–21.
5. Pisipati S, Pearce I. A review of priapism: part 1. Br J Sexual Med. 2009;32(1):12–14.
6. Chin JL, Sharpe JR. Priapism and anesthesia: new considerations [letter to the editor]. J Urol. 1983;130:371.
7. Shantha TR, Finnerty DP, Rodriguez AP. Treatment of persistent penile erection and priapism using terbutaline. J Urol. 1989;146:1427–1429.
8. Ruan X, Couch P, Shah RV, et al. Priapism—a rare complication following continuous epidural morphine and bupivacaine infusion. Pain Physician. 2007;10:707–711.
9. Rawal N, Mollefors K, Axelsson K, et al. An experimental study of urodynamic effects of epidural morphine and nalaxone reversal. Anesth Analg. 1983;62:641–647.
10. Torda TA, Pybus DA, Liberman H, et al. Experimental comparison of extradural and i.m. morphine. Br J Anaesth. 1980;52:929–943.
11. Jaganathan R, Roberts S. Priapism: a rare complication following epidural analgesia. Pediatr Anaesth. 2009;19(8):814.
12. Pelavski AD, Suescun MC, Conesa A, et al. Priapism in an infant caused by post-operative analgesia through epidural catheter. Acta Anaesthesiol Scand. 2006;50:632.

A medical dictionary defines prolapse as “the protrusion of an organ or part of an organ into a natural or artificial orifice,”¹ and when discussing pelvic organ prolapse (POP) the protrusion is into the potential space of the vagina. The organs may include the urethra, bladder, uterus, small or large intestines, the rectum, or any combination thereof. The main reason for the development of POP is a defect or weakness in the support mechanism of each of the pelvic organs and surgical correction has traditionally relied on the reapproximation of native tissue.² These techniques have been utilized for over a century and are widely considered to be the first-line surgical options for women with POP.²

While variations of these techniques have been widely implemented, the often-poor quality of a woman's native tissues may lead to a significant degree of anatomic failure.³ Interposition grafting has been proposed in an attempt to address the perceived inadequacies of native tissue and, to date, several cadaver allografts and xenografts have been used with good short-term success.^4–11 The recent introduction of commercial prolapse repair kits utilizing polypropylene mesh has added additional weapons to our collective armamentarium in the battle to correct POP. Indeed, the decision to augment a prolapse repair is a controversy that has dominated the forums of pelvic surgeons in the last several years.

The goals of this review are to: (1) summarize the available literature regarding the transvaginal placement of synthetic mesh for prolapse repair, with a focus on the outcomes and complications of commercial prolapse kits; (2) draw comparisons with standard prolapse repairs; and (3) address common questions regarding vaginal mesh placement. The data presented in this review has been abstracted from a MEDLINE search of English language manuscripts and those translated using GOOGLE translator. As several groups have published multiple updates of their data, only the most recent update of that group's findings was considered. Due to the large number of meeting abstracts describing outcomes of mesh kit repairs, only full articles in print have been considered. Our discussion will focus on synthetic mesh placed transvaginally for the purpose of repairing POP, with an emphasis on the commercial prolapse repair kits.

BACKGROUND AND EPIDEMIOLOGY OF PELVIC PROLAPSE

Recent studies estimate that the prevalence of prolapse and its subsequent surgical repair is significant. Two recent retrospective cohort studies encompassing a total of nearly 300000 women have estimated the lifetime risk of undergoing a single operation for prolapse or incontinence by age 80 to be over 11%.^{3, 12} Other studies have focused their findings solely on women with POP. A cross-sectional analysis of nearly 2000 women from the National Health and Nutrition Examination Survey (NHANES) cited a weighted overall prevalence of prolapse to be 2.9%.¹³ The prevalence increased from 1.6% in women ages 20–39 years to 4.1% in women ages 80 years or older. Likewise, in a community-dwelling population of over 4100 women administered the Epidemiology of Prolapse and Incontinence Questionnaire (EPIQ), Lawrence et al reported a 6% prevalence of POP.¹⁴ Using population projections from the US Census Bureau, Wu et al estimated that the number of women with prolapse will increase by 46% from 3.3 to 4.9 million from the years 2010 to 2050.¹⁵

Several international studies have cited an even higher prevalence. A study from Western Australia found that the lifetime risk of surgery for POP in the general female population was 19% based on nearly 45000 incident cases.¹⁶ Likewise, a cross-sectional study of nearly 3000 women from the Netherlands reported the prevalence of POP to be 11.4% (defined as the feeling or seeing of a vaginal bulge).¹⁷ Finally, a French study found the prevalence of symptomatic POP to be 3.6% and that of surgery for POP to be 2.7% in 2640 responders to a questionnaire.¹⁸

The demand for services to care for pelvic floor disorders is on the rise. Luber et al estimated a 45% growth in demand by the year 2030, while the net growth of the same population segment is estimated to be 22%.¹⁹ In light of the 200000+ surgeries already performed annually for POP (a high of 22.7 per 10000 women in 1997), these numbers will likely only increase in the future.^{20, 21} The cost of treating pelvic prolapse is also substantial. In an analysis of the 1997 National Hospital Discharge Survey, Subak et al found that the direct costs of prolapse surgery were 1012 million dollars, with US$279 million (28%) for cystocele and rectocele repair.²² If all operations were reimbursed by non-Medicare sources, the annual estimated cost would increase by 52% to US$1543 million.

Living with pelvic prolapse is known to significantly impact a woman's quality of life (QoL). Women with advanced prolapse were significantly more likely than normal controls to feel self-conscious and less likely to feel physically and sexually attractive on the Short Form Health Survey (SF-12) and the Pelvic Floor Distress Inventory-20 (PFDI) QoL scale.²³ Additionally, women with advanced POP had a significantly lower QoL on the physical scale of the SF-12 and scored significantly worse than normal controls on the prolapse, urinary, and colorectal scales and overall summary score of the PFDI-20. Furthermore, women with POP completing the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire (PISQ) scored significantly lower than controls without prolapse.²⁴ It is clear from these studies that POP is prevalent, costly, and causes a significant impact on a woman's QoL.

ANATOMY OF PELVIC PROLAPSE

Prior to a discussion of surgical options for POP, an overview of normal anatomic support of the vagina and other pelvic organs is warranted. Vaginal support, cephalad to caudad, may be classified into three levels.²⁵ Level I support corresponds to the cardinal ligaments anchoring the upper vagina and cervix to the pelvic sidewall. In the mid-vagina, the vesicopelvic ligament extends from the arcus tendineus fasciae pelvis (ATFP) to support the bladder base and the anterior vaginal wall (Level II support) while the posterior vaginal wall is attached laterally to the fascia of the levator ani muscle. Level III support in the anterior vagina originates from the urethropelvic ligaments that provide support to the urethra. In the posterior compartment, the vagina is separated from the rectum by the rectovaginal septum and, like the pubocervical fascia in the anterior compartment, this septum is trapezoidal with the narrow end located distally.²⁶ The rectovaginal septum is fused distally with the urogenital diaphragm and proximal perineal body (Level III support) and is attached laterally to the arcus tendineus fasciae rectovaginalis in the distal one-third of the vagina and to the ATFP in the proximal two-thirds.^{25, 27} Proximally, the septum fuses with the uterosacral ligaments laterally and the pericervical ring centrally.

Anterior compartment prolapse arises from herniation of the bladder and urethra through the potential space of the vagina.²⁸ Isolated loss of distal support (Level III) may result in urethral hypermobility and stress urinary incontinence (SUI) without a concomitant descent of the bladder base. Defects of bladder support may be central, lateral, or a combination of both. Central anterior compartment defects result from an attenuation of the pubocervical fascia with intact lateral attachment of the vesicopelvic ligament to the ATFP. Lateral defects result from an intact pubocervical fascia and disrupted attachment of the vesicopelvic ligament to the ATFP either unilaterally or bilaterally. Central defects are often associated with loss of Level I support at the cardinal ligaments and may present with a concomitant enterocele. Traditional repair of a central anterior compartment defect has involved a plication of the pubocervical fascia in the midline (anterior colporrhaphy), while a lateral anterior compartment defect is addressed with reattachment of the vesicopelvic ligament to the pelvic sidewall (paravaginal repair).^{2, 28}

Proximal detachment of the rectovaginal septum from the uterosacral ligaments may be associated with an enterocele, while disruption of the distal attachment to the perineal body may result in weakening of the perineal body itself.²⁹ Reapproximation of the perineal body (perineorrhaphy) addresses Level III weakness, while a plication of the rectovaginal fascia in the midline (posterior colporrhaphy) has been traditionally employed to repair a Level II defect. Additionally, a “site-specific” posterior repair may address discrete rents in the rectovaginal fascia in lieu of a midline plication.³⁰ Additionally, procedures for concomitant apical prolapse (suspension from the sacral promontory, uterosacral or sacrospinous ligaments, or the iliococcygeus fascia) may be necessary.

WHY CONSIDER INTERPOSITION GRAFTING?

The impetus behind the recent interest into augmented repairs is the underlying concern that standard, plication-type repairs are not durable in the long-term. Several authors have reported high reoperation rates after traditional prolapse and incontinence surgery. Nearly 30% of 395 women from the Kaiser Permanente Northwest database underwent reoperation for incontinence or prolapse, and the time intervals between procedures decreased with each successive repair.³ In a separate analysis of the same database, Clark et al employed survival analysis to determine that 13% of women underwent reoperation by 71 months.³¹ Undergoing previous prolapse and incontinence surgery increased the risk of reoperation to 17% compared with 12% for women who underwent a first procedure. Sixty percent of the women underwent reoperation at the same anatomic site, while 32.5% developed an occult support defect and underwent reoperation at a different site.

While there have been some reports of low (<5%) long-term recurrence rates after anterior colporrhaphy,³² most authors have cited recurrence rates of ≥40% in the anterior compartment.^33–35 Conversely, isolated posterior compartment repair are associated with anatomic cure rates that typically exceed 85%.^{30, 36–38} These findings should be interpreted with caution, as published outcomes are often difficult to compare due to variations in patient populations and surgical technique, definitions of success and failure, and indications for repair. The addition of concomitant procedures for SUI and prolapse in other compartments, as well as reporting of adverse events and complications, presents additional challenges in comparing studies of surgical outcomes.³⁹ Nevertheless, these data suggest that traditional plication-type repairs, especially in the anterior compartment, may be associated with significant recurrence rates.

BACKGROUND OF INTERPOSITION GRAFTING

Graft augmentation to buttress or replace weak native tissue has been an effective adjunct in other surgical applications for some time. In several prospective randomized controlled trials (RCTs) and meta-analyses, mesh augmentation of inguinal hernia repairs has been widely shown to significantly reduce recurrence rates over traditional plication-type repairs.^{40, 41} Graft augmentation in POP repair may have the additional advantage of addressing multiple defects with a single graft. A single graft that spans from pelvic sidewall to sidewall may buttress the entire pubocervical and rectovaginal connective tissue layers and, thus, may address both central and lateral compartment defects simultaneously. Furthermore, a graft may be anchored to an apical landmark or placed suburethrally to provide concomitant Level I and Level III support, respectively. Several allografts and xenografts have been employed for repair of anterior and posterior compartment defects and, while short-term anatomic cure rates after graft-augmented repairs often approach 90%, success rates often waned with longer follow-up periods.^4–11

As in pubovaginal sling surgery, the use of polymeric mesh has been employed to minimize the often unpredictable nature of biologic materials. Julian was the first to describe experience with a polypropylene mesh (Marlex) graft sutured to the obturator/levator fascia to repair an anterior compartment defect.⁴² The author reported a 0% recurrence rate at 2 years of follow-up. Since then, several additional groups have retrospectively reported outcomes after anterior and posterior interposition procedures employing synthetic materials.^43–48 Owing chiefly to extensive experience with midurethral sling (MUS) surgery, macroporous, monofilament, polypropylene mesh (Type I) has been found to have the most favorable biocompatibility profile out of all current synthetics.⁴⁹ Its lack of interstices allows native collagen ingrowth and the pores are sufficiently large to allow entry to macrophages and other immune mediators. However, it must be mentioned that even synthetic materials with favorable biocompatibility profiles may induce a potentially persistent immune response long after implantation.⁵⁰

BACKGROUND AND ANATOMY OF COMMERCIAL PROLAPSE REPAIR KITS

The interest in commercial POP kits has recently peaked for several reasons. First, as previously mentioned, augmented prolapse repairs have been typically associated with high short-term anatomic success rates. Second, the successful incorporation of MUS kits into surgery for female SUI has contributed to increasing confidence in performing “minimally invasive” POP repairs. Owing to standardized technique, well-recognized landmarks, percutaneous placement, and “all-inclusive” kit, the MUS has made it possible for many additional surgeons to perform slings with reproducible anatomic and functional results. Third, the prospect of a minimally invasive approach to correcting apical prolapse is appealing. Traditional apical repair has included abdominal sacral colpopexy (ASC), a maximally invasive procedure, or vaginal vault suspension that, although less invasive, has typically required additional training and significant comfort with transvaginal pelvic anatomy. The addition of laparoscopy or robotics to minimize the morbidity of ASC requires additional training and may be associated with a significant learning curve. Hence, the dearth of a simple, reproducible, and effective transvaginal repair of apical prolapse has spurred an increased interest in kit repairs.

Since the introduction of the posterior intravaginal slingplasty (PIVS; US Surgical, Tyco Healthcare Group, Norwalk, CT) in 2001, several other manufacturers have unveiled variations of the prolapse kit (Table 1). The mesh in all of the currently available kits is constructed from Type I, macroporous, monofilament polypropylene, with the Avaulta mesh coated with acellular collagen.⁵¹

To correct a Level II support defect in the anterior compartment, two sets of trocars are typically advanced percutaneously through the obturator foramen into a vaginal incision. The superior trocars exit near the bladder neck while the inferior trocars exit along the ATFP near the ischial spine. The mesh arms are attached to the trocars and pulled through the skin until the mesh reduces the anterior compartment in a tension-free manner. During placement of mesh through a posterior approach, trocars are passed through bilateral perianal incisions to exit near the ischial spine. Mesh arms are connected to the trocars and the proximal part of the mesh is pulled to a tension-free position.

One concern regarding the first generation kits has been the lack of support for concomitant Level I defects at the vaginal apex. Using three-dimensional (3-D) anatomic reconstructions generated from magnetic resonance imaging, Larson et al found that the anterior vagina typically extends above and posterior to the proximal suspension points utilized in the first-generation kit procedures.⁵² This conclusion was echoed by Hinoul and Jacquetin, further suggesting that the first-generation kits may not have been intended for repair of midvaginal defects associated with Level I POP.⁵³ A second generation of kit procedures (Elevate, Uphold, and Ascend; Table 1) has been recently introduced in an attempt to address concomitant apical POP while still providing Level II support. These kits are novel in that all dissection is performed under direct vision and there is no percutaneous mesh advancement. Suture passers or specialized trocars are employed to attach the mesh arms to the sacrospinous ligament and, once the mesh arms are tightened, the mesh may be trimmed and sutured distally to ensure flat, tension-free placement.

CONTROVERSIES ASSOCIATED WITH PELVIC ORGAN PROLAPSE (POP) KITS

1. Are all meshes created equal?

Although all of the available meshes are constructed from monofilament, macroporous polypropylene, several differences exist. To date, the in vivo consequences of mesh properties such as rigidity, weight, thickness, and total mesh load have not been investigated as risk factors for erosion or extrusion. Other differences exist, as well. As previously mentioned, the Avaulta Plus Biosynthetic Support System (C.R. Bard) features a porous, acellular, ultra-thin sheet of cross-linked collagen attached to a stiffer polypropylene mesh that serves to establish a protective barrier between mucosal tissue and the polypropylene mesh and contains apertures uniformly sized to allow the ingrowth of host tissue and capillary vessels.⁵¹ The Prolift+M (Gynecare, Ethicon) is a recently introduced kit that combines Monocryl (poligleraprone 25) suture material with polypropylene mesh.⁵⁴ The delayed-absorbable suture material is interwoven between the polypropylene fibers to provide optimal rigidity of the mesh and to help it lie flat and avoid wrinkling. While, in theory, these modifications aim to improve the biocompatibility profile of a mesh product and decrease the inflammatory response, it is important to keep previous experience with sling materials in mind. Stiffer polypropylene meshes such as Marlex have been associated with poor acceptance rates in sling surgery despite monofilament, macroporous construction.⁵⁵ Likewise, biologic coatings have not always improved the biocompatibility profile of a particular mesh. ProteGen, a woven polyester mesh impregnated with acellular collagen was associated with a significant number of erosions and was subsequently recalled in 1999.⁵⁶ Likewise, polytetrafluoroethylene mesh coated with antimicrobials was also associated with vaginal extrusion.⁵⁷

2. Are outcomes after kit prolapse repair durable in the long-term?

It is quintessential to mention that categories of outcomes vary widely in the literature. Anatomic success is often achieved when there is minimal or no recurrence by Baden-Walker or pelvic organ prolapse quantification (POP-Q) staging in the compartment that was surgically repaired. Success may also be functional, especially when symptoms such as pelvic pressure or elimination dysfunction are relieved. Additionally, success may be claimed after a significant improvement on validated QoL indices. It is important to note that anatomic success (objective) may not always equal functional success (subjective) and, while the success of repair in the original compartment may be durable, recurrence in other compartments may occur. Furthermore, the impact of surgical prolapse repair on urinary storage and voiding symptoms can also be unpredictable. To illustrate the point, Barber et al assessed 18 different surgical success definitions and found that success varied widely with definition used (19%–97%).⁵⁸ Definitions of success utilizing stricter, more proximal stages of anatomic support had the lowest treatment success, and the absence of vaginal bulge symptoms postoperatively had a significant association with a woman's assessment of overall improvement. Conversely, anatomic success alone did not.

At the time of manuscript compilation, only articles describing Prolift and Apogee/Perigee kits have been published. No articles with a minimal follow-up of ≥48 months were located. Two studies included some patients who completed as many as 36 months of follow-up; however, mean follow-up was typically <24 months.^{59, 60} Anatomic success rates with the Perigee procedure exceeded 95% in both case series and 87.3%–97.4% were subjectively cured. Two additional studies describing self-tailored polypropylene mesh for anterior compartment prolapse were located, each with a minimal follow-up of 36 months.^{60, 61} Recurrence in the anterior compartment ranged from 13% to 20%, while QoL improvement was noted at 36 months in one of the studies.⁶² The aforementioned study used a kit called TVM (transvaginal mesh), which was the prototype of the Prolift procedure. Recently, 5-year outcomes of this procedure were presented at the 2010 International Continence Society Meeting; however, the outcomes have yet to be published (personal communication). Finally, a systematic review of 17 electronic databases encompassing 54 studies and 7054 women receiving mesh for uterine or vault prolapse estimated that the clinical recurrence after infracoccygeal sacropexy ranged from 0% to 25% (mean follow-up of 13 months).⁶³ In conclusion, although promising in the short- and medium-term, long-term outcomes after kit prolapse repairs have yet to mature.

3. Is one kit procedure associated with higher success rates than another?

This question, too, is difficult to answer definitively owing to a small number of studies addressing the topic. A recent meta-analysis of manuscripts and meeting abstracts encompassing 30 studies with 2653 patients calculated the objective success rates to be 95% for Apogee, 87% for Prolift, and 88% for PIVS.⁶⁴ Additionally, a recent retrospective, nonrandomized trial of 108 women undergoing either Apogee/Perigee or Prolift concluded that both devices were associated with comparable success rates.⁶⁵

4. How do outcomes after mesh prolapse repairs compare with standard repairs?

A direct comparison is inherently challenging, as the majority of the outcomes is represented in retrospective cohort studies and often reflects the short-term experience of a single surgeon or small group. While retrospective studies are valuable in prolapse surgery, there is no substitute for RCTs and meta-analyses.

A 2008 Cochrane review of anterior compartment prolapse repairs compared anterior colporrhaphy with anterior compartment repair with mesh reinforcement.⁶⁶ The authors found that data from two small trials suggested that reinforcement with polyglactin mesh had lower objective failure rates than colporrhaphy alone (RR 1.48, 95% CI, 1.07–2.04).^66–68 In anterior compartment repair, there was short-term evidence that a mesh or graft of any type significantly reduced objective prolapse recurrence rates compared with no mesh/graft (RR 0.48, 95% CI, 0.32–0.72).⁶⁹ Nonabsorbable synthetic mesh had a significantly lower objective prolapse recurrence rate (8.8%, 48/548) than absorbable synthetic mesh (23.1%, 63/273). A recent update of the Cochrane database revealed that standard anterior colporrhaphy was associated with more anterior compartment failures on examination than for polypropylene mesh repair used as an overlay (RR 2.14, 95% CI, 1.23–3.74) or armed transobturator mesh (RR 3.55, 95% CI, 2.29–5.51).^{70, 71} Data relating to polypropylene mesh overlay were extracted from conference abstracts without any peer-reviewed manuscripts available. No differences in subjective outcomes, QoL data, or reoperation rates for prolapse and incontinence were identified.

There are fewer RCTs comparing standard posterior colporrhaphy with mesh interposition. Sand et al concluded that posterior compartment recurrence was similar after colporrhaphy with or without polyglactin mesh reinforcement (RR 1.13, 95% CI, 0.40–3.19).^{66, 67} Two additional recent RCTs compared anterior and posterior colporrhaphy with colporrhaphy augmented with monofilament, polypropylene mesh. At 12 months of follow-up, Carey et al observed anatomic success rates of 81% in the mesh group vs 65.6% in the no-mesh group (p=0.07).⁷² A high level of satisfaction with surgery and improvements in QoL parameters were observed vs baseline in both groups; however, these outcomes were not significantly different between the two groups. Lopes et al compared anterior and posterior colporrhaphy with unilateral sacrospinous ligament fixation (SSLF) at hysterectomy to polypropylene mesh with bilateral SSLF.⁷³ The authors found no significant difference in anterior compartment recurrence at 12 months. Finally, the 2010 updated Cochrane database concluded that no data exists on the efficacy or otherwise of polypropylene mesh in the posterior vaginal compartment.⁷¹

Although there are few high-quality RCTs comparing outcomes of standard vaginal prolapse repairs and those with mesh augmentation, several conclusions can be drawn. First, in the short-term, grafting of any type in the anterior compartment significantly reduces recurrence rates. Second, the implantation of nonabsorbable synthetic mesh was associated with significantly lower recurrence rates than other grafts. Third, there is currently insufficient information to support interposition grafting of any type in the posterior compartment.

5. Are mesh repairs associated with more complications than standard repairs?

Since the adoption of synthetic mesh in POP repair, a spotlight has been pointed on mesh-related complications. Between 2006 and 2008, several groups, including The French Health Authorities’ and the Society of Gynecologic Surgeons Systematic Review Group, have concluded that there may be additional risks to using transvaginal mesh.^{74, 75} These suggestions culminated in October 2008 when the US Food and Drug Administration released a warning prompted by over 1000 reports of complications associated with mesh devices used to repair prolapse and SUI.⁷⁶ The FDA recommended surgeons to: (1) obtain specialized training for each mesh placement technique; (2) inform patients that surgical mesh implantation is permanent, and that some mesh complications may require additional surgery; and (3) provide patients with a written copy of the patient labeling from the surgical mesh manufacturer, if available.

Adverse outcomes of kit prolapse repairs may be divided into nonspecific complications such as bleeding, pelvic pain, dyspareunia, and specific complications. Specific complications may be further separated into intraoperative trocar injuries to viscera and complications related to extrusion, erosion, and aberrant healing. In a review of four retrospective studies of each encompassing >100 women, the rate of intraoperative organ injury was as follows: bladder (0.9%–5.3%), rectum (0%–0.7%), and ureter (0%–1.4%).^77–80 A recent meta-analysis of over 70 studies and case reports likewise estimated the rates and spectrum of adverse events associated with synthetic graft use.⁸¹ These adverse events included bleeding (0%–3%), visceral injury (1%–4%), urinary tract infection (0%–19%), graft extrusion (0%–30%), and fistula formation (1%). The 2010 update of the Cochrane database concluded that intraoperative blood loss with transobturator meshes was significantly higher than for standard anterior repair.⁷¹ Mesh erosions were reported in 10% (30/293) of anterior repairs with polypropylene mesh. There were insufficient data regarding de novo dyspareunia, sexual, voiding, or defecatory dysfunction. Mesh type may also be associated with an increased rate of complications, as the PIVS (a Type III, multifilament, polypropylene tape)⁴⁹ has been associated with significant rates of extrusion, abscess, and fistula formation.^82–84

6. Do patients have higher rates of dyspareunia after implantation of transvaginal mesh?

A causal relationship between the implantation of synthetic mesh and dyspareunia has been a challenging one to prove for several reasons. First, it is well accepted that the rate of dyspareunia after a traditional, unaugmented transvaginal prolapse repair, and posterior colporrhaphy in particular, may approach 40% in some studies.⁸⁵ This incidence may actually be higher than the 10%–13% rate of dyspareunia reported in some series after prolapse repairs augmented with mesh.^{44, 80, 86} Gauruder-Burmester et al reported no de novo dyspareunia in 120 women who underwent Apogee and Perigee, while Nguyen and Burchette found that rates of de novo dyspareunia were not significantly different between women randomized to Perigee and standard anterior colporrhaphy.^{70, 87} Second, dyspareunia may be multifactorial, as estrogen deficiency and vaginal foreshortening or narrowing from previous surgery may play a significant role. Third, as augmented or nonaugmented repairs may be simultaneously performed in other compartments, identifying the problematic repair or site may be challenging.⁸⁸ Finally, a recent editorial proposed that preoperative pelvic pain and dyspareunia may be associated with significant hypertonic pelvic floor musculature and/or pain of myofascial origin and should be strongly suspected in the absence of prolapse at the introitus or beyond.⁸⁹ The 2010 update of the Cochrane database concluded that there were insufficient data regarding de novo dyspareunia in standard and mesh repairs.⁷¹

7. Does mesh size and shape change following implantation?

Several studies suggest that polypropylene mesh may retract or contract after implantation. Svabik et al estimated that Prolift shrank by 16%–20% based on ultrasound measurements, while Gauruder-Burmester et al estimated that polypropylene mesh may retract by as much as 66% relative to its original dimensions.^{87, 90} The contraction was seen both in length and width, suggesting that total vaginal length and girth may be potentially compromised. Likewise, Velemir et al noted moderate and severe mesh retraction in 80% and 9.3% of their patients undergoing Prolift Anterior, respectively.⁹¹ As mesh contraction may often be asymptomatic, it is not immediately clear whether this contraction affects coitus and dyspareunia.⁹² Additional research into graft characteristics such as weight, elasticity, and flexibility may ultimately aid in our understanding of this phenomenon and assist in minimizing this complication.

8. Who is the ideal patient for vaginal mesh implantation?

Thoughtful patient selection cannot be overemphasized in optimizing the success of mesh-augmented prolapse repairs. In 2005, the International Urogynecological Association Grafts Roundtable proposed that pelvic irradiation, severe urogenital atrophy, immunosuppression, active infection, and comorbidities such as poorly controlled diabetes, morbid obesity, and heavy smoking may serve as relative contraindications to biomaterial use in pelvic floor reconstruction.⁹³ Conversely, some authors have suggested that women with prolapse grade ≥III had a significantly higher risk of developing recurrent prolapse after unaugmented repair.⁹⁴ Others have suggested that mesh use may not be the best option in young women with primary prolapse.⁹⁵ This may present a treatment dilemma, as women most likely to benefit from graft placement such as those with previously failed repairs may also be at greater risk for complications due to hypoestrogenism, comorbidities, and poor tissue quality. Hence, a detailed discussion of potential risks and benefits is paramount to obtaining informed consent.

CONCLUSIONS

The decision to perform a mesh-augmented prolapse repair is often a difficult one for even the most experienced pelvic surgeon. While the data regarding suboptimal outcomes of standard prolapse repairs cannot be swept under the rug, it is clear that traditional colporrhaphy is not associated with trocar-related or mesh-related adverse events. On the other hand, the short-term data suggests that mesh-augmentation and kit use decreases the incidence of anatomic recurrence in the anterior compartment. However, these repairs are associated with potentially more bleeding and unique complications that may add significant morbidity to the procedure. Furthermore, delayed complications such as potential mesh contraction add some uncertainty regarding the long-term implications of synthetic mesh implantation. There is currently no evidence-based data to support mesh use in the posterior compartment. Finally, there is some emerging data that mesh may contract in size with longer periods of follow-up; however, the clinical significance of this is not currently understood.

In conclusion, the use of mesh augmentation and kit repairs in particular appears to be only increasing; however, their role is not yet clearly defined and the routine use of these products should be discouraged until further research and long-term results are available. It is important to remember that mesh characteristics are unique to each kit and the published biocompatibility profile of a particular mesh is often based on bench models and experience in other surgical milieus. As the ideal patient for mesh implantation has yet to be agreed upon and no guidelines exist, careful patient selection and detailed informed consent prior to these surgeries is vital. Furthermore, adequate surgeon training, a solid comfort level with variations in pelvic anatomy, and comfort in treating potential complications cannot be overstated.

Disclosure: The authors declare no conflict of interest.

Keywords

pelvic organ prolapse, polypropylene, vaginal mesh, extrusion, erosion, dyspareunia

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In vivo experimental models of overactive bladder (OAB) have been frequently used as tools to explore the OAB. It is unquestionable that animal OAB models should closely resemble the OAB in humans. It is crucial for further understanding its pathophysiology, as well as for the development of new pharmacological therapies to treat the bladder overactivity.

The international literature provides several studies describing experimental models of OAB syndrome. Still, the most commonly used method to induce urinary bladder dysfunction, especially its overactivity, is animal supply of non- or irritative agents (eg, cyclophosphamide, acetic acid, adenosine triphosphate—ATP, capsaicin, dimethyl sylfoxide, xylene, mustard oil, and turpentine) in different protocols. However, other methods for OAB induction concerning neurogenic modulation were described (eg, spinal cord transection, cerebral infarction, etc.), metabolic (hypercholesterolemia), genetic (spontaneously hypertensive rat—SHR), hormonal (ovariectomy, basic fibroblast growth factor—bFGF implication), and so on. The motor activity of urinary bladder is estimated by cystometry in either anesthetized or conscious rats. In spite of many well-designed studies, still, there is no standardization in accordance with cystometric protocol. Consequently, significant differences of cystometrograms and cystometric parameters values occur, especially in the case of similar models of OAB. Therefore, the comparison of bladder motor activity in different OAB models is difficult and almost impossible in most of the cases.

PURPOSE AND EVIDENCE ACQUISITION

The aim of this study was to perform a systematic revision of the literature in order to identify articles related to the experimental models of overactive bladder. This review is based on a systemic literature search. MedLine, Embase, and Web of Science databases were browsed to identify original and review articles, as well as editorials addressing “overactive bladder,” “urodynamic evaluation,” “cystometry,” “experimental model,” “methodology,” and “rat” in urinary bladder dysfunction. The controlled vocabulary of the Medical Subject Headings (MeSH) database was used to ensure accuracy of the searching. This review is focused on the backgrounds, methodology, and outcomes of the described models. Additionally, based on our previous studies and experience, we discuss the procedures during cystometric protocol and provide some proposals for performing cystometry that should be taken into consideration in a standard urodynamic protocol in a rat.

EVIDENCE SYNTHESIS

The studies of different experimental models of overactive bladder (OAB)—detrusor overactivity (DO) in animals were presented in this review article. Each OAB model study was divided in three sections as follows: backgrounds, methodology, and outcomes with cystometrogram traces presentation. In the background section, the basic information according to the pathogenesis of detrusor overactivity and pathophysiology changes were presented. In the methodology section, the different ways of detrusor overactivity induction were described. The third part of each OAB model studies was focused on the experimental observations, results, and theories describing the OAB and DO development of analyzed models based on the presented methodology.

Intravesical infusion of irritative agents during cystometry (eg, acetic acid, citric acid, protamine sulfate and potassium chloride, adenosine triphosphate—ATP, capsaicin, dimethyl sylfoxide, xylene, mustard oil, and turpentine) is one of the most commonly used methods of OAB development, as well as is crucial for investigating the pathophysiology of OAB and its therapies. In experimental practice, three types of irritative OAB models (as described below) induced by acetic acid, protamine sulfate and potassium chloride, adenosine triphosphate, and capsaicin are commonly used.

Acetic Acid (ACA)-Induced Bladder Hyperactivity

Chemical irritation by acetic acid (ACA) given intravesically produces acute inflammation of the urinary bladder and consequently facilitates micturition reflex in rats. The ACA continuous intravesical instillation is accompanied by an increase of bladder contractions frequency and an increase in the frequency of external urethral sphincter bursting during micturition.¹ Also, spinal expression of an immediate early gene (eg, c-fos) increases dramatically.²

Methods

Mitobe et al ³ determined the urinary bladder activity after transient intravesical application of ACA solutions (.2–.75%) in conscious rats for 9 hours using voiding frequency (VF) and total urine volume (TUV) estimation. Additionally, to determine the differences in the bladder responses between daytime and nocturnal applications of ACA, .5% ACA solution was intravesically applied for 5 minutes at 9:00 or 17:00, respectively, and micturition patterns were monitored. Under isoflurane anesthesia, the intravesical bladder pressure was recorded by the catheter inserted through external urethral orifice. After the residual urine removal from the bladder, ACA solution (diluted to .2%, .5%, and .75% with saline) was injected into the bladder until the bladder pressure reached 10 cmH₂O. Five minutes later, the ACA solution was removed and the inside of the bladder was gently washed, twice with saline, and the rat was again placed in the metabolic cage. Contrary, a different mode of ACA-induced OAB was performed by Mitsui et al.⁴. Bladder hyperactivity was induced by constant .1% ACA intravesical infusion at a rate of .1 ml/min. The frequency of bladder contractions stabilized and became fairly regular after about 30 minutes of infusion.

Outcomes

Mitobe et al ³ observed that the transient intravesical application of ACA solutions (.2–.75%) increased VF in a concentration-dependent manner. Infusion of a .5% ACA caused a significant increase in VF (3.5 times), without influencing TUV or inducing significant histopathological inflammatory alterations in the bladder urothelium. In the histopathological examination, the control rats were characterized by slight neutrophil infiltrations in the lamina propria in the urinary bladder. No significant differences were observed in the morphological alterations between the saline-treated rats and acetic acid-treated rats at concentrations of .2% and .5%. Infusion of .75% ACA induced intensive urinary inflammation changes (neutrophil and/or macrophage infiltrations, hemorrhages in the lamina propria, and moderate desquamation accompanying vacuolar degeneration and necrosis in the urothelium) and a decrease in TUV, as well as an increase in VF (4.1 times). The .5% ACA infusion-evoked bladder hyper-responsiveness—whether applied at night or during the day. However, VF was increased more by the nocturnal ACA application, while there were no significant differences in basal levels of VF between daytime and nighttime. Also, Mitsui et al ⁴ observed that continuous infusion of ACA in control rats elicited irritative bladder responses characterized by a marked decrease in the intercontraction interval and a marked increase in maximal intravesical pressure (Figure 1a).

The experimental protocol described by Mitobe seems to minimize the secondary effects of surgical procedures and anesthesia on urinary bladder motor activity.³ Therefore, the noninvasive rat OAB, induced by a transient intravesical application of ACA leading to the hypersensitization of nociceptive afferent fibers, may be useful for OAB investigating.

Intravesical Supply of Protamine Sulfate and Potassium Chloride as a OAB Model

An acute OAB model can be achieved by intravesical infusion of an agent thought to break down urothelial barrier function such as protamine sulfate (PS) and also by potassium chloride (KCl).⁵

Methods

Chuang et al ⁵ performed continuous cystometry by filling the bladder (.04 ml/min.) with saline followed by infusion of a KCl (100, 300, and 500 mM) or PS (10 and 30 mg/ml) for 60 minutes under urethane anesthesia. Subsequently, the 10 mg/ml PS-treated animals were infused intravesically with 100, 300, and 500 mM KCl.

Outcomes

Chuang et al ⁵ study showed that high concentrations of PS (30 mg/ml) and KCl (after 1 hour of 10 mg/ml PS administration) induces OAB. Surprisingly, KCl or 10 mg/ml PS alone has no effect on bladder function. The 30 mg/ml PS produced irritative effects with a decreased intercontraction interval (by 80.6%). After infusion of a low concentration of PS, infusion of 300 or 500 mM KCl produced irritative effects characterized by decrease of intercontraction interval by 76.9% or 82.9%, respectively (Figure 1b and 1c). Chuang postulates that intravesical administration of KCl after PS treatment activates capsaicin-sensitive afferents and detrusor muscle and presumably capsaicin-resistant afferents. Modest, noncytotoxic affronts to urothelial barrier function can result in dramatic irritative responses. This model may also be useful in the study of bladder irritation and hyperactivity.

A Model of Detrusor Overactivity Induced by Intravesical Infusions of Adenosine Triphosphate (ATP) and Capsaicin (CAP)

Human and animal bladder urothelial cells release ATP in response to mechanical stimuli.^6–8 It is believed that ATP acts on purinergic P2X3-ATP receptors on sensory bladder nerve endings in the suburothelial space. Cockayne et al ⁹ observed less frequent voiding and larger voided volumes in P2X3 knock-out mice. Additionally, Pandita and Andersson¹⁰ results showed that intravesical ATP infusion in conscious rats cause bladder hyperactivity (increased frequency and amplitude of bladder contractions). On the other hand, CAP triggers an excitatory effect on the C-fibers, mediated through the release of neurotransmitters contained within these afferents.¹¹ CAP may also have a direct effect on the motor limb.¹²

Methods

The bladder overactivity in awake rats was induced in conscious cystometry by infusion of 20 mM ATP or 100 µM CAP at a rate of .072 ml/min. The authors analyzed bladder contraction pressures and contraction frequencies (number of contractions per minute). A bladder contraction was defined as a rise in bladder pressure to at least 60% of its baseline.¹³

Outcomes

In comparison with control, ATP infusion into the bladder significantly increased the frequency of bladder contractions (.78±.10 Hz vs 1.45±.18 Hz). Also CAP significantly increased the bladder contraction frequency (.40±.073 Hz vs 1.24±.34 Hz), and the bladder contraction pressures (47.5±18.0 vs 118±32 cmH₂O) (Figure 1d).¹³ Surprisingly, not all animals developed detrusor overactivity due to intravesical capsaicin administration. Intravesical capsaicin induces bladder overactivity through a release of neuropeptides in sensory afferents, which can trigger bladder smooth muscle contractions. Purinergic mediated detrusor overactivity is thought to occur through the activation of afferent unmyelinated C-fibers of the urothelium, although direct detrusor muscle excitation may also occur simultaneously.^{14, 15} Intravesical instillation of 1 mM capsaicin produced complete inhibition of detrusor contractility, preventing proper voiding function of the bladder after 24 hours. In the storage phase of the micturition cycles, increased spontaneous detrusor overactivity, evaluated as phasic detrusor contractions of low amplitude with the accompanying increased intravesical pressure, is observed. These facts are caused by complete desensitization of vanilloid receptors TRPV1 on bladder afferent C-fibers.

Both CAP and ATP have become valuable tools in assessing the mechanisms and treatment for clinical OAB, despite the uncertainty as to whether these represent the same entities.¹³

Cyclophosphamide (CYP)-Induced Urinary Bladder Overactivity

The CYP treatment damages all mucosal defense lines and induces chemical cystitis leading to OAB in animals and humans. The key factor responsible for that is acrolein, an irritant metabolite of CYP eliminated in the urine.¹⁶ There is a great number of studies describing the pathomechanisms of CYP-cystitis induction in rats with various slight modifications of doses and duration of CYP treatment.^17–19 Three OAB models caused by CYP-induced cystitis: acute (after 4 hours of CYP administration), intermediate (after 48 hours), and chronic (after 7–12 days) have been described under various anesthesia conditions. The evaluations of these models are primary concerned with bladder histology, as well as alterations in neurochemical,^{20, 21} and electrophysiological^{22, 23} properties of bladder afferent neurons and reflex arcs activity in the spinal cord.²⁴ Moreover, the bladder motor activity was well described.²⁵

Methods

Acute, intermediate, and chronic chemical cystitis was induced by CYP. The CYP was administered intraperitonealy in one of the following ways: (1) single dose 150–200 mg/kg i.p. to elicit acute inflammation after 4 hours^{17, 19, 25}; (2) single dose 150 mg/kg i.p. to elicit intermediate inflammation within 48 hours¹⁹; and (3) 75 mg/kg i.p. every third day for 7–12 days (4–6 doses) to elicit chronic inflammation.^{17, 26}

Outcomes

The CYP treatment causes mucosal inflammatory response as indicated by macroscopic and microscopic changes in bladder histology and the presence of inflammatory cell infiltrates.²⁷ Moreover, CYP treatment is associated with various urological complications in rats including: a reduction in the volume threshold for micturition, a reduction in the mean amplitude of bladder contractions, and an increase in micturition frequency.^{22, 28, 29} In accordance with different study protocols of CYP-induced OAB, the urodynamic parameter values are also different; therefore, the comparison of urodynamic parameters values was presented in Table 1 . Moreover, the effect of acute, intermediate, and chronic intraperitoneal administration of CYP on bladder motor activity in comparison with healthy rats was shown in Figure 1e.

Based on the current data of CYP-induced OAB models, we concluded that there are no significant differences in basic cystometric parameters between an acute and chronic model. Thus, both models are equally credible for cystometric evaluation of bladder motor activity in OAB protocols.

Middle Cerebral Artery (MCA) Occlusion Induces Acute OAB

The neural circuitry in the forebrain damage can induce urinary bladder dysfunction (eg, OAB, incontinence).³³ OAB has been attributed to interruption of the inhibitory pathways from the forebrain to the micturition center in the brain stem (the pontine micturition center—PMC) by lesions of the cerebral cortex resulting from tumors, aneurysms, or vascular disease.^{34, 35}

Methods

To induce cerebral infarction (CI) the left carotid bifurcation was exposed through a midline incision of the neck. After division of the left common carotid artery, the left internal carotid artery was isolated and carefully separated from the adjacent vagus nerve. The left pterygopalatine branch was ligated close to its origin. A 4-0 monofilament nylon thread whose tip had been rounded by exposure to a flame was introduced into the left MCA. The origin of the left MCA was occluded by advancing 17 mm of the thread from the carotid bifurcation.^{36, 37}

Outcomes

Yokoyama et al ³⁷ performed the MCA occlusion 1.5 hours after the implantation of the intravesical catheter for cystometry (at a rate of .04 ml/min.). The observations revealed that bladder capacity (BC) in awake rats was significantly reduced (60.8%±1.3%) .5–4.5 hours after MCA occlusion but did not change in urethane-anesthetized rats. Contrary, under halothane anesthesia, BC was significantly reduced from .43±.06 to .16±.04 ml .5 hours after MCA occlusion and remained consistently .18 ml for 4.5 hours after MCA occlusion (Figure 2a). Also, Nakamura et al,³⁴ a day after MCA occlusion, observed the decrement of BC (2.60±.13 vs 1.27±.10 ml) and micturition threshold pressure (12.88±1.21 vs 3.39±.47 cmH₂O), respectively.

Urodynamic evaluations in rats with CI indicate that NMDA (N-methyl-d-aspartate) glutamatergic transmission is important in neurogenic OAB development following a CI. This model seems to be useful in studying the neurogenic voiding dysfunction observed in patients with cerebrovascular disease.

T10 Spinal Cord Transection (SCT) Induces Neurogenic Detrusor Overactivity

Urinary bladder receptors, afferent pathways, and spinal cord interneurons might be involved in the OAB development. Therefore, neurogenic modulation of bladder function by SCT may induce bladder overactivity.

Methods

To achieve SCT at the T10 level, the rat was placed in a prone position. The skin was opened at the T10 level and the paravertebral muscles were split. Laminectomy was undertaken with curved scissors to expose the spinal cord, which was completely severed under magnification, and a piece of gelfoam was placed between the two cut ends. Next, the muscles were approximated with an absorbable 3-0 catgut suture, and the skin was closed with a 3-0 catgut suture. Buprenorphine .01–.05 mg/kg was given before spinalization and every 12 hours for less than 2 days after surgery. During the procedure, the rats were injected subcutaneously with 3–5 ml of lactated Ringer's solution. Preoperative and postoperative antibiotics (trimethoprim 2.2 mg/kg) were given, and each rat was housed in a separate cage containing wood shaving bedding to prevent the formation of decubitus ulcers. Their bladders were evacuated three times daily using the Crede maneuver (finger pressure on the lower abdomen) until reflex voiding was recovered; they were subsequently emptied twice a day. In the paraplegic rats, cystometry (at a rate of .1 ml/min.) was undertaken 3 weeks after SCT, and in awake rats 24 hours after an insertion of a polyethylene tube into the bladder dome.³⁸

Outcomes

Elzayat et al ³⁸ observations revealed that all SCT rats developed neurogenic OAB with spontaneous contractions (Figure 2b). At 3 and 4 weeks after SCT, the mean frequency of contractions was 1.6±.3 and 1.7±.2 contractions/minute, respectively. Significant differences were only seen in the mean cystometric bladder capacity and micturition pressure between 3 and 4 weeks after SCT groups. In comparison with control group, the mean micturition pressure was 11.23±3.6 versus 66.8±2.6 versus 105.8±6.9 cmH₂O, respectively. While, the cystometric bladder capacity was .62±.17 versus 1.1±.2 versus .51±.1 ml, respectively.

The SCT model of OAB has given an excellent opportunity for further investigations to determine the neurogenic OAB pathophysiology.

Overactive Bladder Model in Rats With Hypercholesterolemia

A new vasculogenic erectile dysfunction (ED) model in hypercholesterolemic rats was recently reported by Park et al.³⁹ This model features hypercholesterolemia and vascular abnormality. Epidemiologic studies revealed that lower urinary tract symptoms (LUTS) are correlated with ED, as well as LUTS and ED, and are very common in elder patients.^{40, 41} Considering these facts, Son et al ⁴² hypothesized that if ED and LUTS are very closely related in terms of their pathogenesis and if vascular abnormality is one of the major causes of voiding dysfunction, this vasculogenic ED model could have an overactive bladder. Therefore, they evaluated the bladder function in hypercholesterolemic rats.

Methods

The rats were on a regular 1% cholesterol diet (CRF-1, Oriental Yeast, Osaka, Japan) for 8 weeks to induce hypercholesterolemia. Additionally, 3 mg/ml NG-nitro-L-arginine methyl ester was added to their drinking water for 2 weeks to induce intimal changes that would make them vulnerable to atherosclerosis.⁴²

Outcomes

The cystometric data and detrusor strip contraction study confirmed the voiding dysfunction in hypercholesterolemic rats. These animals considerably revealed more frequent voiding, shortened micturition interval, decreased voided volume, and functional bladder capacity defined as the sum of the voided volume and postvoid residual urine volume (Figure 2c ). No significant difference was found in the postvoid residual urine volume, basal, and peak micturition pressure. In the detrusor strip study, the hypercholesterolemic rats had greater tension in spontaneous activities and an increase in the proportion of purinergic components.

This hypercholesterolemic OAB rat model characterized by frequent voiding, increased in basal spontaneous contraction and purinergic neurotransmission, seems to be very similar to some studies devoted to aging, idiopathic, or interstitial cystitis patients. This model might be useful for future studies of OAB.

The Spontaneously Hypertensive Rat (SHR) Used as a Model of OAB

The SHR is a genetic model of hypertension, which is also known to exhibit abnormal bladder function. In particular, SHRs characterize the reduced bladder capacity and voided volume, increased urinary frequency, and increased occurrence of nonvoiding contractions in comparison to their genetic control strain rat.^{43, 44} In vitro studies revealed a great amount of differences in the activity of bladder smooth muscle between SHRs and control rats, which confirmed to be indicative of fundamental changes in the innervation and physiological response to stimulation of the bladder in SHRs.^45–47 The exact pathomechanisms of OAB development in SHR rats is not fully understood. A pivotal factor seems to be the increased nerve growth factor (NGF) levels that have been shown to be produced by bladder smooth muscle from SHRs.⁴⁸ The SHR bladders present also increased levels of calcitonin gene-related peptide immunoreactive fibers (presumably afferent) and that neuronal cross-sectional area profiles for bladder afferents in the L6–S1 dorsal root and major pelvic ganglia are significantly larger in SHRs than in control animals.⁴⁹ The development of hypertension in SHR rats and hyperactive voiding in rats with urethral obstruction are characterized by abnormal smooth muscle growth, increased tissue levels of NGF, and altered patterns of innervation. The results of the Spitsbergen et al ⁵⁰ study supported the hypothesis that elevated NGF secretion by bladder smooth muscle is associated with hyperinnervation of bladder and hyperactive voiding in SHRs.

Methods

The origin of SHR rats was described by Okamoto.⁵¹ The SHR animals originate from an outbred Wistar Kyoto (WKY) male with a spontaneous hypertension and a female with slightly higher than normal blood pressure. Subsequently brother × sister pairs are selected for a spontaneous hypertension.

Outcomes

Persson et al ⁴⁴ cystometric investigations (infusion saline rate: 10 ml/h) in SHRs and control WKY rats were performed without any anesthesia (3 days after the bladder catheter implantation) revealed significant differences between these groups. In comparison to control rats, the SHR rats had a significantly reduced micturition volume and bladder capacity. Also the amplitude of nonvoiding bladder contractions (NVCs) in between micturitions was significantly higher. The threshold pressure to trigger micturition was slight, although not significantly lower in SHR (Figure 2d). Additionally, Jin et al ⁵² observed that SHRs were characterized by increased intravesical pressure rises (IVPRs) during the bladder filling phase in comparison with control Wistar rats. Detrusor overactivity represented approximately 76% of total IVPRs, the others were caused by abdominal straining (AS), which may be a part of hyperactive behavior. The SHRs showed an increased amplitude but not frequency of AS. The variability of intra-abdominal pressure due to hyperactive behavior and AS may lead to misinterpretation of intravesical pressure during cystometry and, secondarily, to an OAB report failure. Three-quarters of the intravesical pressure changes recorded during conventional conscious rat cystometry reflect detrusor activity. Despite these facts, the SHR animals constitute a useful model for OAB evaluations.

Ovariectomy (OVX)-Induced Bladder Dysfunction

The prevalence of voiding dysfunctions increases in the postmenopausal period. The OVX leads to hormonal disturbances that are associated with increased voiding frequency in awake and anesthetized rats.^{53, 54}

Methods

Kullmann et al ⁵⁵ removed the ovaries bilaterally via dorsal incisions of the skin and muscle 1 cm lateral to the vertebral column. The muscle and skin were sutured using silk thread, and rats were given a single injection of antibiotic (ampicillin, 100 mg/kg). Cystometry was done at a infusion rate of .04 ml/min.

Outcomes

Kullmann et al ⁵⁵ observations showed that OVX increased voiding frequency and decreased bladder capacity by 25% in awake rats and induced irregular cystometrograms in urethane-anesthetized rats (Figure 3a).

The OVX leads to the estrogen-deficiency state that may be related to the onset of OAB. Estrogen replacement therapy may be effective for OAB symptoms; however, sometimes such a therapy is unacceptable for a clinical application because of its possible severe adverse results. Therefore, a further investigation of estrogen-like compounds with a low incidence of adverse events for a clinical application is strongly required. For that reason OVX-induced OAB model seems to be crucial.

Basic Fibroblast Growth Factor (bFGF) Causes Urinary Bladder Overactivity Through Gap Junction Generation in the Smooth Muscle

Overactive bladder is a highly prevalent clinical condition that is often caused by bladder outlet obstruction (BOO). Increased coupling of bladder smooth muscle cells (BSMC) via gap junctions has been hypothesized as a mechanism for myogenic OAB in BOO. Overactive bladder in BOO is believed to result from neurogenic changes in detrusor innervation or myogenic changes in detrusor excitability.^{56, 57} Recent investigations of the mechanisms of neurogenic changes have suggested that the nerve growth factor, as well as c-fiber bladder endings activity are the pivotal candidate mediators of the process.^{58, 59}

Methods

Imamura et al ⁶⁰ fixed a gelatin hydrogel containing bFGF (0, 1, 5, and 10 µg/site) over the ventral side of each bladder with four 8-0 nylon sutures before a cystometric procedure. Sham operated rats did not receive the gelatin hydrogel treatment. In 2 weeks’ time saline was infused into rat bladders at the rate of 2.8 ml/h under 900 mg/kg urethane anesthesia. Micturition was recorded for at least 2 hours in each experiment. Micturition and residual urine volume were measured at the time of final contraction by aspiration of urine with a syringe. Bladder capacity was defined as micturition volume plus residual urine.

Outcomes

Cystometric data showed that treatment with 10 µg bFGF/site induced some features of detrusor overactivity compared with the sham-operated group (Figure 3b ). The frequency of micturition in the bFGF-treated group was significantly higher than in the sham-operated group (20.0±4.4 vs 8.7±1.6 per hour, respectively). The bladder capacity and maximum voiding pressure in the bFGF-treated group were significantly lower than that of the sham-operated group (.18±.03 vs .34±.05 ml and 11.4±2.2 vs 15.6±1.8 mmHg, respectively). Imamura et al ⁶⁰ analyses of bFGF/site rat model showed typical features of OAB. They postulate that these findings suggest that bFGF from the urothelium could induce bladder hypersensitivity to acetylcholine via gap junction generation in the smooth muscle, thereby contributing to the myogenic overactivity of obstructed bladders.

The bFGF could be a key signal for inducing OAB in bladder with BOO through the gap junction expression in urinary bladder smooth muscle cells. This model may provide a molecular basis for new therapeutic approaches to OAB.⁶⁰

Bladder Dysfunction After Acute Urinary Retention (AUR)

Overactive bladder in men is often associated with urethral obstruction due to benign prostatic hyperplasia (BPH). Bladder outlet obstruction and its related AUR induce OAB. Long-lasting bladder overdistension leads to stretch damage of the detrusor muscle and bladder microstructures resulting in deterioration of detrusor contractility. As reported previously, overdistension of the bladder influence the alteration of biochemical and metabolic status of the bladder.^61–63 Recently, it is believed that the nerve growth factor at least partly underlies the development of hyperactive voiding in obstructed animals.

Methods

Under sodium pentobarbital (50 mg/kg, i.p.) anesthesia, AUR was induced by clamping the distal urethra of rat with a small clip, and then infusing 3 ml (.6 ml/min.) of saline with an infusion pump through a transurethral catheter (22 G). The obstruction was sustained for 60 minutes and the clip was removed and then the bladder was allowed to drain through the catheter. The bladder function was estimated by voiding behavior studies (at 3 days, 1, 2, 3, and 4 weeks), as well as cystometric studies, organ bath studies (using KCl and carbachol), and histological changes evaluation (at 2 and 4 weeks after the induction of AUR).⁶⁴

Outcomes

The Saito et al ⁶⁴ study showed that AUR causes bladder weight enlargement within 2 weeks and at 4 weeks return to the control level. The AUR influenced voiding behavior, leading to a significant increase in micturition frequency per day and a decrease in a single voiding volume at 3 days, and this voiding behavior continued for more than 2 weeks. A significant decrease was shown in a single-voided volume at 2 weeks with rats when compared to control rats or at 4 weeks after the occurrence of AUR. However, there were not statically significant differences in a maximum detrusor pressure during voiding, single-voided volume, and residual urine volume between AUR groups and control group. The histological studies showed significant infiltration of neutrophils and lymphocytes, and an increase in turnover of epithelium at 2 weeks AUR rat bladder. However, at 4-week AUR rats’ bladder, a significant increase in fibrosis in submucosal layer was observed, while infiltration of neutrophils and lymphocytes and an increase in turnover of epithelium were less evident.

The data mentioned above suggest that at least within 2 weeks, the AUR rats were under OAB condition. This study demonstrated that bladder dysfunction in the rat model caused by AUR needs more than 2 weeks of a recovery period. The AUR-associated alterations in the bladder may represent a key clue to understanding the underlying pathophysiological mechanisms that take place in an OAB syndrome.⁶⁴

Hyperosmolar Model of OAB

Hyperosmolarity determines the local effector function of C-fiber nerves by changes in vanilloid receptors activity.⁶⁵ Hypertonic urine may penetrate submucosal layers of the urinary bladder and activate capsaicin-sensitive C neurons and, consequently, induce neurogenic inflammation leading to OAB.

Methods

Under urethane anesthesia, the bladder overactivity was induced during continuous cystometry using hypertonic concentrations of saline solution (1553, 2080, and 3222 mOsm/l) at a rate of .046 ml/min.⁶⁶

Outcomes

Juszczak et al ⁶⁶ data revealed that intravesical infusion of hypertonic saline induces OAB. The severity of OAB depends on the concentration of saline (Figure 3c ). A 1553 mOsm/l of saline caused an increase of detrusor activity (243%); where 2080 mOsm/l saline caused a decrease of intercontraction intervals (104%) and functional bladder capacity (100%). Additionally, an increase of basal pressure (118%), detrusor activity (413%), and motility index (33%) were observed. Also, 3222 mOsm/l saline induced the utmost OAB as characterized by a decrease of micturition voiding pressure (34%), intercontraction intervals (433%), functional bladder capacity (435%), and compliance (168%), and also by an increase of basal pressure (206%), detrusor activity (517%), and motility index (55%).

These observations show that hypertonic saline within physiological osmolarity range induces concentrated-dependent OAB. The authors postulate that 2080 mOsm/l model of OAB can be established as less-invasive and more physiological when compared with CYP-induced OAB. Furthermore, it may determine a more reliable tool for evaluating novel therapeutics for OAB as compared to CYP-induced models.⁶⁶

CONCLUSIONS

Overactive bladder (OAB) is defined by International Continence Society (ICS) as urgency, with or without urge incontinence, usually with frequency and nocturia, if there is no proven other etiology.⁶⁷ From a practical standpoint, the ICS definition of OAB is too restrictive. Therefore, Blaivas et al ⁶⁸ considered OAB to be a symptom complex caused by one or more of the following conditions: detrusor overactivity (DO), sensory urgency (uncomfortable need to void that is unassociated with DO), and low bladder compliance. The symptoms of OAB are usually attributed to involuntary contractions of the detrusor muscle.⁶⁹

In accordance with multifactorial OAB ethiopathogenesis, there are plenty of OAB models in conscious or anesthetized rats. However, a wide range of differences in experimental protocols concerning anesthesia and urodynamic evaluation (especially in the case of infusion rate and analyzed cystometric parameters) of bladder motor activity still occur. Also in the majority of papers, the way of calibration of intravesical pressure measurement systems is passed over. All these factors can exert influence on bladder motor activity recordings and, consequently, can lead to differences in cystometrogram traces and cystometric parameters values even though the same experimental protocol was used. Therefore, the standardization of cystometric protocol and cystometrogram's parameter values seems to be pivotal for a correct bladder motor activity assessment. Based on our experience and the previously described studies we suggest some steps that should be always taken to minimize the artifacts occurrence during cystometric protocol, we also provide a proposal of cystometrogram's parameters, which should be considered in the case of a complex cystometric evaluation of bladder dysfunction.

Firstly, the bladder catheter (o.d. 0.97mm/i.d. 0.58mm) should be implanted gently in the bladder dome posteriorly and close to the medial umbilical ligament through 1 mm incision and sutured with one round 4-0 suture with a blunt needle. Also the preparation of perivesiacal tissue must be reduced to a minimum. Secondarily, a two-point calibration (with at least 35 cm level difference) of the measurement kit must be performed before and after catheter implantation. During recording, the sampling frequency should be set at 1 Hz. Thirdly, the cystometry should begin only 1 hour after catheter implantation to enable the proper “bladder cells balance” after a surgical manipulation. We observed significant differences in bladder motor activity in the case of cystometric recording just after a surgical procedure. Such bladders revealed shortened intercontraction intervals with nonvoiding contraction occurrences. Fourthly, the infusion rate of saline must be standardized and set at about .04 ml per minute. Fifthly, we postulate to include in all cystometric protocols the complex description of the bladder motor activity provided by cystometric parameters, shown in Figure 3d, as follows: basal (BP), threshold (PT), and micturition voiding (MVP) pressure [cmH₂O]; intercontraction interval (ICI) [min.]; compliance (defined as: fBC/TP-BP) [ml/cmH₂O]; functional bladder capacity (defined as: ICI [min]×infusion rate [ml/min.]) [ml]; motility index (MI) in 10–20-minute intervals (defined as the enclosed area between the sampled data and their minimum on the selected interval) [cmH₂O×s/min.]; and also detrusor index (DI) in healthy rats or detrusor overactivity index (DOI) in rats with OAB (depicted as quotient of the sum of amplitudes of all detrusor contractions during filling phase and functional bladder capacity: DI(DOI)=(A₁+A₂+A₃+…+MVP)/fBC) [cmH₂O/ml].^{25, 66, 70, 71} In urodynamic studies on human DOI, the measurement of the height of waves of the detrusor pressure curve during cystometry has been used as a method of describing the severity of DO.⁷²

Disclosure: The author declares no conflict of interest.

Keywords

overactive bladder, cystometry, rat, method

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Treatments for uretero-pelvic junction obstruction (UPJO) have been well established and are highly efficacious. Historically, open pyeloplasty (OP) has been the treatment of choice with success rates exceeding 90%. Recent developments in instrumentation have allowed the development of more minimally invasive treatment options in the management of UPJO, which have comparable efficacy but with significantly less morbidity and shorter convalescence. Indeed, while OP is still largely considered the criterion standard for UPJO in infants, laparoscopic pyeloplasty (LP), with or without robotic assistance, is the treatment of choice in older children and in most adults. Pathogenesis and diagnostic workup will be briefly touched upon in this review; however, the focus will be on surgical options in the management of UPJO. The surgical principles of repair, initially described by Foley, are still applicable today and include formation of a funnel, dependent drainage, and a watertight and tension-free anastomosis. Current treatment options reviewed in this article include antegrade and retrograde endopyelotomy, endopyeloplasty, LP, robotic-assisted pyeloplasty (RAP), and conventional and robotic laparoendoscopic single-site surgery (LESS).

DIAGNOSTIC WORKUP

The pathogenesis of UPJO is still debated, but its incidence of 5 per 100000 makes it one of the most common abnormalities of the urinary tract. Etiology is likely largely due to congenital causes in the majority of cases, including aperistaltic ureteral segment, aberrant crossing vessel, true intrinsic obstruction, high insertion of the ureter, or an extrinsic compression. Acquired causes include stone disease, postinflammatory stricture, and iatrogenic. Patients can present with intermittent flank pain with nausea and vomiting, pyelonephritis, recurrent infections, a palpable flank mass (neonates), or may be incidentally found. Rarely patients will present with azotemia or hematuria.

Workup is initiated with anatomic imaging of the renal unit and UPJ to identify both the anatomic site and functional significance of the obstruction. Obstructing calculi must be ruled out as they can mimic a true UPJO. Excretory urography has largely been supplanted by ultrasound and/or CT imaging to characterize the anatomy. A spiral CT angiogram is helpful when there is suspicion of a crossing vessel. Next, a Mercaptoacetyl-Tri-Glycine (MAG3) diuretic renal scan is used to confirm the obstruction and determine the split differential function. Kidneys with less than 15% differential function on renogram are considered nonsalvageable in adults. A retrograde pyelogram, which can be performed early on to help establish the diagnosis or at the time of surgical treatment, is used to confirm the UPJO. In addition to characterizing the stricture location and length, a lack of dependent drainage of the renal pelvis should be visualized. An algorithm is provided to help with the general diagnostic and treatment approach (Figure 1), although case- specific considerations should always be made. Indications for intervention for UPJO include symptoms associated with the obstruction (ie, flank pain, nausea, and vomiting), impairment of ipsilateral function, and the development of stones or infection.

ENDOSCOPIC TREATMENTS

Endopyelotomy

First described in 1903 by Albarran as a full thickness incision of a narrowed segment of ureter, the endopyelotomy via retrograde endoscopy was popularized as endoscopic instrumentation improved in the 1980s ^1–3. Advantages over OP include shorter operating time, shorter hospital stay, and reduction in postoperative pain due to lack of a flank incision. The three main types of procedures are antegrade (percutaneous) endopyelotomy, retrograde (ureteroscopic) endopyelotomy, and Acucise (Applied Medical, Rancho Santa Margarita, CA) endopyelotomy. Balloon dilation of a UPJO is generally inferior to endopyelotomy. An endopyelotomy cannot be performed safely by any technique until guide wire access across the UPJ is established. A main principle in the technique involves a full thickness incision “down to the fat” and allowing the ureter to heal by secondary intention over a ureteral stent. The UPJ can be incised with a cold knife, electrocautery, or a laser with equal efficacy and no advantage of any single technique. This technique can allow for a sustainable increase in the caliber of the strictured ureteral segment, despite the potential wound contracture that may occur.

Success after endopyelotomy is variable, generally reported at 60%-90% ^4–7. Factors that portend a worse outcome include long stricture length (>2 cm), presence of a crossing vessel, severe hydronephrosis, poor ipsilateral renal function (<25%), and multiple previously failed endopyelotomies. The presence of a crossing vessel may adversely affect the efficacy of an endopyelotomy. Van Cangh and colleagues reported increased success with endopyelotomy when a crossing vessel was not identified ⁴. However, Gupta and colleagues ⁵ found only 4% of endopyelotomy failures to be caused by the presence of a crossing vessel, more recently confirmed by Ost and colleagues. ⁷ Butani and Eshghi ⁶ showed that with strict inclusion criteria of stricture less than 2 cm, renal function greater than 25%, and an absence of severe hydronephrosis, a 94% overall success rate for endopyelotomy could be achieved. Additionally, long-term data suggests that the durability of endopyelotomy is questionable, as success rates decline with longer follow-up, except for a recent publication by Butani and Eshghi that showed a 94.5% success rate at 60 months (Table 1). This may indicate better patient selection for endoscopic management as this is a more recently published series. These poorer success rates can be mitigated by careful selection of optimal candidates for endopyelotomy.

Prior to incising a UPJ obstruction, it is prudent to review the preoperative image of the adjacent ureteral vasculature. As an adjunct, endoluminal ultrasonography has been investigated as a real-time evaluation for the presence or proximity of blood vessels prior to an endoscopic incision ⁸. A guide wire must be placed across the UPJ regardless of the approach. An endopyelotomy incision is performed through the area of obstruction with a laser, electrocautery, or endoscopic scalpel. The incised ureter may also be dilated with a balloon catheter. A ureteral stent is left in place for a period of 4-8 weeks.

Stent size and duration have been studied ^9–13. Davis empirically described a 6-week stenting period in his initial description of an intubated ureterotomy ³. This paradigm has been challenged, including a study by Mandhani and colleagues ¹². who found no significant differences between 2 or 4 weeks duration of stenting by diuretic renography or questionnaire-reported stent-related symptoms after endopyelotomy. No comparison was made with 6 weeks of stent duration. Additionally, caliber of stent size has been debated, on the theory that a larger stent would equate with a larger final ureteral caliber as the ureter heals around the stent after endopyelotomy. Results on studies of variable stent caliber have been mixed and no consensus has been reached ^{9, 10, 13, 14}.

Techniques

In general, the following techniques have similar efficacy in the appropriately selected patient. Difficulty arises in comparing the data of different techniques from various institutions as there is variability in the definition of success. Data from large series of endopyelotomies with long-term follow-up is presented in Table 1. Single institution comparative studies ^{15, 16} do suggest that overall, the antegrade approach is more efficacious than the retrograde approach. Retrograde endopyelotomy was associated with less postoperative pain, shorter hospital stay, and fewer complications. In a prospective randomized trial, El-Nahas and colleagues ¹⁷ evaluated Acucise and ureteroscopic endopyelotomy, with 30-month success rates of 65% and 85%, respectively. Ultimately, surgeon preference is based on familiarity with technique, anatomic considerations, the presence of concomitant stone disease, and optimal access to the UPJO.

Antegrade (percutaneous) endopyelotomy

Antegrade (percutaneous) management of UPJO is particularly advantageous when there is a significant associated upper tract stone burden. This allows for management of the renal calculi at the time of the endopyelotomy. The stone should be addressed before the endopyelotomy is performed. If an endopyelotomy is performed first, stone fragments have the potential to migrate into the peripyeloureteral tissue. As with retrograde endopyelotomy, care must be taken to ensure that the incision is placed posterolaterally to minimize risk of injury to the renal pedicle. Antegrade endopyelotomy has excellent overall efficacy and slightly superior to other endopyelotomy techniques (Table 1).

Retrograde (ureteroscopic) endopyelotomy

This is the most widely performed approach for endopyelotomy as it is relatively straightforward and technically simple as technological advancements in ureteroscopes have developed. Further, it has decreased morbidity, no incision, shorter hospital stay, shorter operative time, less bleeding, and fewer complications than the antegrade approach. When performed with a laser, the incision is made with a holmium: YAG laser at 10 W. Radiographic success rate ranges from 73% to 95% ^{6, 17, 20–22}. Further, retrograde endopyelotomy has been successfully used in secondary UPJO, most notably in failed pyeloplasty as a low-morbidity salvage procedure with a reported success rate of 83.3% in an excellent series by Geavlete and colleagues.²³

Acucise endopyelotomy

Acucise endopyelotomy is a balloon electrocautery incision under fluoroscopic guidance in a retrograde fashion, without direct visualization, while incising the UPJO. Initially described in 1993 ²⁴, overall results and efficacy approximate those of other endopyelotomy techniques as seen in Table 1, ^25–28. This technique gained initial popularity due to lack of needing advanced ureteroscopic skills and the ability to perform it with a traditional cystoscopic technique. However, due to the lack of direct visualization while making the incision, shortcomings of this technique include difficulty controlling the depth of incision and therefore an increased risk for hemorrhage. Indeed, 3%-10% of cases were found to have bleeding complications ²⁶.

Endopyeloplasty

Endopyeloplasty was first described by Oshinsky and colleagues ²⁹. by using a laparoscopic suturing device through a nephroscope. The novel technique involved incising the UPJO longitudinally and suturing the incision in a Heineke-Mikulicz fashion to widen the caliber of the UPJ. Gill and colleagues ³⁰. explored the feasibility of the technique in a small series of nine primary UPJOs. Inclusion criteria included <1 cm stenotic length, absence of a crossing vessel, and primary UPJO. Suturing was performed using a novel 5 mm laparoscopic suturing device passed through the nephroscope to place one to four endopyeloplasty sutures per repair. Mean total operative time was 100.8 min, with a suturing time of 26.6 min.

A retrospective matched cohort study compared endopyeloplasty (n=15), endopyelotomy (n=15), and LP (n=14) in patients with primary UPJO, with 1-year of follow-up data ³¹. Study inclusion criteria were short stricture length (<1 cm), no prior surgery for UPJ obstruction, and no crossing vessels in groups. Results were promising overall with 100% resolution of symptoms and 100% successful radiological resolution of obstruction in the endopyeloplasty cohort at mean follow-up of 11.6 months. Similarly, success rates were found to be 93% and 88% for percutaneous endopyelotomy (mean follow-up 31.4 months), and 93 and 100% for laparoscopic pyeloplasties (mean follow-up of 20 months), respectively. Ost and colleagues ⁷. performed endopyeloplasty after with only 40% success (n=5). The low success rate was attributed to sequelae related to the use of a balloon dilator on the UPJO. Further study is necessary to prove proficiency at other institutions and to determine long-term efficacy. Although the findings are promising, endopyeloplasty has failed to gain widespread acceptance as it is more technically demanding than endopyelotomy and as the popularity of robotic- assisted LP has increased.

LAPAROSCOPIC PYELOPLASTY (LP)

Despite good results with endopyelotomy, long-term follow-up has brought into question its durable success ^{32, 33}. Dimarco and colleagues ³³. found that although most endopyelotomy failures occurred within 2 years, failures were found to occur at 5 and even 10 years after endopyelotomy. LP was first described in 1993 by Schuessler and colleagues ³⁴. as a less invasive means of reconstructing the ureteropelvic junction under direct vision in a fashion similar to the reference standard, OP. Numerous studies have shown LP to have higher subjective and objective success rates over endopyelotomy ^{7, 35, 36}. In multiple comparative series, LP was significantly more successful than endopyelotomy: 98% vs 84% ⁷, 95.3% vs 55.4% ³⁵, and 94.4% vs 72.6% ³⁶, respectively.

Advantages of LP over endopyelotomy are numerous. As previously indicated, LP is preferable with the presence of a crossing vessel, allowing for transposition of the UPJ. Additionally, patients with long stricture length (>2 cm), severe hydronephrosis, or differential function less than 30% are better served with LP rather than endopyelotomy. Patients with a redundant renal pelvis can have the extra tissue excised at LP. Renal calculi can be addressed with laparoscopic grasping instruments or utilizing a flexible cystoscope and nitinol stone baskets with 90% stone-free rates achieved ³⁷, Additionally, anatomic variants including pelvic and horseshoe kidneys are not contraindications to the procedure. Indeed, success rates of LP are comparable to OP, consistently reported to be above 90% ^{7, 35–38}.

Advanced laparoscopic techniques are required for some of the manipulation and reconstruction of the UPJ, limiting its widespread adoption in the surgical community. Despite the inherent technical challenges, LP (and robot-assisted iterations) has become the gold standard approach to UPJO due to equivalent efficacy to OP with considerably less morbidity ^{38, 39}. In conjunction with purely laparoscopic LP, robotic-assisted laparoscopy has gained widespread adoption. As a tool to facilitate laparoscopy, robotic-assisted techniques further disseminate the advantages of laparoscopy to surgeons who may not be as comfortable with laparoscopic suturing and advanced laparoscopic techniques. In the sections below, we will discuss various approaches to the renal pelvis, reconstructive techniques and options, and positioning to minimize complications.

Approach

The patient is placed in a 45° lateral decubitus position that minimizes potential neuromuscular complications that may occur with the 90° flank position. A roll or bolster is placed behind the ipsilateral shoulder and down to the ipsilateral pelvis to keep the operative side elevated and stable. An axillary roll is not usually necessary. Neither the kidney rest nor flexion of the operating table are usually necessary to minimize pressure injuries. The contralateral arm is placed on an arm board abducted 90° from the table, and the ipsilateral arm is placed across the chest with stacked pillows and folded blankets between the arms. Care is taken to protect all pressure points with foam. The lower knee is bent slightly, and the ipsilateral leg is kept almost straight with pillows or foam placed between them to prevent pressure ulcers and neurologic injury. The patient is secured to the table with foam and wide cloth tape placed across the upper shoulder and arm and across the hip. The table is then rotated prior to draping to ensure that the patient is secured.

Access to the UPJ can be managed by either a transperitoneal or retroperitoneal approach. A transperitoneal route is the more common approach due to greater operative space and familiarity with anatomic landmarks. Difficulties inherent to the retroperitoneal approach include decreased working space, unfamiliarity with the retroperitoneal approach, or reduced ability to identify an anterior crossing vessel. A retroperitoneal approach could be employed in patients with previous transperitoneal or abdominal surgeries or in morbidly obese individuals. Prior to positioning the patient, the authors recommend performing a flexible cystoscopy and retrograde pyelogram to confirm the obstruction at the UPJ. After a guide wire is passed into the renal pelvis, a 5 French open-ended stent is left at the level of the obstructed segment. Although infrequent, equivocal cases may require direct visualization of the UPJ with an ureteroscope to confirm a stenotic segment or obstruction. Only after confirmation of a UPJO should the laparoscopic trocars be placed. For an LP, the authors usually perform a transperitoneal approach (Figure 2). In obese patients, the trocars may be shifted laterally.

After placing trocars for a transperitoneal approach, the retroperitoneum and renal hilum can be accessed by either mobilizing the colon along the line of Toldt or via a transmesenteric approach. The transmesenteric approach may offer advantages of decreased operative time and ileus in appropriately selected cases. This approach is primarily useful in left-sided cases because the splenic flexure lies cephalad to the UPJ. It is technically feasible in cases with a laterally displaced colon and relatively thin mesentery, more frequently encountered in pediatric cases and thin women. Rather than reflecting the colon, a longitudinal window is created in the mesentery overlying the UPJ, taking care to avoid mesenteric vessels. A stay suture through the abdominal wall can be used to elevate the renal pelvis and UPJ. From this vantage point, the proximal ureter and renal pelvis are dissected and the repair of choice is performed.

Technique

The techniques described for OP are very closely approximated with LP and RAP. Dissection usually follows superiorly along the proximal ureter to expose the UPJ and dilated renal pelvis. Extensive ureteral dissection is avoided to minimize compromising its blood supply. A thick rind can develop at the UPJ due to chronic obstruction and attendant inflammatory reaction and should be dissected off sufficiently. This rind may be made worse if previous attempts have been made at endopyelotomy or balloon dilation. If necessary, a redundancy of the renal pelvis can be excised to optimize dependent drainage and renal stones removed prior to final reconstruction.

A variety of reconstructive techniques exist. An Anderson-Hynes dismembered pyeloplasty is the procedure of choice for a crossing vessel. Dissection of the proximal ureter and UPJ (Figure 3A) is performed as described above. The renal pelvis is then incised (Figure 3B) and reduction of the redundant pelvis is performed if necessary. The proximal ureter is spatulated medially. Laparoscopic suturing (Figure 3C) is performed by starting at one corner of the repair using laparoscopic needle drivers, or with an Endo-Stitch device, to close the posterior aspect first. Lastly, (Figure 3D) the redundant pelvis is closed in a running fashion.

Alternatively, a Foley Y-V plasty can be performed in the absence of crossing vessels or when there is a high ureteral insertion. The Y incision of the UPJ is outlined (Figure 4A) to ensure vascular viability of the flap prior to incising it. The apex of the flap is advanced to the distal ureteral incision and secured using interrupted sutures (Figure 4B and C). A tension- free, watertight repair is confirmed (Figure 4D). A nondismembered pyeloplasty (Fenger) can be used for a short stenotic segment in the absence of a crossing vessel or when anatomic considerations limit access. A vertical incision extending 1 cm proximal and distal to the stenotic segment is made. The incision is then closed horizontally, in a Heineke-Mikulicz fashion, to produce a widely patent segment. A long ureteral stent (26 cm or 28 cm) is left in place to ensure that the distal stent does not migrate into the ureter.

Patients with pelvic, and even calyceal, calculi can achieve excellent stone-free rates with LP ³⁷. If calculi cannot be removed laparoscopically, a flexible nephroscope is introduced into the renal pelvis for stone extraction. Care is taken not to tear, disrupt, or injure the renal pelvis as the primary objective must always be to reconstruct the UPJ. Residual calculus disease can be addressed at a future date via ureteroscopy or percutaneous nephrolithotripsy.

Additional reconstruction is sometimes required in cases where a very long stricture is present or the anastomosis is under tension. This is more likely to occur in cases of secondary UPJO. In these cases, it is critical to assess the UPJ and stricture length prior to transecting the UPJ. In order to ensure a tension-free anastomosis and optimize the patency of the reconstruction, it may be necessary to create a vertical or spiral flap of renal pelvis to reconstruct the UPJ and gain adequate length. Mobilization of the superior attachments of the kidney can allow additional inferior displacement of the kidney to provide additional length. In redo salvage situations and rare cases with a very long stricture, a laparoscopic ureterocalicostomy or ileal ureter may be employed.

After the anastomosis is completed, the pneumoperitoneum pressure is dropped to 5 mm Hg to assess for adequate hemostasis of the operative site and for injury to adjacent structures. A closed bulb suction drain is placed in the retroperitoneum to lie adjacent to but not in direct contact with the newly completed anastomosis. The drain is brought out through a small stab incision in the posterior axillary line and secured.

LP has been an established and efficacious technique for UPJO. Worldwide, large volume series with lengthy follow-up are presented in Table 2. Overall success rates for LP range from 88% to 100% ^37–42, including both subjective (symptomatic) success and objective (radiographic) success. This compares favorably to endopyelotomy and is equivalent to the reference standard, OP. A direct comparison of LP and OP was performed by Bauer and colleagues,⁴³ reviewing 42 LPs and 35 OPs. No significant differences were found in symptomatic or radiographic success between LP and OP, the latter with 98% vs 94% success, respectively.

ROBOT-ASSISTED PYELOPLASTY (RAP)

RAP is quickly supplanting LP as the minimally invasive surgery of choice for UPJO. This can be attributed to the increasing prevalence of the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA), ease of suturing with the wristed robotic instruments, and increased facility with robotic surgery due to familiarity with robotic prostatectomy. Indeed, RAP has been readily adopted by surgeons without extensive laparoscopic experience ⁴⁴. Laparoscopic trocars are placed in a similar fashion to LP (Figure 5), but with an additional 10 mm trocar as an assistant port and to allow the passage of sutures.

Multiple studies have shown RAP to be safe, efficacious, and have long-term durability (Table 3) ^44–48. Further, Nayyar and colleagues ⁴⁹ assessed the feasibility and outcomes of RAP for complicated UPJO (n=29). These UPJO were complicated by multiple calculi (n=4), calyceal calculi (6), secondary UPJO (4), malrotated kidney (1), horseshoe kidney (2), ectopic kidney (1), giant hydronephrosis (4), poorly functioning kidney with GFR <20 ml/min (5), and duplicated renal pelvis (1). All were performed as RAP, with one conversion to open. Overall success rate was 96.6% and 8 of 10 cases with calculi were rendered stone-free.

The cost associated with RAP may still be a consideration. Initial institutional investment in a robotic system (>US$1 million) and increased per procedure cost compared with traditional LP may limit availability. For experienced laparoscopic surgeons facile with LP, this results in an increase in cost of 4.7 times ⁵⁰. This may be balanced, however, by the increased number of surgeons now able to offer RAP who would not undertake a LP and the concomitant advantages inherent over OP. Additionally, as more robotic systems become available for other uses, utilization for RAP and other laparoscopic procedures should increase ⁴⁵.

Retroperitoneal RAP has been reported in significant numbers in the pediatric literature ⁵¹. Recently, Kaouk and colleagues have successfully performed retroperitoneal RAP in adult patients ⁵². Difficulties inherent to the retroperitoneal approach are noted above, but the decreased working space is further exacerbated in this technique due to collision of the robotic arms. Advantages, however, include direct access to the UPJ, reduced urinoma formation, and potential as an outpatient procedure.

LAPAROENDOSCOPIC SINGLE-SITE SURGERY (LESS)

Single-site surgery is a relatively new development in the evolution of minimally invasive techniques. In July of 2008, a multidisciplinary consortium of experts met and determined that the term “laparoendoscopic single-site surgery” (LESS) was scientifically accurate and would be adapted as the future standard for the reference. Advantages of LESS include improved cosmesis and theoretically decreased analgesic requirements and shorter convalescence. Impediments to the technique include tight working area, crossing of instruments, the need to learn new instrumentation, and a steep learning curve. The majority of LESS literature in urology pertains to nephrectomy, including donor nephrectomy where a cosmetic closure is arguably slightly more significant. Overall, most experienced laparoscopists have found little difference in outcomes between LESS and conventional laparoscopy ^53–57.

Renal LESS series have been published, with some reporting on their LESS pyeloplasty experience (Table 4) ^53–55. White and colleagues ⁵³ described their experience with 100 LESS renal surgeries, 8 of which were LESS pyeloplasties. Operative time of 233 min was slightly long compared with most conventional LP series, owing largely to the adaptation necessary to new instrumentation and ergonomic constraints. They achieved 100% success with no radiographic failures. The sole complication recorded was a port site hernia.

Desai and colleagues reviewed their overall LESS experience of 100 cases as well, 17 of which were pyeloplasties ⁵⁴. Additionally, these same LESS pyeloplasties were compared by Stein and colleagues ⁵⁷ in a matched cohort retrospective analysis to 32 standard LPs. They concluded no benefit imparted for LESS pyeloplasty over standard LP beyond the aesthetic advantages. The LESS pyeloplasty operative time was longer (215±78 min vs 183±29 min for LESS pyeloplasty and LP, respectively), although this difference did not quite meet statistical significance (P=.055). A questionnaire showed overall similar convalescence and decreased postoperative narcotic requirement in the LESS group, though this did not reach statistical significance. However, it must be noted that in all 17 cases, in addition to the umbilical port, a 2 mm assistant port was placed to aid in suturing of the pyeloplasty.

Renal LESS, without the use of accessory trocars, was described by Rais-Bahrami and colleagues ⁵⁵. All procedures (n=11), including the two pyeloplasties, were performed with a 5 mm flexible tip laparoscope and flexible working instruments. No comparisons were made to traditional laparoscopy and no follow-up was provided. They concluded that renal LESS is feasible without the need for additional ports by using flexible laparoscopes and instruments, with overall equivalent efficacy, operative time, blood loss, and hospital stay when performed by advanced laparoscopic surgeons.

CONCLUSIONS

A number of excellent surgical options are currently available to treat UPJO. Patient selection is paramount for successful outcome. The algorithm provided (Figure 1) is an approximation that can be used in the decision process for patients with UPJO. Ng and colleagues ¹³ evaluated long-term success for secondary UPJO after failed primary intervention. In patients who have a suboptimal result from endopyelotomy, repeat incision can be performed with success. However, pyeloplasty (LP, RAP) is generally indicated for failed endopyelotomy assuming patient selection is appropriate. Conversely, when pyeloplasty fails, regardless of the technology or approach, endopyelotomy is particularly useful as there may be scar contracture at the anastomosis. The scarring and reactive inflammation that can take place after a failed endopyelotomy, however, can make a LP more difficult. Therefore, for “secondary” UPJ obstruction, it is reasonable to recommend an open or laparoscopic approach to any patient who has failed primary endourologic management and an endourologic approach to those who have failed open or laparoscopic repair. Robotics has further enhanced LP by reducing its steep learning curve. It may also serve a role in future LESS surgeries by obviating some of the difficulties inherent to single trocar LESS procedures.

Disclosure: The authors declare no conflict of interest.

Keywords

pyeloplasty, ureteropelvic junction, reconstructive urology, minimally invasive surgery, endoscopy/ureteroscopy, laparoscopy, robotic-assisted surgery

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Prostate cancer is the most common cancer in men and the second leading cause of cancer related deaths in the Western World ¹. After the introduction of a prostate specific antigen (PSA), it has become a standard method of prostate cancer screening and although the incidence of prostate cancer has increased, many patients are diagnosed with the localized disease and have excellent survival and high cure rates with standard treatments ². However, approximately 30%–50% of treated patients will have a local or distant recurrence despite definitive local therapy ³. Androgen deprivation therapy (ADT) via surgical castration or hormonal manipulation using luteinizing hormone releasing hormone (LHRH), antiandrogens, or both has become the standard treatment of patients with the metastatic disease. Although the disease initially responds to ADT, most of the patients eventually progress to a state of castration-resistant prostate cancer (CRPC). CRPC refers to prostate cancer that has progressed despite castrate levels of testosterone (<50 ng/dL or <1.7 nmol/L), has three consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with a PSA>2 ng/mL and the patient on antiandrogen withdrawal (AAW) for at least 4 weeks ⁴. The PSA concentration increases in almost 90% of the patients and bone metastasis, substantive pain and soft tissue/lymph node metastasis are observed in 90%, 35%, and 20% of the patients, respectively ⁵. Unfortunately, the majority of the patients progress to an androgen independent stage that is also termed CRPC, mostly unresponsive to further hormonal manipulations ⁶.

An earlier publication by Yagoda and Petrylak ⁷ revealed that among 1001 men with CRPC who had received chemotherapy in 26 trials, the overall response rate was only 8.7%. Prostate cancer thereby was considered resistant to chemotherapy until the mid-1990s. However, the entry criteria for these trials included the presence of the measurable disease, which usually means late stage or metastatic disease in prostate cancer. Subsequently, after the introduction of surrogate end points for the prostate cancer clinical trials including a >50% PSA response, pain response, and quality of life measures, more patients with a less extensive disease, fewer symptoms, and better performance status were included in later trials demonstrating far better results ⁸.

This review highlights the current approaches and recent developments, particularly focusing on the most encouraging results with new agents that might be candidates for the routine clinical practice in the management of CRPC ( Table 1 ).

SECONDARY HORMONAL THERAPY IN CRPC

Although nearly all patients develop tumor progression despite castrate levels of testosterone, many patients remain sensitive to secondary hormonal manipulations aimed at further lowering androgen levels or targeting the androgen receptor (AR) through alternative means ⁹. Multiple mechanisms have been thought to contribute to the androgen independent state and the proposed—and most notable—mechanisms include the AR gene amplification and/or mutation that further lead to promiscuous ligand or cofactor interaction, ligand independent AR activation, and AR activation by nonclassical ligands and other signaling pathways ^9–11. Recent studies showed that intraprostatic testosterone concentrations of the patients with CRPC were equivalent to those of eugonadal patients with benign prostatic hyperplasia (BPH) and that intraprostatic DHT levels were reduced only to 80% of untreated individuals ¹².

Additionally, prostate adenocarcinomas are thought to be capable of de novo androgen biosynthesis from cholesterol precursors, and thus do not require adrenal androgens as substrates in some cases. An explanation to these clinical observations comes from a study showing the enhanced expression of enzymes that takes place in cholesterol biosynthesis in CRPC patients relative to the samples taken from untreated patients with prostate cancer ¹³. Therefore, in this situation, prostate cancers would not require adrenal androgens as substrates. Therefore, tumor associated molecular alterations in enzymes involved in androgen metabolism, resulting in biologically relevant concentrations of ligand for AR activation could explain the failure of the castration approaches and afford opportunities for the development of novel methods for targeted treatment ¹¹.

Current standard treatment for a patient with a rising PSA while on ADT still remains as the AAW phenomenon. Although the exact mechanism is not fully known, this treatment modality is based upon the observations made in the earlier studies of clinical responses and PSA regressions after the cessation of oral antiandrogens like flutamide ¹⁴. The most dominant hypothesis about this phenomenon is thought to be the altered equilibrium between corepressors and coactivators of the AR in a backdrop of AR amplification ⁹. Since a second antiandrogen usually presents a positive effect, AAW seems to be drug specific. Suzuki et al ¹⁵ reported AAW rates of 15.5% and 12.8% for bicalutamide and flutamide, respectively, and after relapse of first-line therapy, patients received an alternative antiandrogen and a PSA decline was observed in 61.2% of the patients in response to the treatment.

Further approaches to manipulate hormones include pharmacologic “adrenalectomy,” which formerly was performed surgically to decrease the effect of adrenal androgens that was thought to influence prostate cancer growth. Aminoglutethimide and ketoconazole were the initial drugs used for that purpose and produced response rates of about 40%–50% in castrated patients having disease progression ¹⁶. After phase I and II trials using ketoconazole demonstrated a clinical and PSA response in CRPC, a phase III study that randomized 260 patients with metastatic prostate cancer despite ADT to AAW alone or in combination with high dose ketoconazole (400 mg orally three times daily with hydrocortisone replacement therapy) was conducted ¹⁷. The study showed that the patients in the combination arm had a >50% decline in PSA compared to only 11% of patients receiving AAW alone. Further analysis revealed that the patients who experienced a 50% decline in PSA while on ketoconazole had a median survival of 41 months compared with 13 months in those who did not receive ketoconazole (P<.001). Despite initial encouraging results, ketoconazole use in clinical practice is limited and complicated by several factors including requirement for corticosteroid replacement, drug–drug interactions, and problems with dosing. Promising results of the efforts to develop new agents aroused as novel antiandrogens and selective enzyme inhibitors that will be discussed below in details.

SYSTEMIC CHEMOTHERAPY

Docetaxel as first-line therapy in CRPC

In 2004, two large landmark randomized phase III trials, TAX 327 and SWOG 9916, demonstrated a survival benefit with docetaxel-based chemotherapy compared to mitoxantrone plus prednisone for patients with metastatic CRPC ^{18, 19}. In the TAX 327 trial, 1006 patients with CRPC-received docetaxel (75 mg/m²) every 3 weeks, docetaxel (30 mg/m²) weekly, or mitoxantrone (12 mg/m²), all combined with low dose prednisone (10 mg) daily. Patients who received the 3-weekly docetaxel regimen had significantly longer survival (median 18.9 vs. 16.5 months, which corresponds to a 24% reduction in the risk of death) and higher PSA and pain response rates compared with the patients who received mitoxantrone. In 2008, an updated survival analysis from the TAX 327 study showed that the significant improvement in survival in the 3-weekly docetaxel regimen was sustained at 3 years (19.2 vs. 16.3 months) ²⁰.

The SWOG 9916 study was designed on the expectations that the combination of two cytotoxic agents would have the greatest therapeutic potential. Similar to TAX 327, patients in the docetaxel arm had increased survival compared with the mitoxantrone arm (17.5 vs. 15.6 months, which corresponded to a 20% reduction in the risk of death). Patients in the docetaxel arm also had a significant improvement in time to progression (TTP) (6.3 vs. 3.2 months; P<.001) and a higher PSA response (≥50% decrease) rate (50% vs. 27%; P<.001). Given that both docetaxel-based regimens resulted in a similar survival benefit, the combination of docetaxel plus prednisone is preferred in routine daily practice for the first-line treatment of CRPC, in order to avoid estramustine-related side effects ( Table 2 ).

New cytotoxic agents and docetaxel-based combinations

Tyrosine kinase inhibitors

In normal cells, tyrosine kinases mediate multiple signaling pathways responsible for cell proliferation, migration, apoptosis, and angiogenesis. Abnormal tyrosine kinase signaling has been consistently linked with cancer formation and resistance to treatment ²¹. Several tyrosine kinase inhibitors with different targets such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) are being investigated as individual drugs or in combination with docetaxel for CRPC.

The EGFR inhibitors, gefitinib, erlotinib, and vandetanib and PDGFR inhibitor imatinib showed modest activity and a high level of toxicity in patients with CRPC in separate and docetaxel combined phase II trials ^22–25. Sorafenib is a multikinase inhibitor of several targets including vascular endothelial growth factor receptor (VEGFR) and PDGFR and in phase II studies in patients with CRPC, sorafenib was well tolerated as a single agent. Although it showed modest activity and decreases in bone scan lesions were observed, paradoxically increasing PSA levels questioned if PSA was an appropriate end point for proper assessment or not in clinical trials ^26–29. Sunitinib is another inhibitor of VEGFR and PDGFR that is approved for use in metastatic renal cell cancer. In a phase II trial ³⁰ of 36 patients with prior docetaxel chemotherapy, median PFS was found 19.4 weeks with sunitinib. This trial used radiologic and clinical determinants of progression with 2 (11.1%) of 18 patients with the measurable disease demonstrated a 30% decline of tumor size according to RECIST and 8 (44%) patients displayed some shrinkage. However, drug discontinuation due to toxic effects occurred in 52.8% of patients. A combination of sunitinib with docetaxel exhibited more encouraging results. In a phase I/II study of sunitinib plus docetaxel and prednisone as a frontline therapy in metastatic CRPC, median time to PSA progression was found at 42 weeks and the overall survival (OS) probability at 48 weeks was 92%. Moreover, 33% of assessable patients had confirmed partial response according to RECIST ³¹. A phase III trial of sunitinib plus prednisone vs. prednisone alone in patients with docetaxel failure is currently recruiting participants (clinicaltrials.gov identifier: NCT00676650).

Antiangiogenic agents

Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF) that is a key activator of tumor angiogenesis. While single agent studies have failed to demonstrate significant results, a phase II trial of bevacizumab and docetaxel-estramustine chemotherapy in patients with metastatic CRPC has been conducted by the Cancer and Leukemia Group B. This trial (CALGB 90006) showed a posttherapy PSA decline in 81% of the patients and an OS of 21 months. The use of bevacizumab in the treatment of metastatic CRPC has been investigated in a phase III trial comparing docetaxel with or without bevacizumab (clinicaltrials.gov identifier: NCT00110214). In that trial, 1050 patients with chemotherapy naive, metastatic CRPC were prospectively randomized to receive docetaxel (75 mg/m² IV over 1 hour q 21 days), plus prednisone 5 mg po BID with either bevacizumab (15 mg/kg given intravenously q 3 weeks following docetaxel) or a placebo. The primary end point was planned as OS and median OS was found 22.6 months in docetaxel and prednisone plus the bevacizumab arm and 21.5 months in the docetaxel and prednisone arm (HR=0.91 [0.78-1.05], 95% CI, P=.181).

Despite an improvement in PFS (9.9 vs. 7.5 months, HR=0.77 [0.68–0.88], 95% CI, P<.0001), a measurable disease response (53.2% vs. 42.1%, P=.0113) and posttherapy PSA decline (69.5% vs. 57.9%, P=.0002), the addition of bevacizumab to docetaxel and prednisone in CALGB 90401, did not meet its primary objective of extending OS compared to chemotherapy and prednisone alone and was associated with greater morbidity and mortality. The median OS of patients treated with standard docetaxel and prednisone (21.5 months) was longer than previously reported (19 months) ³².

Thalidomide is an oral angiogenesis inhibitor with an unknown exact mechanism of action. The phase I/II studies using high doses of thalidomide as a single agent have yielded low PSA response rates ^{33, 34}. However, in a randomized phase II study of docetaxel plus thalidomide versus docetaxel alone in patients with metastatic CRPC, the thalidomide arm had an insignificant increase in PSA response rate (53% vs. 37%; P=.32) and at a median follow-up of 26 months, an improvement in PFS (median 5.9 months vs. 3.7 months with docetaxel alone) and a higher 18-month survival rate (68% vs. 43%) were reported ³⁵. Although safety was acceptable, thalidomide resulted in thromboembolic events in 28% of the patients who did not receive anticoagulant prophylaxis. Additional toxicities with thalidomide include neuropathy, sedation, fatigue, and constipation. Newer thalidomide analogues with immunomodulatory features have been developed that lack the neurotoxicity of thalidomide ^{3, 36}.

Lenalidomide and CC-4047 are more potent second generation compounds and phase I and phase II studies with lenalidomide have revealed PSA and partial radiological responses, both when used alone and when combined with ketoconazole or docetaxel ^37–40. A phase III study of docetaxel with or without lenalidomide with a planned accrual of 1015 patients with CRPC has recently been initiated (clinicaltrials.gov identifier: NCT00988208).

Aflibercept (VEGF Trap) is a recombinant fusion protein consisting of human VEGFR extracellular domains fused to the Fc domain of human immunoglobulin G1 (IgG1) and it has a higher affinity for VEGF than bevacizumab in vitro ⁴¹. Phase I trials have demonstrated the safety of aflibercept in combination with docetaxel and adverse events are similar to bevacizumab ⁴². A phase III study (VENICE) that investigates the combination of standard docetaxel/prednisone therapy with aflibercept for the first-line treatment of CRPC has been initiated and recently completed the accrual of the planned 1200 participants (clinicaltrials.gov identifier: NCT00519285).

Antiapoptotic agents

OGX-011 (Custirsen) is a phosphothioate antisense molecule that serves to increase potency and tissue half-life. It has been shown to significantly decrease a 75–80 kDa secreted heterodimer disulphide-linked glycoprotein that has been shown to be antiapoptotic ⁴³. Phase I trials have shown that OGX-011 can inhibit the clusterin expression in prostate cancer tissues in humans and it can be delivered at biologically active doses as standard chemotherapy ⁴⁴. A phase II trial of OGX-011 with either docetaxel or mitoxantrone in patients with CRPC who had previously progressed on docetaxel showed interesting results by means of antitumor activity ⁴⁵. In patients treated with OGX-011 with mitoxantrone, 27% of the patients had a PSA decline >50% from baseline and median OS was found at 11.4 months. In patients who received OGX-011 and docetaxel, 40% had a PSA decline >50% from baseline and median OS was 14.7 months. A phase III trial comparing docetaxel plus OGX-011 vs. docetaxel in patients with metastatic CRPC is currently recruiting participants (clinicaltrials.gov identifier NCT01083615). The primary end point was planned as OS and 292 patients were enrolled.

Bone targeted agents

Atrasentan is a highly selective endothelin A receptor antagonist and has extensively been investigated in prostate cancer ⁴⁶. In a phase II trial, atrasentan monotherapy revealed encouraging clinical effects; however, in phase III trials in patients with CRPC atrasentan failed to meet primary end points of delaying disease progression when used alone ^47–49. A phase III trial (SWOG-S0421) has been initiated to test the combination of atrasentan with standard docetaxel in men with metastatic CRPC (clinicaltrials.gov identifier: NCT00134056).

Zibotentan (ZD4054) is another endothelin A receptor antagonist that was shown to extend OS in patients with CRPC and bone metastasis in a phase II trial ⁵⁰. In that study, a total of 312 patients with metastatic hormone-resistant prostate cancer were randomized (ZD4054 10 mg, n=107; ZD4054 15 mg, n=98; placebo, n=107). At the primary analysis, median TTP, which was the primary end point, was 3.6 months, 4.0 months, and 3.8 months in the placebo, ZD4054 10 mg, and ZD4054 15 mg groups, respectively, with no statistically significant difference between ZD4054 groups and the placebo (hazard ratio [HR] vs. placebo for the ZD4054 10 mg group: 0.88 [80% CI: 0.71–1.09]; HR vs. placebo for the ZD4054 15 mg group: 0.83 [80% CI: 0.66–1.03]). However, a survival benefit was confirmed after a subsequent analysis after 118 deaths that was previously noticed after 40 deaths (HR vs. placebo for the ZD4054 10 mg group, 0.55 [80% CI: 0.41–0.73], P=.008; HR vs. placebo for the ZD4054 15 mg group, 0.65 [80% CI: 0.49–0.86], P=.052) but the differences in TTP remained nonsignificant. Median OS was 17.3 months, 24.5 months, and 23.5 months in the placebo group, the ZD4054 10 mg group, and the ZD4054 15 mg group, respectively. A comment was made on the discordance between results for TTP and OS as it might be due to the sensitivity of the definition of progression. A phase III trial (ENTHUSE M1C) of zibotentan combined with docetaxel in patients with metastatic CRPC is currently recruiting patients with an aimed target of 1044 patients (clinicaltrials.gov identifier: NCT00617669).

NOVEL TARGETED THERAPEUTICS AND NEW TREATMENT STRATEGIES

Targeting androgen metabolism and novel antiandrogens

Abiraterone acetate

This novel molecule affects CRPC by targeting the cytochrome P450 enzyme CYP17A1 that catalyses two key steroid reactions involving 17α-hydroxylase and C(17,20)-lyase, both of which are critical enzymes in the testosterone synthesis pathway that is also the same target of ketoconazole. Clinical development of this drug has focused on three phase I studies showing that abiraterone can suppress testosterone levels ^{9, 51}. In a phase I trial ⁵² that enrolled 21 patients with CRPC, five escalated doses of abiraterone (250–2000 mg) were used in three patient cohorts. The PSA declines of ≥30% and 50% were observed in 66% and 57% of the patients, respectively. Adverse effects associated with abiraterone use were mostly due to its partial inhibition of adrenal hormone synthesis pathways and a secondary increase in mineralocorticoids that results in hypertension, edema, and hypokalemia. The majority of these side effects, however, could be managed by an administration of corticosteroids and an aldosterone antagonist (eplerenone). A similar phase II trial ⁵³ also reported a >50% PSA decline in 67% of the patients and a >90 PSA decline in 19% of the patients. Furthermore, partial responses according to RECIST (Response Evaluation Criteria in Solid Tumors) were obtained, circulating tumor cell (CTC) counts were decreased, and median TTP was 225 days.

Abiraterone has also been used as a secondary treatment option in patients previously treated with docetaxel and ketoconazole. In a recent presentation of results on 33 men with chemotherapy-naïve CRPC, ≥50% decline in PSA was observed in 55% of the patients, including 47% of patients with prior ketoconazole therapy and 64% of patients without prior ketoconazole therapy ⁵⁴. In another recent phase II trial ⁵⁵, 47 patients with CRPC who were previously treated with docetaxel were enrolled. The PSA declines of ≥30%, ≥50%, and ≥90% were seen in 68%, 51%, and 15% of the patients, respectively. In 8 (27%) of 30 patients with the measurable disease, partial responses according to RECIST were observed and the median TTP was 169 days. A placebo-controlled randomized phase III study (clinicaltrials.gov identifier: NCT00638690) with the aim of securing FDA licensing approval in the post-docetaxel setting is now open to accrual; 1180 patients will be randomized 2:1 for abiraterone acetate plus prednisolone (or prednisone) vs. prednisolone (or prednisone) plus placebo, with a primary end point of OS ⁵⁶. A second phase III study to test the effect of abiraterone on survival when administered in the prechemotherapy setting is being planned.

MDV3100

MDV3100 is a potent, small molecule AR antagonist that blocks nuclear translocation and DNA binding of AR and possesses no agonistic activity ⁵⁷. In preclinical studies, MDV3100 was shown to induce tumor regression significantly in animal models of CRPC ³. In a phase I/II study in 140 patients with CRPC, MDV3100 has shown promising activity. Patients with progressive, metastatic CRPC were enrolled in dose escalation cohorts and antitumor effect was noted at all doses ⁵⁸. In 78 patients (56%), the PSA level was decreased ≥50%. The extent and proportion of patients showing PSA decreases were dose-dependent from 30 to 150 mg per day, but reached a plateau between 150 and 240 mg per day, above which additional antitumor effects were noted. Additionally, soft tissue responses were seen in 22% of patients and bone lesions were stabilized in 56% of the patients. The CTC counts were changed from unfavorable to favorable in 49% of the patients and median TTP was 47 weeks for radiological progression. The maximum tolerated dose for sustained treatment (>28 days) was 240 mg and the most common grade 3–4 adverse event was dose-dependent fatigue (16 [11%] patients), which generally resolved after a dose reduction.

A multinational, double-blind phase III trial (clinicaltrials.gov identifier: NCT00974311) is currently recruiting participants and will randomize 1200 patients with progressive CRPC previously treated with docetaxel based chemotherapy 2:1 to receive either MDV3100 or a placebo.

TOK-001

Although the two agents above are certainly promising, other molecules are in development to address CRPC, also targeting intratumor androgen activity. The TOK-001 is a novel molecule and like abiraterone, inhibits the cytochrome P450c17 step in androgen synthesis ⁵⁹. Moreover, it is a potent blocker of the AR and has actually decreased the amount of AR. Thus, this agent potentially inhibits three critical pathways. A phase I/II trial about the safety and efficacy of TOK-001 in patients with CRPC (clinicaltrials.gov identifier: NCT00959959) is currently recruiting patients.

Immunotherapy

Prostate cancer has not been thought of as a target for immunotherapy previously. However, the natural course of prostate cancer is relatively slow compared to many other cancer types that may allow the immune system necessary time to generate an antitumor response and to overcome immunosuppressive factors. There are currently multiple immunological strategies in different stages of clinical development for prostate cancer. Among those, the options that have generated the most interest in recent years include the GVAX allogenic recombinant whole cell platform, the Sipuleucel-T (Provenge) autologous prostatic acid phosphatase (PAP) loaded dendritic cell product, the Prost-Vac poxviral vector vaccine and immune check-point inhibitors like CTLA-4 (cytotoxic T-lymphocyte associated antigen 4), and programed cell death-1 (PD-1) ⁶⁰.

Sipuleucel-T uses the patient's own dendritic cells isolated via leukopheresis and loaded with PAP antigen ex vivo. Three randomized phase III trials have been conducted in patients with asymptomatic CRPC. D9901 consisted of 127 men with asymptomatic metastatic CRPC and compared sipuleucel-T with the placebo in a 2:1 ratio. The final 3-year follow-up showed a median survival benefit of 4.5 months (25.9 vs. 21.4 months) and a threefold improvement in survival at 36 months for patients who received sipuleucel-T. Subsequently, a similar trial (D9902) of 98 men demonstrated a benefit of 3.3 months. An integrated analysis of both studies showed that sipuleucel-T resulted in a significant survival benefit compared with placebo (HR=1.50, P=.011). In both studies, the vaccine was well tolerated and most of the side effects were transient flu-like symptoms ^{2, 61, 62}. IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) was conducted in 512 patients with OS as the primary end point. The patients were randomized in a 2:1 ratio to receive sipuleucel-T (n=341) or control (n=171). Eligible patients had metastatic disease in the soft tissue and/or bone, with evidence of progression either at these sites or in means of PSA. Exclusion criteria included the presence of liver, lung, or brain metastases; moderate to severe prostate cancer related pain; and the use of narcotics for cancer-related pain ⁶³. The results of this trial were presented at the American Urological Association (AUA) Annual Meeting in 2009 and confirmed a median survival advantage of 4.1 months (25.8 vs. 21.7 months) for patients treated with sipuleucel-T compared to a placebo. The 3-year OS was increased by 38% ⁶⁴. This vaccine has shown the greatest promise to date, and is poised to become the first U.S. Food and Drug Administration (FDA) approved vaccine for advanced prostate cancer ².

The GVAX has drawn attention with its encouraging phase II results that subsequently led to two phase III clinical trials (VITAL-1 and VITAL-2). The first trial compared GVAX with docetaxel and prednisone for 6 months and the second trial compared docetaxel and GVAX with docetaxel and prednisone. Both of the trials were terminated because of unfavorable futility analysis and excessive deaths in the GVAX arm ⁶⁴. A phase II trial of Prost-Vac in 122 men with metastatic CRPC failed to show a difference in the primary end point of progression-free survival against placebo. However, updated 3-year results revealed an OS benefit in the Prost-Vac arm (median survival 25.1 months vs. 16.6 months) and a 44% reduction in the death rate ⁶⁵. A randomized phase III study using docetaxel with or without Prost-Vac as a first-line therapy in CRPC has been planned. Ipilimumab, a human antibody that binds to CTLA-4, blocks its activity, thereby allowing sustained immune response. Two phase I studies have reported clinical activity in CRPC and later, in a phase II trial of ipilimumab alone and in combination with radiotherapy in patients with metastatic CRPC, 22% of patients had PSA declines of ≥50% and the median duration of response was 23 weeks ⁶⁶.

FUTURE DIRECTIONS IN EVALUATING THE STATUS OF THE DISEASE

Circulating tumor cells (CTCs)

Although the metastatic spread typically has been considered a late process in the natural progress of malignant diseases, several studies have shown that immigration of cancer cells to distant sites might be an early event in tumorigenesis ⁶⁷. Moreover, malignant cells can bypass lymph nodes, which serve as a natural barrier and disseminate directly to other organs via circulatory system ⁶⁸. These findings have constituted an area of research for the detection of disseminated tumor cells and CTCs in bone marrow and peripheral blood, respectively. Because bone marrow aspiration is an invasive and inconvenient technique for the patients and not suitable for repeated analysis, recent efforts have particularly focused on detecting CTCs in peripheral blood.

The CTCs can be easily detected by PCR in blood samples anytime during the course and management of the disease and an increased number of CTCs have been found to associate with a high Gleason score and stage ⁶⁹. Additionally, higher CTC counts were found in patients with bone metastasis alone (median 10.5 cells) and in patients with both bone and soft tissue tumor involvement ⁷⁰. Higher CTC count and PSA were correlated with worsening survival and when compared to ≥5 CTCs, <5 CTCs were correlated with improved survival (22.7 vs. 9 months, P=.01). A similar trial evaluating the CTC counts before and after the treatment showed that when patients were grouped as favorable (<5 CTCs) and unfavorable (≥5 CTCs), median OS was found by 21.7 months in the favorable group and by 9.5 months in the unfavorable group ⁷¹. Another trial, which revealed that a baseline CTC count of 5 cells/7.5 mL or more of blood before therapy represents a powerful predictor of a poor OS, supported this finding ⁷². The study of CTC dynamics following treatment revealed that the CTC count predicts clinical outcome better than PSA-based algorithms ⁷³.

Technical limitations of PCR and the need for detecting CTCs with a more standardized method have led to the development of novel technologies. The CellSearch (Veridex) is a device recently approved by FDA for the monitoring of several malignancies including prostate cancer ⁶⁷.

IS PROSTATE SPECIFIC ANTIGEN (PSA) A RELIABLE MARKER AS A PRIMARY END POINT IN CLINICAL TRIALS?

OS is the key end point of phase III trials in CRPC. In phase II trials however, alternative primary end points including rates of PSA decline, tumor and pain responses, or change in bone lesions are used. Assessment of PSA response is widely used to determine the antitumor effect of novel agents quickly. The PSA response may not be the best measure of antitumor activity for all classes of targeted treatment and is not a good indicator of long-term clinical benefit or a validated surrogate for OS in advanced prostate cancer ^{74, 75}. In phase II studies, PFS may be a reliable end point to select promising new agents for phase III trials, but there is still a lack of consensus on how best to define PFS in patients with CRPC ². Neither radiological progression nor PSA progression correlates well with OS alone ⁷⁶. However, if disease progression is defined according to the criteria including standard radiographical measures, PSA level, and pain, PFS can be a good surrogate for OS ⁷⁷.

The Prostate Cancer Clinical Trials Working Group (PCWG2) recently published updated recommendations regarding clinical trial design and clinical end points for investigating new therapies for CRPC ⁷⁸. These guidelines have suggested measuring TTP instead of measuring a response in phase II trials. Disease progression was defined again that was based on changes in PSA level, bone and soft tissue lesions, and symptoms. The PCWG2 definition of PSA progression (a ≥25% increase from nadir and an absolute increase of at least 2 or 5 ng/mL) was independently analyzed and this analysis showed that PSA progression was significantly associated with OS (P<0.001) ⁷⁹. Therefore, one can conclude that PSA progression may be a suitable end point for phase II trials, but for phase III studies a more reliable definition of disease progression is recommended by PCWG2.

CONCLUSION

The treatment of advanced prostate cancer has significantly developed over the past decade. Although ADT remains the cornerstone treatment for advanced and metastatic disease, the majority of the patients will progress within several years and effective treatment methods for CRPC remain limited and do not go beyond palliation and a restricted increase in survival.

Despite its modest benefits, docetaxel chemotherapy still remains as a cornerstone and the standard care for the treatment of metastatic CRPC. Since the approval of docetaxel by the FDA in 2004, no new treatment modality could change our daily practice; however, the number of agents in different stages of development is higher than ever before and many promising agents are in late-stage clinical testing that will hopefully affect the management of patients with CRPC imminently.

Disclosure: The authors declare no conflict of interest.

Keywords

castration-resistant prostate cancer, chemotherapy, immunotherapy, hormonal therapy, targeted therapeutics, vascular endothelial growth factor, androgens

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With the advent of laparoscopy in the late 20th century, urologists and gynecologists are now able to perform abdominal and pelvic surgeries in a minimally invasive manner. Traditional pelvic reconstructive techniques, which were limited to open abdominal operations with large incisions and long hospital stays, are now performed with smaller incisions and occasionally on an outpatient basis. Laparoscopy has provided surgeons with the ability to perform these procedures in a similar fashion to open procedures, albeit through much smaller incisions. Most laparoscopic procedures have less blood loss, and a quicker recovery compared to open surgery. However, in conventional laparoscopy, multiple trocars are required due to the limited degrees of freedom of the instruments and need for triangulation. A two-dimensional view of the surgical field further hampers surgical efforts.

Accordingly, robotic surgery has evolved throughout the last decade and has been able to overcome many of these hurdles encountered by traditional laparoscopy. The Da Vinci robot (Intuitive Surgical, Sunnyvale, California) affords the surgeon with seven degrees of freedom for greater intracorporeal maneuvering. Furthermore, because the robotic system is relatively easy to use, improves optics, enhances magnification, and limits surgeon hand tremor, the Da Vinci has piqued the interest of both the expert and novice laparoscopic surgeon.

Recently, surgeons have pushed the envelope even further. With evolving technology, we have been able to decrease the number of working ports to complete surgery successfully through a single small incision. Originally called “Natural Orifice Transluminal Endoscopic Surgery,” or NOTES, this surgery was performed through a single small incision in a naturally occurring orifice such as the mouth or vagina. More recently, the term “Laparoendoscopic Single-Site,” or LESS surgery has been used to describe these surgeries, which may be performed through a single incision anywhere in the body ¹. When performed in locations such as the mouth, vagina, or umbilicus, these surgeries are essentially “scarless,” leaving the patient without any visible incision (Figure 1).

For the most part, descriptions of the utilization of some of these innovative techniques in the field of female urology and urogynecology have been limited to case reports and retrospective reviews. Nevertheless, it appears that these types of surgical approaches are here to stay and could potentially become the future gold standard. Herein we review the available literature on managing common conditions treated by the female urologist and urogynecologist by laparoscopic, robotic-assisted, and LESS surgery.

SURGERIES FOR URINARY INCONTINENCE

Laparoscopic Burch Colposuspension

The former gold standard for stress urinary incontinence treatment was the Burch colposuspension. In the late 1990s, several reports of laparoscopic Burch colposuspension were published ^2–4. This procedure involved suspending the periurethral fascia on either side to the ileopectineal ligament with a permanent suture.

In a recently published clinical trial, 200 women with urodynamic stress incontinence were randomized to undergo open or laparoscopic Burch procedures ⁵. Outcomes measured were urodynamic stress incontinence at 6 months, postoperative pain, and length of stay. Not surprisingly, laparoscopic colposuspension took longer to perform (87 minutes vs 42 minutes, p<.0001). However, the laparoscopic approach minimized blood loss and postoperative pain (p=.03, p=.02, respectively). The incidence of recurrent stress incontinence was identical in both groups.

Kitchener et al published results of their randomized clinical trial comparing open to laparoscopic Burch colposuspension ⁶. There were 291 patients randomized to the two groups over a 3-year period. The primary outcome was patient satisfaction and negative 1-hour pad tests at 24 months. Using these criteria, the objective cure rate was 70.1% in the open group and 79.7% in the laparoscopic group (p=.096). Interestingly, the subjective cure rate was much lower—with cure rates of 54.6% and 54.9% of patients being satisfied after open and laparoscopic Burch, respectively (p=.389). The authors concluded that laparoscopic Burch is not inferior to open Burch.

A recent Cochrane review evaluated the open and laparoscopic Burch procedure ⁷. While the available literature on the open Burch procedure included 46 trials and nearly 5000 subjects, the authors commented that data on the laparoscopic approach was scarce. Therefore, they concluded that the laparoscopic Burch colposuspension should provide patients with quicker recovery and appears to have equal effectiveness as the open procedure. Regardless, both open and laparoscopic Burch procedures are being largely replaced by the midurethral synthetic sling, due to the long-term success and minimally invasive technique ⁸.

SURGERIES FOR PELVIC ORGAN PROLAPSE

Laparoscopic Sacral Colpopexy

Abdominal sacral colpopexy remains the gold standard therapy for the treatment of apical vaginal prolapse. This procedure involves placement of a strip of polypropylene mesh on the anterior and posterior aspects of the vaginal wall, and suspending this to the anterior longitudinal ligament on the anterior border of the sacrum. Typically, the mesh is retroperitonealized to prevent bowel adhesions or other complications related to intraperitoneal mesh. Laparoscopic sacral colpopexy was first described by Nezhat et al in 1994 ⁹. This original report paved the way for others to evaluate the laparoscopic technique (Figure 2).

In 2005, Ross published his series of 51 women who underwent laparoscopic sacral colpopexy for grade III or IV prolapse ¹⁰. At 1 year, 50/51 women (98%) had a successful outcome, defined as the absence of symptoms and anatomic with grade 0, I, or II prolapse. At 5 years, eight patients were not available for follow-up. Of the remaining 43, 40 (93%) were asymptomatic and deemed cured.

Paraiso et al described their retrospective review of 56 patients who underwent laparoscopic sacral colpopexy and 61 who underwent open sacral colpopexy ¹¹. At a mean follow-up of 13.5 months in the laparoscopic group and 15.7 months in the open group, outcomes including complication and reoperation rates were similar between the two groups. Mean operating time was significantly shorter in the laparoscopic group (218±60 minutes vs 269±65 minutes, p<.0001). Blood loss was less in the laparoscopic group (172±166 mL vs 234±149 mL, p=.04). Perhaps most importantly, hospital stay was significantly shorter (1.8±1.0 days vs 4.0±1.8 days, p<.0001).

Similar results were found in another retrospective review of anatomic and perioperative outcomes during laparoscopic or open abdominal sacral colpopexy ¹². This study compared 43 subjects who underwent the laparoscopic approach, and 41 subjects who underwent an open abdominal approach. Anatomic outcome was similar between the two groups. However, the hospital stay was significantly shorter in the laparoscopic group (35.4 hours vs 63.3 hours, p>.001). Complication rates were comparable between groups; however, unlike the aforementioned study, mean operative time was similar in both laparoscopic and open groups (183 minutes vs 168 minutes, respectively).

Despite the lack of randomized trials between laparoscopic and other techniques, the available literature appears to support the laparoscopic approach as being as effective, with lower blood loss, and decreased hospital stay when compared with the open approach.

Robotic Sacral Colpopexy and Sacrohysteropexy

While laparoscopic sacral colpopexy appears to have equivalent outcomes when compared to open sacral colpopexy, widespread utilization of the laparoscopic technique has not occurred. This is likely due to the need for laparoscopic training when performing laparoscopic sacral colpopexy, as well as the challenge of suturing both the mesh to the vagina and closing the peritoneum over the mesh with traditional laparoscopic instruments. The use of the Da Vinci robot allows the surgeon excellent magnified visualization with increased instrument maneuverability when compared to traditional laparoscopy. These features allow faster suturing, especially to the surgeon without formal laparoscopic training (Figure 3).

The first robotic-assisted laparoscopic sacral colpopexy was reported by Di Marco et al ¹³. In his series of five patients, all had a successful anatomic repair at 4 months follow-up. No complications related to the robotic approach occurred. The same institution published their series of 30 patients who underwent robotic-assisted laparoscopic sacral colpopexy at a minimum follow-up of 12 months (mean 24 months) ¹⁴. Mean operative time was 3.1 hours (range 2.15 to 4.75). All but one patient was discharged home on the postoperative day one. Long-term complications were low; one patient developed a recurrent grade III rectocele, one had recurrent vault prolapse, and two patients had vaginal mesh extrusion. One subject required conversion to an open procedure.

The utilization of the Da Vinci robot for posthysterectomy vaginal vault prolapse has expanded to include women with uterine prolapse. In women who desire uterine-sparing approaches for uterine procidentia, sacrohysteropexy can be performed. The authors have reported on this technique, which includes suturing a strip of mesh to the posterior cervix and attaching the mesh proximally to the anterior longitudinal ligament on the sacrum ¹⁵. Alternatively, anterior mesh may be placed and tunneled through the broad ligament to provide a Y-shape mesh and provide anterior support. In our institution, POP-Q staging was used to determine outcomes in women undergoing sacral colpopexy or sacrohysteropexy. Of 15 women, two (13.3%) were not able to be completed laparoscopically or robotically. Before surgery, the mean POP-Q stage was 3.1, and this decreased to zero postoperatively at 6 months. Mean blood loss was 81 mL (range 50-150 mL) and mean hospital stay 2.4 days (range 1 to 7 days).

There is a paucity of data on long-term outcome data on both sacral colpopexy and sacral hysteropexy. Nevertheless, both procedures appear promising with equal anatomic outcome in the short-term. Whether the uterine-sparing approach can be shown to be equal in efficacy to nonuterine sparing approaches is not known at this time.

Laparoendoscopic Single-Site (LESS) Sacral Colpopexy

Single-port laparoscopic surgery was initially reported in 1998 and was performed for cholecystectomy and appendectomy ^{16, 17}. With these techniques, a single incision is made (typically umbilical) and a specially designed multichannel trocar is inserted. Our institution reported our experience utilizing single-port technology for abdominal sacral colpopexy in four patients ¹⁸. Using curved laparoscopic instruments, we successfully performed the procedure in a mean of 2.5 hours (range 2 to 3 hours) with a mean blood loss of 90 mL.

Following this initial feasibility study, we performed single-port sacral colpopexy on 10 patients, and compared outcomes to laparoscopic sacral colpopexy (n=10) and robotic sacral colpopexy (n=10) ¹⁹. Over a 2.5-year period, 30 women laparoscopic, robotic, or single-port sacral colpopexy for stage II (n=6), stage III (n=23), or stage IV (n=1) prolapse. Twenty-seven women had 6 months follow-up, with all demonstrating excellent apical support and prolapse reduction.

The main drawback in LESS surgery for apical prolapse is the need for numerous suture placement and knot-tying—an extremely challenging technique, even for the trained laparoscopist. As technology evolves, however, LESS techniques will likely become commonplace in hospital settings throughout the world.

Laparoscopic Uterosacral Vault Suspension

Suspension of the vaginal vault to the uterosacral ligaments is a commonly performed procedure at the time of vaginal hysterectomy. This procedure is typically performed via a transvaginal route, as the ligament is readily palpable with intraperitoneal access after the uterine specimen has been removed. One study retrospectively compared their laparoscopic approach to uterosacral vault suspension (n=22) to those who underwent a transvaginal approach (n=96). There were four (4.2%) episodes of intraoperatively recognized ureteral compromise, and six (6.3%) cases of anatomic recurrence in the vaginal approach, compared with no ureteral compromise or anatomic failure in the laparoscopic group. However, the difference was not statistically significant ²⁰.

SURGERIES FOR OTHER PELVIC CONDITIONS

Robotic and Laparoscopic Vesicovaginal Fistula Repair

Nezhat et al described the original case report of using a laparoscopic approach for vesicovaginal fistula repair ²¹. Since then, others have also performed the procedure successfully using tissue interposition flaps such as omentum ^{22, 23}. Like other laparoscopic procedures, it appears that the laparoscopic vesicovaginal fistula repair results in lower morbidity, shorter hospital stay, and a quicker return to recovery when compared with abdominal approaches ^{24, 25}. In one larger series, Sotelo described laparoscopic vesicovaginal fistula repair in 15 patients, 14 (93%) of which were posthysterectomy fistulae ²⁶. Four of these patients had already undergone prior attempts at closure and failed. Repair consisted of cystotomy and dissection of the bladder off of the vagina past the level of the fistula. All patients had a tissue interposition flap placed between the vagina and bladder to aid in success. Mean operative time was 170 minutes (range 140 to 240) and mean hospital stay was 3 days. At a mean follow-up of 26.2 months, all but one (93%) of subjects had no further leakage. Laparoscopic vesicovaginal fistula repairs have also been performed in cases of fistulae due to prolonged obstetric labor. Even though obstetric fistulae typically have extensive tissue necrosis and rather large defects, the laparoscopic approach has proved successful even in these cases ²⁷.

The initial use of the Da Vinci for vesicovaginal fistula repair was reported by Melamud et al ²⁸. The robotic approach to vesicovaginal fistula repair provides the surgeon with excellent magnified views of the deep pelvis—allowing for improved access compared with traditional open abdominal approaches to vesicovaginal fistula repair. The robotic technique involves similar principles of the laparoscopic approach. Suturing the bladder and vaginal defects are easier with the robotic technology. However, the need for steep Trendelenburg positioning can hamper efforts to obtain omentum for tissue interposition unless this is obtained at the beginning of the procedure with pure laparoscopic instruments. Alternatively, many choose to use a flap of peritoneum as an intermediate layer.

The first case series with long-term follow-up was published by Sundaram et al in 2006 ²⁹. He described five patients with vesicovaginal fistula, four of which were due to hysterectomy (one patient with postmyomectomy fistula). Mean operative time was 233 minutes (range 150 to 330) and estimated low blood loss at 70 mL. While the mean hospital stay in this study was 5 days, in the authors’ experience, most patients may be discharged home on the first or second postoperative day. At 6-month follow-up all patients voided well without evidence for fistula recurrence.

Subsequent to the initial report by Sundaram et al, the same authors published their series of robotic-assisted laparoscopic repair of recurrent vesicovaginal fistula in seven patients (not part of the original series) ³⁰. In this series the fistulas were large, with a mean size of 3 cm. Despite significant scarring and the need for extensive lysis of adhesions, the mean operative time for repair in these patients was only 140 minutes (range 110 to 160). When omentum was unavailable, tissue interposition was performed with a local peritoneal flap or sigmoid epiploic appendage. The authors report success in all seven patients, although follow-up was only 3 to 12 months.

LESS for Management of Sling Complications

The authors reported the first use of single-port technology to manage mesh erosions into the urinary bladder ³¹. Traditional approaches to foreign body removal in the bladder involve retropubic operations with an open cystotomy for complete removal of the material and closure. By using LESS, the authors inserted a single-port access system through a 2 cm incision directly into the bladder. After insufflation, the mesh material is resected deep to the detrusor muscle and the defect closed. Currently three patients with polypropylene mesh erosions from retropubic synthetic midurethral slings have been managed successfully with LESS. The mean operative time was 107 minutes (range 71to 155) and blood loss was minimal (mean 83.3 mL). No suprapubic catheters were placed in any of the subjects. Follow-up has been short at a mean of 10.3 months, but all subjects are doing well without any recurrence of mesh erosion.

LIMITATIONS AND FUTURE DIRECTIONS

As with any new technology there are limitations that exist with each of these minimally invasive techniques. Each has its own learning curve, although true learning curves have not been established for robotic, laparoscopic, and LESS female pelvic surgery. At the present time, limitations with LESS surgery relate to instrumentation and surgical training. The use of articulating laparoscopic instruments and the elimination of triangulation are challenges even for the trained laparoscopist. However, as technology evolves, these techniques will become easier to perform and more adaptable within training programs.

CONCLUSION

The literature on minimally invasive techniques for pelvic reconstruction, incontinence surgery and management of bladder-related complications are scarce. Nevertheless, it appears that the use of laparoscopic, robotic, and LESS technology for the management of these common conditions provide patients with significant benefits when compared to traditional open surgical techniques. Urologists and urogynecologists must familiarize themselves with this constantly evolving technology. Further research will determine the continued feasibility and long-term outcomes of these surgeries.

Disclosure: Courtenay Moore is a consultant with Astellas.

Keywords

Laparoscopy, robotics, pelvic organ prolapse, incontinence, stress, surgical procedures, minimally invasive

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The most common primary malignancies associated with metastasis to the adrenal gland include breast, lung, colon, and kidney cancers, as well as malignant melanoma.¹ The frequent use of abdominal imaging in patients with a known primary malignancy has led to an increase in the diagnosis of adrenal masses.² While patients with metastatic disease often present with synchronous metastases to the adrenal gland and other organs, some patients present with an isolated adrenal mass. These patients may benefit from resection of the adrenal gland in an attempt to offer a curative therapy.

Laparoscopic adrenalectomy (LA) was first described in 1992 and has gained popularity for the management of benign adrenal tumors. Compared with open adrenalectomy (OA), LA has been associated with a decrease in postoperative pain, shorter hospital stay, and improved cosmetic results.^3–6 The use of LA for malignancy has been slow to gain acceptance due to concerns regarding the oncologic efficacy of the laparoscopic technique.

A thorough understanding of the biology of metastatic adrenal lesions, as well as the indications for resection and choice of operative approach are critical. In this review, we focus on the diagnosis and surgical management of adrenal metastases including a comparison of laparoscopic and open techniques.

INCIDENCE AND DIAGNOSIS OF ADRENAL METASTASES

In an autopsy review of 1000 patients with a history of a primary malignancy, metastases to the adrenal gland were found in 27% of the cohort.⁷ A retrospective review at one institution found an overall rate of metastatic tumors to the adrenal gland found at autopsy to be 3.1%.² Most patients with adrenal metastases are asymptomatic at the time of diagnosis, though some patients may experience abdominal pain, retroperitoneal hemorrhage, or Addisonian crisis.⁸ A metastatic lesion to the adrenal gland can present at any time, but is often found within the first year after diagnosis of the primary tumor. In one series, the mean time between diagnosis of the primary lesion and diagnosis of the adrenal metastasis was as short as 7 months.²

In most cases, adrenal metastases are discovered with synchronous metastases to other organs, while isolated adrenal metastases are less common.⁹ Rarely, bilateral adrenal metastases can occur. In a case report, Kondo et al ¹⁰ describe a two-stage approach to a patient with hepatocellular carcinoma with synchronous bilateral adrenal metastases. The patient was managed with partial hepatectomy and right adrenalectomy in one setting, followed by left adrenalectomy 3 months later. There was no evidence of disease recurrence during the reported 10-month follow-up period.

It is difficult to compare outcomes of patients undergoing surgery for isolated adrenal metastases versus chemotherapy alone, as these patient groups often differ. However, surgical management for the isolated adrenal metastasis appears to offer improved survival outcomes for appropriately selected patients. When evaluating patients with a solitary adrenal metastasis from nonsmall cell lung cancer (NSCLC), Luketich et al ¹¹ noted increased survival in patients undergoing surgery as compared to chemotherapy alone.

CLINICAL OUTCOMES AFTER ADRENALECTOMY

There are a number of factors that predict overall survival (OS) and disease-free survival (DFS) after adrenalectomy for isolated adrenal metastases. Sebag and colleagues¹² reported that survival was not influenced by the site of the primary malignancy, the size of the lesion, or the completeness of the resection. In contrast, Muth et al ¹³ reported that the primary malignancy does affect survival, with increased mortality in the setting of malignant melanoma and NSCLC. They also found that prior surgery for metastases to other organs negatively impacted patient survival. The role of temporal diagnosis of the lesion in relation to the primary malignancy is controversial. Synchronous lesions may portend a worse prognosis than metachronous lesions, with a longer disease-free interval (DFI) associated with better outcomes.⁹ Similarly, Tanvetyanon et al ¹⁴ performed a literature search of patients presenting with adrenal metastases associated with NSCLC, finding that overall median survival was shorter for the patients diagnosed with synchronous lesions, though at 5 years the survival for both groups was similar (approximately 25%). In contrast, two recent reviews suggest that surgery for metachronous and synchronous lesions may lead to similar outcomes.^{14, 15} Strong et al ¹⁵ also found that the lack of local recurrence and size of the lesion less than 4.5 cm predicted improved survival outcomes.

RADIOGRAPHIC IMAGING

Radiographic imaging is an important component in the work-up of the adrenal mass. A properly performed computed tomography (CT) scan—with and without intravenous contrast—is the initial step of the radiographic evaluation. Malignant lesions can be heterogeneous and have an irregular contour in contrast to adenomas, which often have smooth margins and homogeneous density. These are not reliable predictors of malignant potential and, therefore, additional criteria are used to aid in differentiation.

In general, adenomas are high in intracytoplasmic fat, leading to a lower attenuation on a noncontrast CT scan [<10 Hounsfield units (HU)]. Metastases usually have attenuation values greater than 10 HU on noncontrast imaging due to a lower fat content than adenomas. Approximately 30% of adenomas are fat-poor and, therefore, classification as malignant lesions would be inaccurate based on this quality alone. Vascular perfusion differences can be used to help differentiate metastatic lesions from adenomas. Adenomas often display faster wash-out of enhancement after administration of intravenous contrast when compared to metastatic lesions. In delayed imaging studies, a metastatic lesion can retain higher attenuation values when compared to an adenoma.¹⁶ Lymphadenopathy and local invasion are additional features noted on a CT scan that are more likely found with metastatic adrenal lesions.

Magnetic resonance imaging (MRI) can provide additional information when CT findings are indeterminate. The MRI can reveal small amounts of adipose tissue within lesions and improve the assessment of tissue planes and local invasion into surrounding structures. When evaluating T2-weighted images, malignant lesions often display heterogeneous enhancement and hyperintensity compared to adenomas. The technique of chemical shift MR imaging has shown to have the highest sensitivity as compared with T1, T2, or vascular enhancement in differentiating adenomas from metastases.¹⁶

Positron emission tomography (PET) can be helpful in the diagnosis of adrenal malignancies. The advantages of PET include the ability to image the area of the primary tumor, which can be helpful in cases of an unknown primary lesion and its ability to detect other small metastases. For some primary malignancies such as lung cancer, PET scan has been shown to have both sensitivity and specificity greater than 90% for detecting adrenal metastases.¹⁷ The PET scan is limited in the diagnosis of metastatic lesions originating from a genitourinary primary lesion as many of these primary lesions do not exhibit uptake during a PET scan.

The timing of imaging in relation to surgery may be important as well. Sebag et al ¹² reported their experience with 16 patients undergoing LA for adrenal metastases. Five of the attempted LAs (31%) were converted to an open procedure, with four of the five conversions necessary due to difficulty with dissection. In four of the conversions, the preoperative imaging was at least 2 months old, which may have led to an underestimation of the true tumor burden and extent of disease. Based on their experience, the authors recommend imaging close to the time of surgery.

SEROLOGIC EVALUATION

When an adrenal mass is diagnosed, further serologic testing is necessary to exclude a hormonally functioning lesion. A complete discussion of the metabolic evaluation of adrenal lesions is beyond the scope of this review. However, it is important to note that a pheochromocytoma should be meticulously excluded before proceeding with surgical management. Adler et al ¹⁸ suggest that the incidence of pheochromocytoma in patients with an isolated adrenal mass and a history of cancer is higher than one would expect. In their single-institution experience, 33 patients with a history of malignancy underwent adrenalectomy. Eight patients (24%) were found to have pheochromocytomas. The authors note that while the pheochromocytomas tended to be smaller than metastatic lesions, imaging could not reliably rule out a diagnosis of pheochromocytoma and, thus, a thorough metabolic evaluation is critical in this scenario.

ADRENAL BIOPSY

Adrenal biopsy can have a unique role in those patients with a known primary malignancy as the biopsy results can significantly influence management. When a suspicious lesion is noted on an imaging study, it is often difficult to distinguish primary adrenal carcinoma from a metastatic lesion. In addition, some lesions may have characteristics of benign adrenal masses. A diagnostic adrenal biopsy can change clinical management and direct treatment toward an operative or nonoperative protocol. While biopsy can be very useful in the patient with a known primary malignancy, most authors do not recommend its use to differentiate benign and malignant lesions in patients without a known malignancy.^{19, 20}

Eloubeidi et al ²¹ demonstrated the use of adrenal biopsy to guide clinical management in oncology patients. The authors described a series of patients undergoing endoscopic ultrasound (EUS)—guided fine needle aspiration (FNA) of adrenal masses. All patients included in the study had a known nonadrenal primary malignancy. In patients found to have a malignancy on biopsy, treatment was primarily with systemic chemotherapy, as in many of these cases surgical removal of the primary lesion and the adrenal metastasis would not improve outcomes. In patients with a benign adrenal biopsy, treatment for the primary malignancy was focused exclusively on the primary tumor rather than concurrent metastectomy. If a biopsy had not been performed in these patients, some of these patients may have been subjected to unnecessary surgery. The usefulness of adrenal biopsy varies by series. Eloubeidi et al,²¹ as mentioned above, obtained adequate tissue for evaluation in all cases. Of 277 biopsies performed, Welch et al ²² reported a negative predictive value of 80% and a positive predictive value of 99%. Harisinghani et al ²³ reported on 225 adrenal biopsies in patients with a known primary malignancy. The adrenal masses ranged in size from 2.8 to 5 cm. Forty-one patients (18%) had benign tissue on biopsy, with 13 of these patients (31%) undergoing repeat biopsy. In all cases, the repeat biopsy was negative for malignancy. The adrenal mass was found to be benign in two of the patients that had a postmortem evaluation. Burt et al ²⁴ reported a series of 443 patients with operable nonsmall cell lung cancer (NSCLC), of whom 32 patients had an adrenal mass. If adrenal biopsy indicated benign adenoma, the patient then underwent surgery for the primary lung mass. Mean follow-up in these patients was 44 months, with radiographic confirmation of adenoma in all patients. Patients with a solitary metastatic lesion in the adrenal gland as indicated on biopsy underwent surgery for the lung and adrenal mass. The adrenal mass was found to be a metastatic implant from NSCLC in all cases. While the gold standard for assessing the accuracy of adrenal biopsy would include biopsy followed by surgical removal, this is not performed in many patients with a negative biopsy. As reported in these series, the surrogate data includes long-term radiographic follow-up and tissue diagnosis in select patients undergoing adrenalectomy.

Adrenal biopsy can be performed through an anterior or posterior approach, as well as via an endoscopic, transluminal (EUS-guided) approach. The associated risks with each type of biopsy depend on the course of the needle. During the anterior approach, the pancreas can be injured on the left side and the liver on the right side. In one study, the incidence of clinically apparent pancreatitis was 6% after an anterior left side approach.²⁵ Mody et al ²⁶ found an increased complication rate with an anterior transhepatic approach (12%) compared to a posterior approach. In one patient, hepatic needle-tract metastatic lesions developed after the biopsy. The posterior approach risks damage to the pleura or lung resulting in pneumothorax or hemothorax. Hussain²⁷ described posterior biopsy using a tilted CT gantry to predict the course of the needle and avoid injury to the pleura. Using this technique, diagnostic material was obtained in 85% of the biopsies and no complications were encountered. The final approach utilizes endoscopic instruments and ultrasound guidance for transluminal (gastric or duodenal) adrenal biopsy. Most EUS-guided biopsies reported in the literature were performed on the left side, where the only organ traversed is the gastric wall, though biopsy can also be performed on the right side. DeWitt²⁸ reported two cases of right-sided EUS-guided FNA of the adrenal gland with no complications. Quayle et al ²⁰ pointed out the hazards of adrenal biopsy, though the report focused primarily on patients with no known primary malignancy. In this study, complications occurred in 14% of the patients including liver hematoma, duodenal hematoma, and hemothorax. They also highlighted the importance of biochemical evaluation of the mass before proceeding with biopsy to rule out the presence of a pheochromocytoma. In this series, 45% of the patients referred to their practice underwent biopsy before biochemical evaluation was complete.

In summary, adrenal biopsy can be a useful tool to guide clinical management in patients with a known primary malignancy. This is especially true in patients that would not be surgical candidates for the primary tumor if the adrenal lesion represented metastatic disease. Before considering adrenal biopsy, the patient should undergo a complete metabolic evaluation to confirm the absence of a pheochromocytoma.

MANAGEMENT OF ADRENAL METASTASES

The finding of an adrenal metastasis necessitates a multidisciplinary evaluation to determine whether the patient is an appropriate surgical candidate. Patients with multiple sites of metastases or extensive tumor burden may be best managed with nonsurgical therapies.

Several series support surgical management of the well-selected patient with a solitary adrenal metastasis. These studies include patients with nonsmall cell lung cancer (NSCLC),^{11, 29} renal cell carcinoma,^{30, 31} and other malignancies. Tanvetyanon et al ¹⁴ reviewed the literature for outcomes of patients with NSCLC with a metastatic lesion in the adrenal gland. They found that patients with synchronous metastasis had less favorable outcomes when compared to patients with metachronous metastasis. When managed with adrenalectomy, both groups of patients had 5-year survival estimates of approximately 25%. In reviewing several series of patients undergoing adrenalectomy in the setting of metastatic disease, Mitchell and Nwariaku¹⁹ found that surgical management appeared to improve outcomes. However, the authors point out that the patients in these series were well selected and include mostly patients with melanoma and NSCLC, and operative management may not be appropriate for all patients. Mittendorf et al ³² reported on survival in melanoma patients with metastatic disease to the adrenal gland. Twenty-two of the 145 patients with adrenal metastases underwent surgery, with improved survival outcomes in surgically managed patients compared to nonoperative patients. In general, patients with solitary metastases, lengthy disease-free interval after initial diagnosis, and smaller tumor size respond better to surgical management than patients without these features.⁸

Patients with metastatic renal cell cancer (RCC) to the adrenal gland represent a well-studied cohort of patients. The role of prophylactic adrenalectomy at the time of nephrectomy or partial nephrectomy has been controversial, with current evidence suggesting radical nephrectomy without adrenalectomy is acceptable in many cases. In a series of patients undergoing partial nephrectomy (PN) for RCC, Lane et al ³³ found that survival did not differ between patients undergoing PN with or without adrenalectomy. Similarly, O'Malley et al ³⁴ reviewed the literature and found the incidence of ipsilateral adrenal involvement to be 1–5% and concluded that prophylactic adrenalectomy should be performed only in high-risk patients. Higher risk status was associated with increasing size of the lesion, increasing T (Tumor) stage, multifocality, and venous thrombosis. Kuczyk et al ³⁵ reviewed the records of patients undergoing nephrectomy with adrenalectomy for a renal mass. The incidence of metastatic lesions within the ipsilateral adrenal gland was 3.3%. Risk factors for adrenal metastases in this study included the presence of distal metastatic lesions, vascular invasion within the renal tumor, and multifocal RCC within the kidney. The authors concluded that routine adrenalectomy is not indicated if preoperative radiographic studies are normal.

In contrast, ipsilateral adrenalectomy can offer superior survival outcomes in patients with preoperative evidence of a single synchronous metastatic lesion in the ipsilateral adrenal gland. Kuczyk et al ³⁶ reported a series of patients undergoing radical nephrectomy for RCC. Those patients with a solitary adrenal metastatic lesion had similar survival outcomes compared to patients with organ-confined disease. In conclusion, in low risk patients without radiographic evidence of an ipsilateral adrenal metastatic lesion, adrenalectomy at the time of nephrectomy should not be performed. Higher risk patients and patients with a renal mass and radiographic evidence of a metastatic lesion to the adrenal gland should be offered adrenalectomy at the time of PN or radical nephrectomy.

OPEN VERSUS LAPAROSCOPIC ADRENALECTOMY

Earlier reports on the benefit of adrenalectomy for metastatic disease focused on open adrenalectomy (OA). The routine use of laparoscopic surgery in this setting has been extensively debated. Critics of laparoscopic adrenalectomy (LA) note concerns regarding the ability to achieve adequate surgical margins, the potential for trocar site recurrences, as well as the risk of carcinomatosis via spread of tumor cells by the CO₂ gas used to create the pneumoperitoneum. Many of these reservations originate from early case reports of local recurrence and peritoneal metastases in patients operated on for unsuspected adrenal cortical carcinoma.³⁷ A recent review of the literature regarding adrenal cortical carcinoma by McCauley and Nguyen³⁸ showed that local recurrence rates and incidence of peritoneal metastasis was similar for open and laparoscopic approaches. The authors suggest that avoidance of tumor violation or spillage coupled with the standard use of laparoscopic specimen bags can avoid the higher rates of port site and peritoneal metastasis that led to the adverse results in the initial reports. Recent series report positive surgical margin rates that are similar between OA and LA.¹⁵ Some authors suggest that a hand-assist laparoscopic approach may be helpful in some cases to allow palpation of the tumor and tumor bed and perhaps improve the surgeon's ability to resect larger masses.^{9, 39}

The role for open surgery in cases of adrenal metastases is strongest in patients in which preoperative imaging suggests local invasion into surrounding structures. Other indications for open surgery include large adrenal masses (>9 cm), presence of a vena caval thrombus, or significant lymphadenopathy. Relative contraindications for laparoscopic adrenalectomy include extensive adhesions from prior surgery, morbid obesity, uncorrected coagulopathy, and cardiopulmonary disease that precludes hypercapnea that is associated with pneumoperitoneum. These cases must be evaluated on an individual basis, and the surgeon's experience and comfort level must be taken into consideration. While LA may be a feasible approach for many adrenal metastases, a low threshold to convert to open surgery should be maintained.¹⁵

The incidence of conversion to open surgery varies among series. Kirshtein et al ⁴⁰ reported conversion in one case in their series (7%), during which difficulty with tumor dissection was encountered. Muth et al ¹³ reported a higher conversion rate of 33%, citing technical challenges as the reasons for conversion. Sebag et al ¹² describe five conversions from LA to OA (31% incidence). In four of the five conversions, the preoperative imaging had been completed at least 2 months before the planned surgery. Four of the conversions were due to difficulties with dissection, which may have been due to interval increase in the size and complexity of the lesion. As a result, the authors advocate a short time interval between imaging and surgery in order to fully appreciate the complexity of the procedure and appropriately choose LA or OA.

ABLATIVE THERAPIES: CRYOABLATION AND RADIOFREQUENCY ABLATION

Cryoablation has been used as a surgical alternative for the treatment of tumors in many tissues including the prostate, lung, breast, pharynx, liver, and kidney.^41–46 The safety and efficacy of cryoablation in destroying adrenal tissue in the canine model has been demonstrated.⁴⁷ While the exact mechanism of cellular destruction in the adrenal gland remains to be fully elucidated, cryoablation can be performed in a controlled and reproducible manner. Further investigation is necessary to understand the long-term effect of adrenal cryoablation.

Radiofrequency ablation has recently been applied as a treatment modality for malignant lesions in a number of locations including the liver, spleen, lung, bone, breast, prostate, and kidney.^48–52 The few reports of radiofrequency application to adrenal tissue have been for cases of metastatic adrenocortical carcinoma.

Mayo-Smith and Dupuy⁵³ recently reported results from CT-guided radiofrequency ablation in 11 patients with metastatic lesions of the adrenal gland. The mean tumor size was 3.9 cm and all procedures were carried out with intravenous sedation. The majority of the patients were treated on an outpatient basis. Two patients (19%) had enhancement of residual tissue on follow-up imaging suggesting residual tumor. The mean length of follow-up was 11.2 months. The utility of this procedure for adrenal metastases requires further investigation in order to assess its long-term durability.

OPERATIVE TECHNIQUE FOR LAPAROSCOPIC ADRENALECTOMY

Standard preparation for laparoscopic surgery is necessary, including appropriate positioning of the patient and perioperative antibiotics. The two most commonly used laparoscopic approaches to the adrenal gland are the transperitoneal and retroperitoneal approaches. The transperitoneal approach offers more working space and is more familiar to most surgeons. Disadvantages include an increased risk of ileus, adhesion formation, and injury to intraperitoneal viscera. The retroperitoneal approach, while providing the most direct route to the adrenal gland, can be beneficial in patients with extensive intra-abdominal adhesions. However, this approach is not familiar to many surgeons and offers considerably less working space. The technique of LA for metastatic lesions is similar to standard LA for functioning or nonfunctioning adrenal adenomas and has been described previously.⁵⁴

RESULTS OF LAPAROSCOPIC ADRENALECTOMY FOR ADRENAL METASTASES

Several authors have recently reported on their experience with laparoscopic adrenalectomy in the setting of metastasis, with a focus on determining which patients may benefit from laparoscopic versus open surgery. The first group to report their experience with a significant number of LAs for malignancy was Moinzadeh and Gill³⁷ in 2005, in which they described 33 LAs for malignancy of which 26 patients had nonadrenal primaries. At median follow-up of 26 months, 52% of patients were alive, 42% were disease free, and cancer specific survival was 53% at 42-months median follow-up. Tumors ranged in size from 1.8 cm to 10 cm. Seven patients (23%) experienced a local recurrence. Two of these recurrences were in the adrenal cortical cancer group and five in the metastatic group. Of note, only four patients (13%) had minor complications. The authors report that their survival estimates compared favorably to other published series of OA.

Another series compared the outcomes of eight patients undergoing LA for metastatic lesions.⁵⁵ The authors noted that operative time, blood loss, and length of hospital stay were similar to their cohort of patients undergoing LA for benign adrenal masses. There were no conversions to open surgery and at a median follow-up of 20 months, 88% of the patients were still alive.

The largest recent series describing a cohort of LAs was performed by Castillo et al ¹ The authors performed 34 LAs in 32 patients for suspected adrenal metastasis. Patients with tumors >10 cm, evidence of periadrenal infiltration, caval thrombus, or locoregional lymphadenopathy were excluded from a laparoscopic approach. Of the 34 glands resected, 22 (64.7%) contained malignancy upon pathological analysis, with a mean tumor size of 5.1 cm. The mean survival time for patients with malignancy was 26 months. There were two (9.1%) positive margins and no open conversions or port site problems were noted.

Another series of LA for adrenal metastases reported the outcomes of 16 patients with primary malignancies including lung cancer, melanoma, mesothelioma, rhabdomyosarcoma, colon cancer, and renal cell cancer.¹² The conversion rate to open surgery was 31%, and in four of these five patients the imaging had been performed at least 2 months before surgery. The authors felt that the tumor burden had increased significantly during that time period, contributing to the need to convert to open surgery. Median overall survival in this cohort was 23 months and was not influenced by the primary site of malignancy, whether the lesion was metachronous or synchronous, the size of the lesion, and the completeness of the resection.

Robot-assisted partial adrenalectomy has been described in a patient with metastatic renal cell carcinoma.⁵⁶ This patient underwent adrenal-sparing radical nephrectomy and developed an isolated adrenal metastasis in the ipsilateral adrenal gland. After excision of the ipsilateral adrenal, he subsequently developed a contralateral isolated adrenal lesion. This mass was managed with robot-assisted laparoscopic partial adrenalectomy. Pathology of this lesion also revealed metastatic renal cell carcinoma. Postoperatively the patient did not require hormonal supplementation. Intermediate and long-term oncologic follow-up was not described in the report.

COMPARATIVE STUDIES OF LAPAROSCOPIC AND OPEN ADRENALECTOMY

A number of series compare the outcomes of OA and LA. These comparisons are challenging as patients undergoing LA often have different tumor characteristics when compared to patients undergoing OA.

A recent series compared the outcomes of 31 attempted LAs to 63 OAs over an 11-year period.¹⁵ Four patients (13%) required conversion from LA to OA. Median survival did not differ between the two groups. The LA group experienced significantly lower operative time, length of stay, estimated blood loss, and total number of perioperative complications. Microscopic margin rate was similar in the two groups. The authors further analyzed the subgroup of patients with tumor size less than 4.5 cm, finding similar benefits in terms of operative time, length of stay, blood loss, and complications.

Adler et al ⁵⁷ recently compared eight patients who underwent OA to nine patients who had LA for metastatic lesions. The mean size of the adrenal mass in the LA group was 4 cm and for the OA group the size was 8.8 cm. Laparoscopic adrenalectomy was associated with decreased estimated blood loss, fewer complications, and shorter length of hospital stay. At a total combined follow-up of 97 months for all patients, there were no trocar site metastases in the LA group. There were no statistically significant differences in survival between the two groups, although the median follow-up of both groups was slightly over 1 year.

Finally, Kirshtein et al ⁴⁰ reported outcomes of patients undergoing OA and LA, excluding patients with synchronous metastases. The operative time was similar between the two groups, but the length of hospital stay and the estimated blood loss was less in the LA group.

CONCLUSIONS

Adrenal metastases occur in the setting of a number of malignancies and in some cases surgical removal of the mass can improve survival outcomes. While traditionally OA has been offered to those patients who are surgical candidates, recent series have validated LA as a treatment option. For larger tumors or advanced local disease, an open approach may be a better option. While many recent series lack longer term follow-up, patients undergoing LA appear to have similar oncologic outcomes as patients undergoing OA. The decision to surgically remove an adrenal mass and the type of surgical approach remains an individualized decision, taking into account the patient's clinical status, tumor characteristics, and the surgeon's expertise.

Disclosure: The authors declare no conflict of interest.

Keywords

adrenal gland, adrenalectomy, metastasis, laparoscopic, cryotherapy, radiofrequency ablation

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The prognosis for metastatic castrate-resistant prostate cancer (mCRPC) is limited, with a median survival without treatment of about 12 months. However, recent studies have evaluated the efficacy of various cytotoxic compounds in improving these statistics. Taxanes, in particular docetaxel, have demonstrated efficacy and are the therapeutic standard. Docetaxel was approved in combination with prednisone on the basis of results from the phase III TAX 327 study, which showed superior overall survival for the combination compared with mitoxantrone and prednisone ¹. The combination of docetaxel and estramustine has also demonstrated improved progression-free and overall survival compared with mitoxantrone and prednisone in patients with mCRPC ^{2, 3}; however, the value of this addition has not yet been established fully. Epothilones, a new cytotoxic class, have also demonstrated benefit in terms of objective response and progression time, in particular with the combination of ixabepilone and estramustine in a phase II study ⁴; but new compounds that impact overall survival are still needed for the treatment of advanced prostate cancer.

Sipuleucel-T, an autologous active cellular immunotherapy, has shown evidence of efficacy, with a 22% reduction in the risk of death reported in men with mCRPC and a median survival of 25.8 months ⁵. This agent was recently approved by the FDA for the treatment of asymptomatic or minimally symptomatic metastatic CRPC patients. Also, promising results from phase III studies have been recently presented at the American Society of Clinical Oncology and European Society for Medical Oncology Annual Meetings. In the phase III CALGB 90401 study, an addition of bevacizumab to docetaxel had a positive impact on progression-free survival, objective response, and PSA decline, but overall survival was not significantly prolonged ⁶. Furthermore, cabazitaxel demonstrated a statistically and clinically significant improvement in overall survival compared with mitoxantrone and prednisone in a study of mostly symptomatic patients, making it a potential new therapeutic option for mCRPC after failure of docetaxel ⁷. Finally, abiraterone acetate demonstrated a longer median overall survival compared with the placebo in a large phase III trial in patients who had progressed after chemotherapy, half of whom were symptomatic (14.8 months vs 10.9 months; hazard ratio [HR] 0.646; P=.0001) ^{8, 9}.

Other agents, such as ZD-4054 (a receptor inhibitor of endothelin 1) ¹⁰ and denosumab (which targets RANK-ligand) ¹¹ have demonstrated effectiveness for the treatment of advanced prostate cancer in phase I and II trials.

Despite this encouraging therapeutic progress, there are often situations in which these treatments are ineffective. Among the different molecular mechanisms behind the transition from androgen-dependence to androgen-independence, the acquisition of a neuroendocrine phenotype is probably the main cause of treatment failures. This article summarizes the different therapeutic options currently available that target the neuroendocrine transformation of prostate cancer.

NEUROENDOCRINE CELLS IN THE PROSTATE

The prostate is composed principally of mucus-secreting and basal cells, but neuroendocrine cells are also present in normal prostatic tissue, particularly in the acini and excretory ducts. Neuroendocrine cells are also observed in hyperplastic, intraepithelial and malignant lesions ¹². Immunohistochemistry enables neuroendocrine cells to be detected and their involvement in prostatic tumor disease to be studied, whereas conventional microscopic examination usually fails to identify them ¹³.

The term neuroendocrine differentiation encompasses tumors composed exclusively of neuroendocrine cells (small cell carcinomas and very rare carcinoid-like tumors) and, more commonly, conventional prostatic adenocarcinomas with a focus on neuroendocrine cells. In this article, we focus on neuroendocrine differentiation in adenocarcinomas. This focal neuroendocrine differentiation is very often characterized by clumps of neuroendocrine cells dispersed among a more abundant cancer cell population, and is now known to play a role in the pathogenicity and progression of prostate cancer, particularly at the onset of the castrate-resistance phase ¹⁴.

The characteristics of neuroendocrine cells are very different from the other cell types in the prostate. One of the main features is the presence of neuropeptide-rich granules, such as calcitonin, parathyroid hormone-related protein (PH-RP), chromogranin A (CgA) the most sensitive and widely used marker, serotonin, neuron-specific enolase (NSE), bombesin, somatostatin, and vascular endothelial growth factor ¹⁵. In addition, neuroendocrine cells are nonproliferative, as they are found in the G0 phase of the cell cycle ¹⁶ and they overexpress survivin, an antiapoptosis protein ¹⁷. Finally, these cells do not possess androgen receptors, which is probably the origin of the hormone resistance.

Despite all these new findings, the role of neuroendocrine cells in the progression of prostatic cancer has yet to be established. Several in vitro studies have demonstrated transdifferentiation of prostate cells toward a neuroendocrine phenotype in response to interleukin-6 ¹⁸, cyclic AMP, epinephrine (as an inducer of cyclic AMP), androgen deprivation, and genistein ¹⁹. All these factors are said to induce neuropeptide production by neuroendocrine cells that, at the same time, would stimulate progression to a castrate-resistant disease.

IMPORTANCE OF NEUROENDOCRINE BIOMARKERS IN PROSTATE CANCER

Benign and malignant neuroendocrine cells in prostate tissue can be identified by immunohistochemistry using antibodies directed against neuropeptides produced by this type of cell, including NSE, CgA, 5-hydroxytryptamine, somatostatin, human chorionic gonadotropin, thyroid-stimulating hormone, PH-RP, and calcitonin. The majority of these neuropeptides can also be measured in the blood by immunoassay techniques.

One study evaluated the differences in an expression of CgA and NSE as serum markers in patients with normal, premalignant, or primary or metastatic cancerous prostate tissue. The results showed higher CgA levels at more advanced stages of the disease. Contrastingly, despite overall high NSE levels, no differences were found between the disease stages. More specifically, CgA was increased in 36% of patients with metastatic disease at a hormone-sensitive stage versus 45% at the castrate-resistant stage. In addition, high NSE and CgA levels were predictive of a poor prognosis in patients in the castrate-resistant phase ²⁰.

A further study determined the importance of serum CgA levels as markers of neuroendocrine differentiation for monitoring prostate cancers by comparing them with total prostate-specific antigen (PSA), prostatic acid phosphatase, NSE, and testosterone levels. The results showed an increase in CgA and NSE in 62% and 29% of castrate-resistant patients, respectively. For patients with cancer in the hormone-dependent phase, serum CgA was raised in 59% of patients; conversely, there was no increase in NSE in this group. The study also demonstrated that, in combination with PSA, measurement of CgA appears to be an important marker for monitoring prostate cancer patients ²¹.

Other studies in patients with CRPC have shown that a high CgA serum level constitutes an independent factor predictive of poor prognosis ²². In patients whose disease is in the hormone-dependent phase, the role of this factor is not clear, with contradictory results obtained in several studies ²³. In 2007, a study evaluated the importance of the presence of tissue CgA in biopsies as a predictive biomarker of progression to castrate resistance. After a univariate analysis, expression of CgA in <30 or ≥30% of tumor cells was significantly associated with a shorter time to castrate-resistant disease (HR 2.0; 95% CI 1.3–3.1 and HR 6.0; 95% CI 2.7–12.9, respectively). These results were also valid in the multivariate analyses after adjusting for Gleason score, PSA levels, and disease stage (HR 1.7; 95% CI 1.0–2.8 and HR 3.9; 95% CI 1.7–9.0, respectively). However, serum and tissue expression of CgA was inversely correlated with overall survival ²⁴.

The incidence of raised serum CgA levels has also been studied in a group of 89 metastatic patients versus 264 nonmetastatic patients. Both PSA and CgA levels were determined in all cases. Two types of cutoff for high CgA levels were used: >60ng/mL and >90ng/mL. In patients with nonmetastatic disease, 35% of patients exhibited CgA levels >60ng/mL and 6.4% had levels >90ng/mL; whereas in the metastatic patients, 100% had levels >60ng/mL and 69.7% >90ng/mL. The authors concluded that there was a significant elevation of CgA in prostate cancer using a cutoff of 60ng/mL in nonmetastatic patients and a cutoff of 90 ng/mL in metastatic patients ²⁵.

SOMATOSTATIN ANALOGS IN THE TREATMENT OF PROSTATE CANCER

Somatostatin and its analogs: general considerations

Somatostatin is a peptide hormone composed of 14 amino acids. It is found in pancreatic cells as well as in hypothalamic cells and other digestive cells. It is a hormone with a paracrine and autocrine action and possesses a growth suppressing action. Somatostatin analogs have been developed, including octreotide (Sandostatine) and vapreotide (RC-160). In addition, five different somatostatin receptors (SSTR) have been identified. Use of the original somatostatin revealed a high affinity for all receptor subtypes. The analogs, on the other hand, have a preference for the type 2 and 5 receptors; vapreotide also acts on the type 3 receptor ²⁶.

Somatostatin analogs in prostate cancer

Somatostatin analogs have demonstrated growth inhibition of experimentally developed prostate cancers by a direct action via blockade of the somatotropin receptors, but also indirectly by reducing hepatic insulin-like growth factor 1 secretion (Figure 1). Regardless of the mechanism, use of somatostatin analogs has demonstrated beneficial effects in the treatment of cancers ²⁷. A few cases of poor response to these treatments might be explained by the reduction in some patients of the expression of the type 2 receptor gene, which has a higher affinity for this type of analog ²⁸. Table 1 lists studies describing the response of PSA and overall survival with the use of somatostatin analogs in prostate cancer.

In 2001, a first study evaluated the efficacy of the combination of triptorelin, a luteinizing hormone-releasing hormone (LHRH) analog, with dexamethasone and lanreotide, a somatostatin analog, in patients with mCRPC. These patients had relapsed after a combined androgen blockade (LHRH analog plus antiandrogen) followed by withdrawal of the antiandrogen. Eleven patients with diffuse metastatic bone lesions received treatment with oral dexamethasone (at doses of 4mg daily for the first month, 2mg daily for the second month, then 1mg daily thereafter). In addition, lanreotide (30mg intramuscularly every 14 days) was administered in combination with triptorelin (3.75mg intramuscularly every 28 days). The PSA levels, alkaline phosphatase levels, performance status, and course of bone pain were evaluated during treatment. In the study, 10 of the 11 patients (90% of patients; 95% CI 58.7%–99.8%) exhibited a sustained objective clinical response (including a reduction in PSA ≥50% in 8 patients, 72.7%; 95% CI 39%–94%). All patients reported a significant and sustained improvement in bone pain (for a median of 13 months; 95% CI 12–14 months) and performance status (median duration 19 months; 95% CI 13–25 months) without treatment-related side effects. Median progression-free survival was 7 months (95%; CI 4–10 months) and median overall survival 18 months (95%; CI 16–20 months) ²⁹.

Another study was conducted in 2003 according to the same design as Koutsilieris's in 2001. This included 10 patients with progressive stage D3 prostate cancer with bone metastases after hormone therapy. Nine patients (90%; 95% CI 55.5%–99.8%) exhibited an overall objective clinical response, defined by a reduction in PSA greater than 50% (median 87.1%). Normalization of PSA (less than 4 ng/mL) was observed in three patients. All patients exhibited a sustained and significant improvement in bone pain (median duration 17.5 months) and performance status (median 18 months) without major side effects. This study also evaluated the time course of serum CgA levels and revealed a significant reduction during the administration of treatment and at the time of treatment response (median 38.4%, P<.0001) ³⁰.

In 2004, a prospective phase II study compared the efficacy of the combination of a somatostatin analog (lanreotide 30mg intramuscularly every 14 days) with dexamethasone (4mg daily then progressive reduction to 1mg) versus treatment with chemotherapy (estramustine at doses of 140mg three times daily and etoposide 100mg orally for 21 days). Eighteen patients were evaluated in the first group versus 20 in the chemotherapy group. A PSA response (greater than 50% reduction) was observed in 44% of patients from the first group and 45% from the second. The difference was not statistically significant. A partial clinical response was observed for 30% and 29% of patients, respectively, which again was not statistically significant. The improvements in performance status and on the pain scale were not marked in either group. Overall survival was similar for the two groups (18.8 months for chemotherapy and 18 months for the somatostatin analog), with respective times to progression of 4 months versus 6 months overall and 7.7 months versus 8 months for the subgroup of PSA responders. The study, therefore, showed no difference in efficacy between the use of chemotherapy and somatostatin analogs ³¹. Nevertheless these studies are not powered enough to allow any firm conclusions to be made regarding the efficacy of these agents.

Finally, the association between somatostatin analogs and docetaxel has also been evaluated in vitro using PC3 and DU-145 prostate cell lines that express SSTR2 and SSTR5. The combination of docetaxel and octreotide resulted in significant synergistic cytotoxic activity and apoptosis, which was dose- and time-dependent. The combined treatment also resulted in significantly less secretion of stem cell factor and platelet-derived growth factor-AB in PC-3 cells, and transforming growth factor-β and basic fibroblast growth factor in DU-145 cells, than in untreated controls ³². Another study demonstrated that combined treatment with docetaxel and lanreotide inhibited PC3R (PC3 cell line made resistant to docetaxel) cell growth in vitro through an enhanced induction of cell death, compared with treatment with either agent alone. This inhibition was particularly evident in PC3R cells, suggesting that lantreotide could act as a P-glycoprotein inhibitor ³³.

Overall, this evidence indicates that, somatostatin analogs combined with docetaxel might provide a rational treatment option for mCRPC, not only by direct inhibition of cell proliferation but also by inhibiting the secretion of growth factors.

THE NEW CHEMOTHERAPY REGIMENS FOR PROSTATE CANCERS

For patients with progressive metastatic prostate cancer on hormone therapy, docetaxel-based chemotherapy constitutes an effective treatment for the improvement of symptoms and prolongation of overall survival ¹. However, new knowledge about neuroendocrine transformation of prostate cancer as a strong presumption of hormone resistance opens the way to new therapeutic options in terms of cytotoxicity.

Current treatment of neuroendocrine tumors in general

Neuroendocrine tumors represent a heterogeneous group of tumors that can emanate from several primary sites and are manifested in different clinical or laboratory syndromes with different degrees of aggression and prognosis. Histopathological classification (well, moderately, or poorly differentiated), CgA levels, Ki-67 index, patient age, tumor volume, disease stage, and primary site of the tumor constitute important prognostic factors for patients with neuroendocrine tumors ^{34, 35}. Neuroendocrine tumors can be well-differentiated slow proliferation tumors (carcinoids) or small cell carcinomas that are fast growing, with a high Ki-67 proliferation index.

Previous therapeutic options for the treatment of irresectable neuroendocrine tumors, regardless of primary site, have included simple observation and close surveillance of patients, as well as interferon- or somatostatin analog-based therapies ³⁶. When it was found that poorly differentiated neuroendocrine tumors had similar aggressive progress and prognosis to small cell lung cancer (with a median survival of 6 months without treatment) ³⁷, retrospective evaluation of the efficacy of cisplatin- and etoposide-based treatment was conducted in 53 patients with well (n=12) or poorly (n=41) differentiated neuroendocrine tumors. An objective response rate of 41.5% (4 complete responses and 13 partial responses) was found in patients with poorly differentiated tumors, with a median survival of 15 months and a median progression-free survival of 8.9 months. The chemosensitivity of poorly differentiated neuroendocrine tumors to the cisplatin-etoposide combination is, therefore, confirmed despite the continued poor prognosis of these patients ³⁸.

Adaptation to castrate-resistant prostate cancers

A phase II study, published in 2007 (Table 2), investigated the efficacy and toxicity of a chemotherapy protocol combining docetaxel with cisplatin (the latter on the grounds of its efficacy against neuroendocrine tumors in general) in patients with mCRPC with circulating neuroendocrine markers. The study was conducted in 41 patients treated with 75mg/m2 of docetaxel and 75mg/m2 of cisplatin every 3 weeks for a maximum of 6 cycles. Thirteen patients (33%) exhibited a neuroendocrine response with a median response duration of 4 months and the PSA response rate was 48%. A clinical benefit was observed in 45% of patients, with an improvement in pain in particular. The objective response rate was 41% in 29 patients with measurable metastases. Five patients discontinued treatment because of toxicity, particularly asthenia and sensory neuropathy. Median survival was 12 months. The results are therefore unencouraging ³⁹.

The combination of carboplatin and etoposide as a second-line treatment has also been shown to be quite effective and well tolerated, with clinical activity demonstrated for tumors both with and without neuroendocrine features. This prospective study evaluated 40 patients with mCRPC that had received and progressed on therapy with docetaxel (with or without estramustine). A PSA response (a decline greater than 50%) was obtained in nine patients (23%) and median durations of progression-free and overall survival were 2.1 months and 19 months, respectively. A clinical response, characterized by an improvement in pain, was observed in 15 patients (53%). Hematological toxicity was reported, with grade 3–4 anemia observed in 25% of patients and febrile neutropenia in 2% of patients ⁴⁰. Results of these two studies are showed in Table 2.

CONCLUSIONS

Recent progress has been achieved in prostate cancer with a new understanding of the transition from the hormone-dependent to castrate-resistant phases, particularly in respect of the role of the acquisition of a neuroendocrine phenotype. This has allowed an enlargement of the therapeutic armamentarium for managing advanced stages of the disease.

On the one hand, somatostatin analogs have demonstrated inhibition of cell growth and could provide both symptom relief and survival benefits in patients with CRPC. Interesting results have been obtained with somatostatin-based combination therapies and have led to the concept of antisurvival therapy for prostate cancer as a component of anticancer treatments. On the other hand, new combinations of chemotherapy regimens, such as cisplatin and etoposide, have shown a clinical benefit in neuroendocrine tumors and are well tolerated, but no benefit on overall survival has yet been reported.

In practice, there are no validated criteria for deciding when to start a neuroendocrine treatment in CRPC. Neuroendocrine treatments could possibly be considered in patients resistant to docetaxel or for a rapidly progressing disease with an increase of NSE and CgA often discordant with PSA rate. In other cases therapies such as cabazitaxel, and abiraterone that have been validated in phase III studies, should be considered as the most suitable second-line treatment after docetaxel.

However, despite these recent advances in understanding, the treatment of CRPC continues to represent a challenge. Interpretation of current neuroendocrine data is difficult for several reasons. Most clinical studies are based on retrospective data and isolated cases reports; any prospective data are from uncontrolled studies with limited sample size. Also, study endpoints are often not well defined. Improved identification of tumor somatostatin receptors, best use of markers like CgA and, eventually, the determination of PTEN status would help to identify neuroendocrine transformation in patients. Validation of neuroendocrine therapies and the definition of optimal chemotherapy combinations and dosing strategies in randomized, controlled phase III studies are necessary, as well as evaluation of predictive biomarkers in order to determine those patient populations that will benefit most from these therapies.

Disclosure: The authors declare no conflict of interest.

Acknowledgment: Native English editing of the manuscript was performed by Andrea Bothwell of InScience Communications.

Keywords

castrate-resistant prostate cancer, neuroendocrine, chromogranin A, somatostatin, cisplatin, docetaxel, etoposide, carboplatin

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Prostate cancer is the most common cancer in men in western societies, and accounted for around 14% of all new male cancers and approximately 6% of male cancer-related deaths worldwide in 2008.¹ In Europe, prostate cancer accounted for 11.9% of all newly diagnosed cancers in 2008,² and was the most common cancer in men accounting for 22% of male cancers and 9.3% of male cancer deaths.²

Prostate cancer progresses from an intraepithelial neoplastic stage, through locally advanced disease, and eventually to castration-resistant cancer. Early evidence that the survival and proliferation of prostate cancer cells was dependent on androgen stimulation was provided by the work of Huggins and Hodges,³ which demonstrated that tumor regression and symptom palliation could be induced by lowering serum androgen levels. Today, it is accepted that androgens stimulate the growth and survival of prostate epithelial tissue and, as a consequence, prostate cancer.⁴

Androgens are predominantly synthesized in the testes under the regulation of luteinizing hormone (which is itself regulated by the levels of gonadotropin-releasing hormone [GnRH]). Testosterone is the principal androgen and is converted intracellularly to the more potent metabolite dihydrotestosterone (DHT), although both steroids bind to the androgen receptor (AR).^5–7 Suppression of gonadal testosterone has for many years been the central principle of androgen deprivation. Today, the standard treatment for patients with hormone-sensitive disease is to deplete testosterone concentrations by castration using either GnRH analogues or surgical orchidectomy, either alone or in combination with an antiandrogen,^{8, 9} with the recommendation that GnRH therapy is maintained despite elevated prostate specific antigen (PSA) levels indefinitely (Figure 1).¹⁰

Castration with GnRH analogues is one of the most active systemic treatments in oncology and most prostate cancer patients respond to this treatment initially, with declines in serum PSA accompanied by tumor regression. Relapse, however, is common and the median time to progression to a castration-resistant state for patients with metastatic disease, who initially exhibit a biochemical response (decline in PSA) to androgen deprivation, is between 18 and 36 months.^11–13 Such patients are defined as having castration-resistant prostate cancer (CRPC) because of progression of their disease despite castrate levels of testosterone (<50 ng/dL or <1.7 nmol/L).¹⁰

Early research into the mechanism of progression to CRPC proposed the coexistence of both hormone-sensitive and hormone-resistant cancer cells in the tumor. According to this preclinical model, androgen ablation following castration, created an environment in which androgen-independent tumor cells had a growth advantage.¹⁴ As a result, primary exogenous androgen suppression therapy was sometimes discontinued in CRPC patients upon disease progression due to the misconception that the disease had become “hormone resistant.”¹⁵ However, a significant body of evidence now exists showing that CRPC remains AR-dependent^{4, 16} and, therefore, cannot be considered to be either hormone-refractory or androgen-independent.¹⁷

In this review, we will assess the available evidence that CRPC remains a hormonally driven disease and examine the rationale for the continued use of castrative therapy (GnRH analogues) in patients with CRPC.

What Is the Evidence That CRPC Is Still Hormone Dependent?

Immunohistochemical and other studies of tumor samples have demonstrated that the AR is expressed in essentially all human prostate cancers, including those that redevelop after the failure of endocrine therapy. More specifically, it has been shown that the AR is overexpressed in the vast majority of specimens analyzed from patients with CRPC.^{18, 19} In a comparative microarray analysis investigating overall changes in gene expression during prostate cancer progression after androgen deprivation therapy, a 9- to 11-fold increase in the median level of AR expression was observed in castration-resistant metastatic disease when compared with untreated primary tumors (P=.028).²⁰ It can be postulated that such increased AR levels in the tumors of patients with CRPC may result from greater receptor protein stability,²¹ increased activation of the AR promoter,^{22, 23} or amplification of the AR gene leading to hypersensitivity to the ligand.^{24, 25} Approximately 30% of CRPCs have been reported to carry an amplification of the AR gene.²⁶ While in a separate study, increased AR expression has been shown to sensitize prostate cancer cells to low levels of ligand.²⁷

Missense mutations of the AR gene, which are rare in tumors not treated by androgen deprivation therapy, are found in 10%–30% of tumors in patients treated with antiandrogens and can cause promiscuous activation of the AR by alternative ligands such as estrogens, adrenal androgens, glucocorticoids, and progestins.²⁵ In certain cases, binding domain mutations can result in traditional antiandrogens such as bicalutamide and flutamide becoming agonists.^{25, 28, 29} The AR can also be activated in the absence of ligands by membrane-bound tyrosine kinase receptors (eg, HER2/neu) and by signaling molecules, growth factors (eg, keratinocyte growth factor, insulin-like growth factor-1, epidermal growth factor), and cytokines (eg, interleukin-6).²⁵

Studies of cell lines and prostate cancers have also identified a number of alternative splice forms of the AR.^30–32 Elevated expression of AR splice variants lacking the ligand binding domains (ARVs) has been associated with more rapid disease recurrence following radical prostatectomy for localized disease.^{30, 33} The ARV expression has been shown to increase acutely in response to androgen withdrawal and be suppressed by testosterone, indicating that the increase in ARV expression in castrate-resistant prostate cancer is an acute response to castration rather than clonal expansion of castration or antiandrogen-resistant cells expressing gain of function ARVs.³⁴ The most studied variant, AR-V7, activates AR reporter genes in the absence of ligand and could, therefore, play a role in castration resistance. A novel human AR splice variant (AR^v567es) has recently been identified,³⁵ which has been shown to contribute to tumor progression in human prostate cancer xenograft models in mice following castration.

In addition, CRPC cells have been shown to upregulate many of the enzymes involved in the generation of steroids suggesting that the CRPC cells themselves continue to produce androgens during the progression of CRPC.^{20, 36, 37} In CRPC patients, detectable serum testosterone levels have been demonstrated by liquid chromatography tandem mass spectrometry assays.³⁸ Thus, androgens originating from both the prostate cancer cells themselves and from other sources, including the adrenal gland, may continue to act as ligands and result in ongoing AR stimulation. Certainly, intraprostatic testosterone levels fall rapidly after castration in prostate cancer patients but rise to precastration levels after development of castration resistance.³⁹ In support of this observation, de novo synthesis of androgens in an androgen-deprived milieu has been observed in androgen-dependent xenograft tumor models.^{36, 40, 41} Recent studies have also shown increased intratumoral androgen synthesis to be the mechanism of AR reactivation in the majority of CRPCs.^{40, 41} Thus, the experimental and research data clearly suggest that CRPC remains hormone-dependent and implicate the AR as the driver of CRPC.

Clinical evidence of hormone dependence comes from the observation that between 20% and 40% of prostate tumors that progress following androgen deprivation may respond to the addition of second- and even third-line hormone treatments including estrogens, antiandrogens, progestational agents, and adrenal steroid synthesis inhibitors such as ketoconazole and glucocorticoids.^42–44 Of note, the addition of the antiandrogens, bicalutamide or nilutamide to a GnRH analogue, is associated with a >¯50% decrease in PSA in about a third of patients, with median response durations typically being between 4 and 7 months.^45–47 Also, in a retrospective analysis of patients with CRPC who progressed on GnRH therapy, 69% of patients (n=39) had decreased PSA levels 3 months after switching to a different GnRH analogue, with a median time to subsequent PSA increase of 5.2 months.⁴⁸ While, abiraterone, a selective small molecule inhibitor of CYP17, a key enzyme in steroid biosynthesis, has demonstrated >¯50% or greater decrease in PSA in 50%–60% of chemotherapy-naïve CRPC patients^{38, 49} and antitumor activity in patients previously treated with chemotherapy.^{50, 51} Data from a phase III trial in CRPC patients pretreated with docetaxel showed abiraterone to confer a significant survival advantage (14.8 vs 10.8 months, Hazard Ratio [HR] 0.646, P<.0001) over placebo.^{52, 53} MDV3100, a rationally designed small molecule that blocks the AR has also been shown to exhibit significant declines in PSA (>¯50%) in 62% of chemotherapy-naïve and 51% of postchemotherapy patients (P=.23), together with prolonged time to radiological progression in the same patient groups in a phase I/II dose-escalation study.⁵⁴ Phase III studies are ongoing in chemotherapy-naive patients (NCT01212991)⁵⁵ and those previously treated with docetaxel (NCT00974311),⁵⁶ respectively. It is these recent data in prospective trials with targeted agents that provide the strongest evidence to date that CRPC remains a hormonally driven disease.

Is There a Case for Keeping CRPC Patients Castrate?

Today, the evidence for CRPC remaining an androgen-dependent disease seems unequivocal. However, it was early data from clinical studies in patients in whom prostate cancer had progressed despite primary androgen-deprivation therapy that suggested a survival benefit from continued testicular androgen suppression. Taylor and coworkers¹⁵ retrospectively reviewed survival data for 341 patients from four CRPC trials conducted by the Eastern Cooperative Oncology Group (ECOG) and the University of Wisconsin (Table 1), and showed a modest advantage in survival duration for CRPC patients who continued to receive gonadal androgen suppression therapy. If we look specifically at the University of Wisconsin Clinical Cancer Center Study C08586, in which the use of the nonspecific CYP17 inhibitor ketoconazole (with hydrocortisone) in divided doses was studied in 38 patients,⁵⁷ we see that survival duration was significantly superior (P=.01) for orchidectomy patients (9.9 months) compared with those who had had their prior GnRH analogue and/or diethylstilboestrol therapy discontinued on study entry (3.6 months; Table 1, Figure 2).¹⁵ Furthermore, in three of the nonorchidectomized patients whose exogenous hormone therapy was discontinued at the start of the study, plasma testosterone levels well above castrate levels were recorded during the course of ketoconazole administration.⁵⁷ These observations were consistent with the indirect evidence that elevated androgen levels, following the release of CRPC patients from androgen deprivation might promote tumor growth, provided by the results of an early study.⁵⁸ In this study by Manni and coworkers,⁵⁸ exogenous androgens were used as a means of priming prostate cancer cells to enhance the efficacy of cytotoxic chemotherapy in CRPC patients. Significantly, those patients who received “androgen-priming therapy” had a poorer outcome, with median survivals of 10 and 15 months (P=.0047), for patients in the exogenous androgen and control groups, respectively.

Direct evidence of the efficacy of continuing GnRH analogue therapy beyond progression is provided by the recent retrospective analysis of Lawrentschuk and coworkers,⁴⁸ described previously, in which PSA levels were seen to decrease following a switch of GnRH analogues in patients with CRPC. Interestingly, it suggests that although GnRH analogues are a single class of agent they may differ in their pharmacology and raise the possibility that sequencing different GnRH analogues may play a limited role in the treatment of CRPC.

Recognition of the importance of maintaining CRPC patients castrate is reflected in a recent evaluation of the treatment patterns for the management of patients with CRPC in France, Germany, Italy, Spain and the UK between December 2009 and May 2010. The data recorded showed GnRH analogues to be predominate in the first-line treatment of CRPC (47% of patients vs 25% for GnRH analogues plus antiandrogens and 17% for antiandrogens alone). For CRPC patients failing on GnRH analogue therapy, the treating physicians would either add an antiandrogen or switch to another GnRH analogue.⁵⁹ There were, of course, regional variations in the patterns of prescribing but of the physicians who said that they would prescribe a second hormonal therapy after the failure of GnRH therapy, 49% would switch the patient to GnRH therapy plus an antiandrogen and 20% to an alternative GnRH analogue alone. Only 19% of physicians would swap to an antiandrogen alone. In the same survey, physicians estimated that 21% of CRPC patients would fail to respond to initial hormone therapy and that 66% of patients would eventually become resistant. Disappointingly across the five countries, in patients selected to receive chemotherapy, only 52% would receive it together with a GnRH analogue, despite the available evidence in support of this practice,^{10, 15, 58, 60} and the evidence of tumors that progress despite multiple hormone therapies and are currently treated with chemotherapy remain dependent on AR signaling for tumor growth.^51–53

The data presented above and in the preceding section from retrospective and prospective trials demonstrate a clear clinical benefit for continued medical castration in patients with CRPC and support the definition of CRPC as a form of hormone dependent advanced prostate cancer.

SUMMARY AND CONCLUSIONS

Clearly, the growth and survival of the majority of prostate cancer cells in many patients with CRPC remain dependent on AR signaling. Adaptive mechanisms including continued androgen synthesis, increased receptor sensitivity, and the upregulation of AR expression facilitate continued tumor growth in the CRPC disease setting. Consequentially, the majority of the numerous therapeutic interventions currently being investigated for the treatment of patients with CRPC are based on the premise that the involvement of AR signaling is still evident at this advanced disease stage. Principal among these new approaches are the androgen biosynthesis inhibitors abiraterone acetate,^{38, 61, 62} TAK-700,^{63, 64} and TOK-001⁶⁵ and the novel AR antagonists MDV3100,^{54, 66} ARN-509 (NCT01171898),⁶⁷ and AZD 3514 (NCT01162395).⁶⁸ Paradoxically, the replenishment of testosterone levels is still being investigated in CRPC patients with low disease burden⁶⁹ but to date no significant clinical benefit has been demonstrated for this approach.

The GnRH analogues, however, have been the mainstay of treatment for advanced prostate cancer (Figure 1) and remain the cornerstone of the therapy approaches for CRPC in every day practice.^{48, 59} Interestingly, the emergence of new agents has not only added to our increasing understanding of AR biology but provided the necessary unequivocal evidence to ensure that maintenance of the castrate state indefinitely remains an essential aim in the clinical treatment of patients with CRPC (Figure 1).

Disclosure: The author declares no conflict of interest. The writing of the manuscript was supported by a non-restrictive grant and editorial assistant from Astellas Pharmaceutical, the conclusion are entirely those of the authors.

Medical writing support was provided by Dr. Anne Kinsella, writing on behalf of the authors.

Keywords

Androgen-deprivation therapy, androgen receptor, antiandrogens, castration-resistant prostate cancer, gonadotropin releasing hormone analogues, CYP17

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Urinary incontinence is a common condition affecting adult women of all ages with a reported age-related prevalence up to a third of all women. At least half of these women would suffer from stress urinary incontinence.¹ This debilitating condition places considerable burden on the psychosocial functioning and affects the quality of life significantly. Moreover, as the population ages, the prevalence of urinary incontinence is expected to rise even further.²

Stress urinary incontinence (SUI) is defined as involuntary leakage of urine on effort or exertion, or on sneezing or coughing.³ Many national and international governing bodies advocate conservative measures such as fluid management, life-style modification, pelvic floor exercise, and bladder retraining following the diagnosis of urinary incontinence based on history, bladder diary, and physical examination.^4–7 For women who failed conservative measures, the current surgical procedures for stress urinary incontinence are minimally invasive with low morbidity and are highly successful.

The success of these surgical interventions depends largely on selecting the appropriate patient population based on reliable history of SUI. As the symptoms of SUI are often coexisting with overactive bladder symptoms (urgency, with or without urge incontinence, accompanied by frequency, and nocturia), and presence of pelvic organ prolapse may potentially complicates the clinical assessment, a more formal and objective evaluation of SUI should be adapted. Urodynamic investigations are an important diagnostic tool and widely regarded as the gold standard for the evaluation of lower urinary tract dysfunction. Urodynamic studies (UDS) encompasses both filling and voiding studies, thereby providing an objective assessment of the physiological functions of bladder and urethra. Simple UDS uses a single channel to measure bladder pressure whereas multichannel UDS utilizes a rectal line, thereby providing the true assessment of bladder (detrusor) pressure.

Several controversies continue to exist on the utility of UDS in the preoperative investigation value, degree of detrusor- or bladder neck-related voiding dysfunction, application of leak point pressures and urethral pressure profile, and the need for UDS in healthy, treatment-naive woman with no history of prior incontinence or prolapsed surgery.^8–10 The standardization Committee of the International Continence Society (ICS) has published the Good Urodynamic Practice guidelines¹¹ and recognized the importance of standardization UDS values in an attempt to resolve controversies on UDS protocol and reference values. This article examines the current status of and explores the controversies surrounding UDS.

MATERIALS AND METHODS

The Pubmed and Medline database were searched for recent articles published over the last 5 years. Only peer-reviewed articles published in English were evaluated and specific emphasis on major international guidelines, statements from major urinary and incontinence organizations, and published studies from randomized controlled multicenter trials were placed. The search terms were urodynamic, recent controversies, preoperative and surgical outcome, valsalva leak point pressure, and cost-effectiveness.

STATE OF ART REVIEW ON UDS

The current literature on UDS is conflicting due to the differences in the guidelines by the many governing bodies. The National Institute for Clinical Excellence (NICE) in the UK⁴ has published a series of recommendations stating that history taking alone is sufficient to differentiate SUI from the other types of urinary incontinence and all patients should be trialed on conservative treatment. The UDS should only be performed in women preoperatively if there is a clinical suspicion of detrusor overactivity (DO), previous surgery for SUI or pelvic organ prolapse, or if there are symptoms suggestive of coexisting voiding dysfunction. In contrast the International Consultation on Incontinence (ICS)⁵ advocates the use of UDS in complicated cases of urinary incontinence, uncertain pathophysiology, and the presence of neurogenic voiding dysfunction. The benefit of preoperative UDS also extends to women with prior history of extensive pelvic surgeries, radiation, and persistent or recurrence of urinary incontinence.¹⁰

Free uroflowmetry, filling cystometry, and a pressure flow study are essential components of UDS based on the recommendation by the ICS Good Urodynamic Practice guideline.¹¹ The Urinary Incontinence Treatment Network has published extensively on the ideal reference urodynamic values and proposed standardized UDS protocol.^{12, 13} Unfortunately this practice has not been widely adopted and different UDS protocols and set-ups continue to exist.

A systematic review by Martin et al¹⁴ concluded that women with urodynamic evidence of SUI can be correctly identified based on history alone with a sensitivity of 92% and specificity of 56%. On the other hand, the Cochrane review by Glazener and Lapitan¹⁵ reported more patients received pharmacological and surgical interventions following urodynamic testing, perhaps a reflection of the increase confidence among clinicians in advocating certain treatment pathways. An international survey conducted by Duggan et al¹⁶ revealed that 70% of clinicians utilize UDS and 46% of the frequent operators reported lack of access to urodynamic investigations despite having urodynamic clinics in the same city. Uroflowmetry and filling cystometry were only performed by 73% and 72% of subspecialists, these numbers were lower among the generalist surgeons (46% and 44%). The poor understanding and the lack of belief in the UDS was thought to play a significant part in these observations.

Currently, many issues hinder the diagnostic accuracy of UDS such as the lack of protocol standardization, numerous software programs, staff training and funding of the UDS unit, rectal line utilization and concomitant EMG, handling of coexisting large pelvic organ prolapsed, and technical and interpretation issues. Additionally, some experts believed that UDS is a poor investigative tool in detecting DO.¹⁷ Unrecognized and underdetected DO may be due to the fact that DO is not always present during the filling phase, and UDS, being a transitory investigation, is not able to capture DO at its occurrence. Furthermore, conventional UDS employs antegrade filling instead of natural (orthograde) filling, thereby potentially limiting the occurrence of DO in these patients. On the other hand, ambulatory UDS has been shown to be more effective in identifying women with DO (69% vs 18% with conventional UDS).¹⁸

CURRENT CONTROVERSIES

Does Preoperative UDS Predict Continence Outcomes After Surgery?

Most of the major organizations such as the International Continence Society, the International Consultation on Incontinence, and the AUA Guideline for the Surgical Management of Female Stress Urinary Incontinence advice that need for UDS depends largely on the diagnostic uncertainty and the impact that further studies will have on clinical and surgical outcomes.

Through the Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr), the Urinary Incontinence Treatment Network in the United States¹⁹ reported that women with urodynamic SUI had a twofold greater odds of overall success when compared with no urodynamic SUI group; however, this trend did not quite reach statistical significance (OR 2.26; 95% CI .99, 5.17). The odds stress specific success did not differ by urodynamic SUI status and the level of valsalva leak point pressure (VLPP). In addition, the presence of DO did not predict the success of surgical outcome. While SISTEr involves multicenter enrollment and is a highly standardized, quality controlled UDS trial, this study did not categorize patients into high risk groups nor account for other UDS parameters and/or provocative measures for DO, thereby raising concerns on the oversimplification of the role of preoperative UDS and surgical success. Furthermore the SISTEr trial was not designed specifically to randomize patients to UDS versus control nor compare the outcomes between these two groups.

In the UK, a retrospective analysis by Agur et al²⁰ found that only 5.2% of women had pure SUI during the 17-year study period and a quarter of those with pure SUI symptoms went on to receive continence surgery. These findings indicate that only a small proportion of women fulfill the NICE criteria of pure SUI on UDS. Another study showed that up to 20% of all women with pure SUI on the questionnaire had urodynamic findings that would preclude the surgeons from offering surgery as first-line treatment.²¹ Caruso et al¹⁷ reported poor predictive value of UDS in simulating SUI during filling cystometry. This finding is also reciprocated in the SISTEr trial, whereby approximately 10% of women who qualified for stress incontinence surgery with a positive stress test on physical examination did not demonstrate urodynamic SUI and less than 10% of women showed evidence of DO.¹³

Dokmeci et al²² further lent support to this argument and found 56% of patients had SUI on ambulatory compared to none on conventional UDS. The artificial environment in the UDS laboratory and occasional awkward positioning of the patient during UDS could contribute to its poor sensitivity. Furthermore many women reported increased anxiety during UDS, thus influencing urine loss during the study.

The effectiveness of minimal invasive stress urinary incontinence surgery further negates the need for UDS as published literature reveals that 85% of patients with mixed urinary incontinence symptoms reported complete resolution of urge urinary incontinence symptoms following antistress incontinence surgeries.²³ The Cochrane review¹⁵ concludes that performing UDS preoperatively does not influence or dictate the outcome of the anti-incontinence procedure.

Do VLPP and/or UPP Change the Surgical Outcomes?

McGuire et al²⁴ first described the concept of abdominal leak point pressure (ALPP) in the early 1990s and had proposed that the ALPP measure the severity of SUI. For the majority of cases, the abdominal leak point pressure (ALPP) is similar to valsalva leak point pressure (VLPP). The VLPP measures the amount of pressure required to overcome urethral resistance (for urine leak to occur) during a valsalva maneuver. An underlying intrinsic sphincter deficiency was thought to be factor for a VLPP of lesser than 60 cmH₂O, and value greater than 90 cmH₂O was secondary to urethral hypermobility condition. However there are disagreements as to the best means of performing and reading leak point pressures.²⁵ Many published literatures have shown that women with a more severe urinary incontinence are more likely to have a lower VLPP.^{26, 27} Kilicarslan et al²⁷ reported VLPP over 50 cmH₂O was associated with 90% success rate following anterior vaginal wall sling surgery compared to women with lower VLPP. Jung and colleagues²⁸ found ALPP greater than or equal to 72.5 cmH₂O were most predictive of successful surgical outcomes in the transobturator midurethral sling group.

In contrast, equal numbers of studies have found no correlation between VLPP and urinary standardized incontinence scores.^28–31 In the same paper by Jung et al,²⁸ they reported the treatment outcome of transvaginal midurethral sling was not associated with VLPP values. While women with lower VLPP used more urinary pads and reported more severe incontinence complaints, they fared no worse than those with higher VLPP or those who did not leak at all during UDS, following a distal urethral polypropylene sling procedure for SUI.³¹ Although the SISTEr trial found that women with urodynamic SUI were twice as likely to have successful overall outcomes from surgical management with either a Burch or autologous fascial sling surgeries, there was no difference in the mean ALPP values between women who reported success or failure postoperatively.¹⁹ A further publication by Lemark et al³² as part of the SISTEr trial reported that advancing age, lower body mass index, higher maximum flow rate, and lower voiding pressure are all independently associated with lower VLPP in women undergoing surgery for SUI. Lower voiding pressures and higher flow rates among women with more severe SUI may reflect the chronic loss of urethral resistance and some degree of fixed urethral resistance too. Indeed, it appears that VLPP is a relatively poor indicator of urethral sphincteric function overall.³³

Apart from VLPP, urethral pressure profile (UPP) is another common urodynamic test on urethral function. Urethral pressure profile study such as maximum urethral closure pressure (MUCP) adds another dimension to the evaluation of SUI. The data on UPP was mostly derived from retropubic antistress incontinence procedures. Published literature suggests that MUCP below 20 cmH₂O is associated with worse postoperative outcomes.^{34, 35} In a prospective randomized controlled (TOMUS) trial, Nager et al³⁶ reported that VLPP and MUCP had moderate correlation with each other (r = .36, p < .001). However, urodynamic measures of urethral function had little or no correlation with subjective or objective measures of severity. Subjects with a positive supine empty bladder stress test (SEBST) had more subjective and objective severity measures compared to the negative SEBST group, but they did not have significantly different VLPP and MUCP values. This data suggests that the urodynamic measures of urethral function are not related to subjective or objective measures of urge incontinence severity.

The considerable amount of debate in the literature on the impact of VLPP on diagnosis and treatment outcome of SUI is perhaps reflected in the type of population being studied, types of surgical intervention, and the exclusion of other concomitant pathologies such as detrusor overactivity and pelvic organ prolapse. Certainly the advent of minimally invasive midurethral sling surgery and the high success rate in many women without preoperative UDS have shifted the preoperative investigation paradigm.

Do Other UDS Parameters Factor Into Overall Evaluation?

Poor bladder compliance and detrusor hypotonia are potentially dangerous problems that can be exacerbated following an increase in the outlet resistance. However, in healthy women with straightforward SUI, the incidence of such conditions is low. This was supported by Nager et al¹³ who found no patient described as having poor compliance in a series of 655 women with pure or predominant stress urinary incontinence in a multicenter trial.

Other UDS parameters such as opening detrusor pressure, closing detrusor pressure, maximum flow rate, detrusor pressure at maximum flow rate, and acceleration flow rate have been described in literature.^{37, 38} Digesu et al³⁷ reported that women who failed colpo-suspension had a lower preoperative opening and closing detrusor pressures compared to women who were continent postoperatively. Acceleration flow rate, the speed of the detrusor contraction, and opening of bladder neck also appeared to affect the surgical success.³⁸ Provocative maneuvers to elicit DO during filling cystometry have been reported with great success rate.³⁹ Omission of these provocative maneuvers could potentially diminish the rate of detecting DO.¹⁹

Nonetheless these UDS parameters are not universally adopted and the results have not been reciprocated in other studies. Opening and closure detrusor pressures are a subjective assessment of the time delay at which detrusor pressure is measured when flow starts or stops. Furthermore the International Continence Society has not standardized this delay for these calculations.

What is the Role of Ultrasound in UDS Evaluation?

Ultrasound is a useful investigative tool to assess lower urinary tract system during UDS such as exclusion of concomitant bladder pathology, bladder neck descent, and urethral mass. The absence of radiation exposure in patients who undergo UDS is an attractive feature of ultrasound among many patients and clinicians. Furthermore many urological units do not have a proper room or the equipment for fluoroscopic assessment during UDS.¹⁶ Ultrasonographic measurement of bladder wall thickness (BWT) provides an indirect assessment of the detrusor wall thickness, a potential index of underlying DO. It is reported that women with DO has a greater BWT than asymptomatic women⁴⁰ and that the measurement of BWT discriminates the women with confirmed DO against those with urodynamic SUI.³

Published literature has shown similar efficacy between the handheld device and automated ultrasound results using a transabdominal approach.⁴¹ While Kuo⁴² found that transabdominal ultrasound and not transvaginal route provided a better marker of DO as evidence by the greater BWT imaged at bladder capacity; the same group also demonstrated that BWT measured by the transabdominal route was no different in patients with and without OAB, thereby discouraging the use of transabdominal ultrasound as a useful diagnostic test for DO in women with overactive bladder symptoms.⁴³ A prospective trial by Kuhn et al⁴⁴ discovered strong correlation between BWT and detrusor pressure at maximum flow rate and that the value is higher in DO and obstructed voiding than those with pure urodynamic SUI. Serati et al⁴⁵ concluded that ultrasonographic BWT showed a highly significant association with DO and a cutoff of 6.5 mm for BWT had a positive predictive value of 100% for all DO patients.

Although the ultrasound is a relatively inexpensive and easily accessible investigative tool, there are several factors to be considered. The types of ultrasound machines; standardization of protocol with regards to the probe, route, pressure of transducer application, and the degree of bladder wall impression; numbers and sites of measurements in the bladder; as well as volume of bladder need to be addressed. Presently, there are several measurements of BWT such as 5.2 mm by Kuhn et al⁴⁴ and 5.6 mm by Panayi et al.⁴⁶ In the absence of properly conducted double-blind randomized controlled trial with adequate sample size power calculation and taking into account the inter- and intraobserver reliability of an ultrasound, the role of BWT in the field urinary incontinence remains a research quandary.

Is UDS Cost-Effective?

A critical review of Medicare practice in the United States by Anger et al⁴⁷ reported that patients who underwent preoperative UDS were more likely to be newly diagnosed with urge incontinence after surgery. Multivariate analysis revealed that subjects who underwent preoperative UDS were significantly less likely to undergo postoperative UDS than those who did not (OR .34, 95% CI .24–.48). Therefore it appears intuitive that performing preoperative UDS would provide the surgeon with greater understanding of the patient voiding dysfunction and obviate the need for postoperative UDS. The statement by Freeman⁴⁸ that preoperative UDS were not cost-effective in patients with pure SUI was also supported by Weber et al^{49, 50} based on an American economic model on the estimated posterior probability of urge incontinence in patients with urinary incontinence.

While decision analytic models have shown that UDS is no more cost-effective than a basic office evaluation, there are many salient points to be considered. Firstly, these studies did not consider the high rate of postoperative UDS performed in women who did not undergo preoperative testing. The use of hypothetical patients and assumption that all patients ultimately received surgery implies that medical therapies for SUI were ineffective, clearly in contrast with current bodies of evidence. Additionally, other assumptions made such as high numbers of women with postoperative DO would be cured by medical treatment could be criticized by many clinicians and raised more questions on the validity of the economic model. Preoperative UDS may further reduce costs by changing the management course and potentially obviate the need for surgical intervention. Furthermore, the Cochrane review was conducted awhile ago and only took into account the two published randomized controlled trials.¹⁵

Currently two clinical trials have been designed to address the specific issue relating to the cost-effectiveness of UDS. The Value of Urodynamics Prior to Stress Incontinence Surgery (VUSIS) study⁵¹ will attempt to evaluate the positive and negative effects with regards to postoperative outcome, as well as costs of UDS, in women with SUI in whom surgical intervention is considered. The other investigation was conducted to better understand the value and use of preoperative UDS by the Urinary Incontinence Treatment Network. Nager and colleagues⁵² have designed a noninferiority randomized clinical trial to determine the prognostic value of UDS in determining specific treatment options, the improvement in incontinence outcomes, as well as the incremental cost and utility of performing UDS.

CONCLUSION

There is ongoing debate about the diagnostic utility of UDS in the management of women with urinary incontinence. Most patients with urinary incontinence will respond well to conservative measures and/or minimally invasive anti-incontinence surgery without the need for routine urodynamics testing. It is important to remember that UDS is a dynamic assessment tool attempting to replicate patient's symptoms and, therefore, has its limitations and the outcome needs to be interpreted with caution. The value of UDS may reside in better clarification and characterization of urinary symptoms, especially in a woman who is considering invasive surgical intervention. There is no doubt that UDS should be considered and/or required in women with prior stress-incontinence and/or pelvic surgery or radiation, concomitant large pelvic organ prolapse, or who have history of neurological conditions. The dilemma is whether UDS plays an additional role in preoperative counseling and surgical outcomes predictive value in the majority of women with simple SUI.

Disclosure: The authors declare no conflict of interest.

Keywords

Urodynamics, stress urinary incontinence, surgical outcome, controversies

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