A case-mix-adjusted comparison of early oncological outcomes of open and robotic prostatectomy performed by experienced high volume surgeons
Jonathan L. Silberstein*, Daniel Su*, Leonard Glickman*, Matthew Kent†, Gal Keren-Paz*, Andrew J. Vickers†, Jonathan A. Coleman*‡, James A. Eastham*‡, Peter T. Scardino*‡ and Vincent P. Laudone*‡
*Department of Surgery, Urology Service, and †Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, and ‡Department of Urology,Weill Cornell Medical Center, New York, NY, USA
• To compare early oncological outcomes of robot assisted laparoscopic prostatectomy (RALP) and open radical prostatectomy (ORP) performed by high volume surgeons in a contemporary cohort.
METHODS
• We reviewed patients who underwent radical prostatectomy for prostate cancer by high volume surgeons performing RALP or ORP.
• Biochemical recurrence (BCR) was defined as PSA 0.1 ng/mL or PSA 0.05 ng/mL with receipt of additional therapy.
• A Cox regression model was used to evaluate the association between surgical approach and BCR using a predictive model (nomogram) based on preoperative stage, grade, volume of disease and PSA.
• To explore the impact of differences between surgeons, multivariable analyses were repeated using surgeon in place of approach.
RESULTS
• Of 1454 patients included, 961 (66%) underwent ORP and 493 (34%) RALP and there were no important differences in cancer characteristics by group.
• Overall, 68% of patients met National Comprehensive Cancer Network (NCCN) criteria for intermediate or high risk disease and 9% had lymph node involvement. Positive margin rates were 15% for both open and robotic groups.
• Using NCCN risk group as the covariate in a Cox model gave similar results (hazard ratio 0.74; 95% CI 0.47–1.17; P = 0.2). The interaction term between NCCN risk and procedure type was also non-significant.
• Differences in BCR rates between techniques (4.1% vs 3.3% adjusted risk at 2 years) were smaller than those between surgeons (2.5% to 4.8% adjusted risk at 2 years).
CONCLUSIONS
• In this relatively high risk cohort of patients undergoing radical prostatectomy we found no evidence to suggest that ORP resulted in better early oncological outcomes then RALP.
• Oncological outcome after radical prostatectomy may be driven more by surgeon factors than surgical approach.
We report a patient who presented following seminal vesicle-sparing radical retropubic prostatectomy with a complaint of dysorgasmia that was successfully treated with robot-assisted trans-peritoneal seminal vesiculectomy.
Abstract
We report a patient who presented following seminal vesicle-sparingradical retropubic prostatectomy with a complaint of dysorgasmia thatwas successfully treated with robot-assisted trans-peritoneal seminalvesiculectomy.
Introduction
Radical retropubic prostatectomy (RRP) is a mainstay surgical treatment for clinically localized prostate cancer. Improved anatomical understanding of prostate vasculature, sphincteric musculature and autonomic innervation in the 1980s [1] facilitated development of more sophisticated surgical techniques to improve post-operative potency [2] and urinary continence [3].
Traditional RRP involves concomitant removal of the seminal vesicles (SV) in addition to the prostate [4]. Studies assessing pathologic specimens have demonstrated that invasion of the SV is rare in patients with low-risk, clinically localized prostate cancer [5]. This finding stimulated interest in preserving the SV during RRP in an effort to avoid injury to the nearby branches of the pelvic plexus innervating the corpus cavernosa, trigone, bladder neck and posterior urethra. John and Hauri first described the anatomical concept and surgical technique of SV-sparing RP in 2000 [6]. Subsequent reports have shown improved functional outcomes of urinary continence [7] and potency [8] following SV-sparing RRP.
Despite the potential advantages of SV-sparing RP, lingering concerns remain as to the fate of the retained SV, i.e. occult tumor and adverse post-operative symptoms. One documented adverse symptom is dysorgasmia, which is the symptomatic complaint of perineal, penile or abdominal pain following orgasm, that has been reported in 14% of patients post-RRP [9]. This symptom is also present in patients with symptomatic SV cysts, benign prostate hypertrophy, chronic prostatitis, and chronic perineal pain syndrome [10,11]. Herein we present a case of a patient who presented with dysorgasmia following apparent SV-sparing RRP that was refractory to conservative treatments and was successfully treated by robotic excision of the SV remnants with prompt resolution of his symptoms.
Case Presentation
Our patient is a 56 year-old man that presented with progressively worsening perineal pain associated with sexual activity and orgasm three years following RRP performed at an outside institution for pathologic stage pT2cN0Mx Gleason 7 prostate cancer. Postoperative serum PSA has remained <0.1 ng/mL. He reported post-prostatectomy erectile dysfunction managed successfully with intracavernosal injections. Evaluation for his symptoms of dysorgasmia revealed a palpable, tender and fluctuant 3-cm mass on digital rectal examination. Cross sectional imaging with CT revealed enlarged bilateral retained SV remnants (Figure 1). Following failure of anti-inflammatory medication therapy, he subsequently underwent two transgluteal aspirations of the SV remnants. These procedures provided transient relief, but with eventual recurrence of his symptoms. The patient was counseled on therapeutic options and opted for surgical removal of the seminal vesicle remnants.
Seminal vesiculectomy was undertaken with the da Vinci robot (Intuitive Surgical Inc, Sunnyville, CA) using a 4-armed approach similar to that of transperitoneal retrovesical approach to radical prostatectomy. A standard 5-trocar configuration was used with entry into the peritoneal cavity. The vas deferentia were dissected bilaterally and traced distally towards the seminal vesicles. Anterior retraction of the vas allowed for improved exposure and dissection of each SV. Dissection of both right and left SV met with significant adhesions and fibrosis as a result of his prior radical retropubic prostatectomy. Dissection was especially challenging both anteriorly adjacent to the bladder base as well as posteriorly adjacent to the rectum. Use of the Prograsp forceps in the fourth robotic arm was critical in providing retraction and exposure of tissue planes. Both SV remnants were dissected meticulously using a combination of blunt and sharp dissection with limited use of cautery to avoid injury to adjacent structures. Lateral attachments to the SV remnants were clipped and divided.
Once all attachments to the SV remnants were freed, the specimen was placed in an entrapment sack and extracted at the umbilicus at the end of the operation (Figure 2). To test the integrity of the bladder, the urethral catheter was filled with 200 mL of sterile saline with no evidence of leak. Likewise, the integrity of the rectum was assured by transrectal air insufflation while filling the pelvis with saline, which revealed no signs of perforation. A closed suction drain was left draining the retrovesical space.
Following surgery, the patient recovered well and was discharged on postoperative day one. He reported prompt cessation of his dysorgasmia symptoms at his one-month postoperative follow-up appointment and continues to remain pain free at 2.5 years follow up. He suffered no significant change in his voiding pattern and reported stable and persistent erectile dysfunction managed successfully by intracavernosal injection therapy.
Discussion
The precise mechanism for dysorgasmia due to a retained seminal vesicle remnant is still largely unknown. Multiple etiologies for dysorgasmia have been proposed, including spasm of the post-RRP vesico-urethral anastamosis [9], SV congestion secondary to ejaculatory duct obstruction [12], alteration of adrenergic receptor sensitivity causing spastic contraction13, and pudendal nerve compression by muscles contracting during intercourse [14]. The presenting symptoms and management of our patient is similar to symptomatic seminal vesicle cysts, which is a rare disorder that can be congenital or acquired [15] and often presents with complaints of dysorgasmia and perineal pain [10]. There are multiple interventions for symptomatic SV cysts, but the definitive treatment is surgical, including transrectal and transvesical aspiration, transurethral deroofing and surgical excision. While transrectal aspiration is the least invasive and is generally successful at relieving symptoms, recurrence within a few months is common [10]. Open and laparoscopic approaches to seminal vesiculectomy have both shown > 98% efficacy in eliminating SV-produced symptoms [10,16-22], but the laparoscopic procedure is associated with lower morbidity compared with the open approach. Robotic removal of a symptomatic SV cyst was previously described [23] and all subsequent cases have reported total resolution of SV symptomatology with no adverse events [24-26].
In 2005, O’Leary described a patient with symptoms of intense dysorgasmia that developed immediately after SV-sparing RRP [27]. Oral analgesics were the only option offered for pain, providing mild relief of the patient’s symptoms. Surgical removal of retained SV was not pursued in this case report because of concerns of procedure invasiveness and uncertain benefit. Our patient’s complaints were similar to the patient in the O’Leary case report, as well as to individuals with symptomatic SV cysts. As our patient experienced temporary improvement with SV aspiration, this suggested a comparable nociceptive etiology to an SV cyst and that definitive surgical management would provide relief.
Reoperative surgical excision of retained seminal vesicles can prove challenging due to dense scarring and close proximity to vital structures such as the bladder, rectum and neurovascular bundles. In our patient, a robotic approach was elected to improve visualization and facilitate dissection with the use of wristed instrumentation. Extensive scarring was noted around the retained SV remnants resulting in distortion of the anatomy, making this dissection technically challenging. The key manoeuvre during such a case is to maintain the dissection immediately along the surface of the SVs with minimal cautery and use of hemoclips to avoid inadvertent entry or thermal injury to adjacent structures such as the rectum and bladder. As the patient had pre-existing erectile dysfunction following his RP, rigorous attempts at nerve preservation were not made. In the case of a patient with good erectile function, attempts can be made to utilize hemoclips alone without use of electrocautery to minimize the risk of cavernous nerve injury. However, due to anticipated extensive inflammation and scarring present, the patient should be clearly advised on the high likelihood of worsening postoperative erectile function if surgery is pursued. The patient in our case experienced an uneventful perioperative course and reported complete resolution of his symptoms with stable erectile dysfunction.
Conclusion
This case report demonstrates that surgical removal of symptomatic retained seminal vesicles is a viable option for treatment of the rare case of dysorgasmia following SV-sparing RRP. A robotic approach provides a minimally invasive and ergonomically favorable alternative to address reoperative surgery such as in this case. The efficacy of seminal vesiculectomy for eliminating our patient’s symptoms further implicates the seminal vesicles as a prime component in the etiology of dysorgasmia. Further research is necessary to identify the precise mechanism for dysorgasmia.
Figure 1. Non-contrast CT showing apparent cystic mass outlined in red.
Figure 2. Gross specimen of seminal vesicle remnants.
References
1) Walsh PC and Donker PJ: Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982; 128: 492.
2) Walsh PC, Lepor H, Eggleston JC. Radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. Prostate. 1983;4(5):473-85.
3) O’Donnell PD, Finan BF. Continence following nerve-sparing radical prostatectomy. J Urol. 1989 Nov;142(5):1227-8; discussion 1229.
4) Reiner WG, Walsh PC. An anatomic approach to the surgical management of the dorsal vein and Santorini’s plexus during radical prostatectomy. J Urol 1979;121:198-200.
5) Zlotta AR, Roumeguère T, Ravery V, et. al.; European Society for Urological Oncology. Is seminal vesicle ablation mandatory for all patients undergoing radical prostatectomy? A multivariate analysis on 1283 patients. Eur Urol. 2004 Jul;46(1):42-9.
6) John H, Hauri D. Seminal vesicle-sparing radical prostatectomy: a novel concept to restore early urinary continence. Urology. 2000 Jun;55(6):820-4.
7) Albers P, Schäfers S, Löhmer H, de Geeter P. Seminal vesicle-sparing perineal radical prostatectomy improves early functional results in patients with low-risk prostate cancer. BJU Int. 2007 Nov;100(5):1050-4.
8) Sanda MG, Dunn R, Wei J. Seminal vesicle sparing technique is associated with improved sexual HRQOL outcome after radical prostatectomy. J Urol 2002;167:151 (A606).
9) Barnas JL, Pierpaoli S, Ladd P, et al. The prevalence and nature of orgasmic dysfunction after radical prostatectomy. BJU Int. 2004;94:603–605.
10) van den Ouden D, Blom JHM, Bangma C, de Spiegeleer AHVC. Diagnosis and Management of Seminal Vesicle Cysts Associated with Ipsilateral Renal Agenesis: A Pooled Analysis of 52 Cases. Eur Urol 1998;33:433-440.
11) Ilie CP, Mischianu DL, Pemberton RJ. Painful ejaculation. BJU Int. 2007 Jun;99(6):1335-9. Epub 2007 Apr 6.
12) Nadler RB, Rubenstein JN. Laparoscopic excision of a seminal vesicle for the chronic pelvic pain syndrome. J Urol 2001; 166: 2293–4.
13) Demyttenaere K, Huygens R. Painful ejaculation and urinary hesitancy in association with antidepressant therapy: relief with tamsulosin. Eur Neuropsychopharmacol 2002; 12: 337– 41
14) Myers RP. An anatomic approach to the pelvis in the male. In Crawford ED, Das S eds, Current Genitourinary Cancer Surgery, 2nd edn. Baltimore: Williams & Wilkins, 1997: 55–69
15) Kavoussi PK, Costabile RA. “Ch 37. Surgery of the Scrotum and Seminal Vesicle”. Campbell-Walsh Urology, 10th edition. editor Wein AJ. Philadelphia: Saunders 2012; 1115-1126.
16) McDougall EM, Clayman RV, Bowles WT. Laparoscopic excision of mullerian duct remnant. J Urol 1994;152:482–484.
17) Carmignani, G., Gallucci, M., Puppo, P, De Stefani S, Simonato A, Maffezzini M. Video laparoscopic excision of a seminal vesicle cyst associated with ipsilateral renal agenesis. J Urol 1995; 153: 437.
18) Ikari O, Castilho LN, Lucena R, D’Ancona CA, Netto NR Jr. Laparoscopic excision of seminal vesicle cysts. J Urol. 1999 Aug;162(2):498-9.
19) McDougall EM, Afane JS, Dunn MD, Shalhav AL, Clayman RV. Laparoscopic management of retrovesical cystic disease: Washington University experience and review of the literature. J Endourol 15: 815– 819, 2001.
20) Cherullo EE, Meraney AM, Bernstein LH, Einstein DM, Thomas AJ, Gill IS. Laparoscopic management of congenital seminal vesicle cysts associated with ipsilateral renal agenesis. J Urol. 2002 Mar;167(3):1263-7.
21) Moudouni SM, Tligui M, Doublet JD, et al. Laparoscopic excision of seminal vesicle cyst revealed by obstruction urinary symptoms. Int J Urol. 2006 Mar;13(3):311-4.
22) Nassir A. Symptomatic cystic seminal vesicle: a laparoscopic approach for effective treatment. Can Urol Assoc J. 2009 Dec;3(6):E81-3.
23) Carmack AJ, Siddiq FM, Leveillee RJ. Novel use of da Vinci Robotic Surgical System: removal of seminal vesicle cyst in previously dissected pelvis. Urology. 2006 Jan;67(1):199.
24) Moore CD, Erhard MJ, and Dahm P: Robot-assisted excision of seminal vesicle cyst associated with ipsilateral renal agenesis. J Endourol 21: 776-779, 2007.
25) Selli C, Cavalleri S, De Maria M, Iafrate M, Giannarini G. Robot-assisted removal of a large seminal vesicle cyst with ipsilateral renal agenesis associated with an ectopic ureter and a Müllerian cyst of the vas deferens. Urology. 2008 Jun;71(6):1226.e5-7. Epub 2008 Feb 21.
26) Hong YK, Onal B, Diamond DA, Retik AB, Cendron M, Nguyen HT. Robot-assisted laparoscopic excision of symptomatic retrovesical cysts in boys and young adults. J Urol. 2011 Dec;186(6):2372-8. Epub 2011 Oct 20.
27) O’Leary MP. Orgasmic Pain and a Detectable PSA Level after Radical Prostatectomy. Rev Urol. 2005 Fall; 7(4): 240–241.
The idea of a joint fund-raising trek in support of Prostate Cancer UK (formerly Prostate Action) and Well-Being of Women (WoW) dates back to 2005, when almost 100 trekkers joined us to walk across the desert to Petra in Jordan to raise more than £600,000 for these two noble causes. Neither Marcus Setchell nor I thought then that subsequently we would go on to trek in Kenya, Sinai, Kerala, and most recently Morocco, to raise an eventual cumulative sum of £1.3 million.
The fifth and final Hike for Hope started inauspiciously with dark clouds and pouring rain, even though we were in Morocco in September, just a couple of hundred miles North of the Sahara desert. They told us it hadn’t rained for the whole year before we got there! Undaunted, but with little in the way of rain-gear, rather, an excess of redundant sunscreen products, we set off across the Ante-Atlas mountains in the direction of Marrakesh.
This time, there were 27 intrepid trekkers, including the redoubtable Andrew Etherington, Felicity Hoare and Rex Willoughby, veterans who had each accompanied us on all the previous four Hikes for Hope, as well as Rosemary Macaire. Unfortunately on day one the rain became steadily heavier, with the result that the beds of the mountain streams, usually dry, became minor torrents, which were more and more difficult to cross. We made the decision to abandon the last hour’s walking to the camp and instead managed to persuade some of the local people to let us shelter in two of their mountain huts for that night.
Days two and three were tough trekking, but in fine dry weather. We got to the very highest point of the mountain before holding a minute’s silence for those relatives and friends who had succumbed to prostate or pelvic cancer, the cures for which we were raising money. Perhaps as the result of our efforts, we are a little closer to that goal.
On day four the rain returned, this time with even greater intensity, and accompanied by a bitterly cold wind. With little in the way of protective clothing, hypothermia became an issue. Again the amazing hospitality of the local Berber goat herders came to our rescue. Cold, wet and shivering, packed in again like sardines, we managed to get some sleep, occasionally interrupted by a goat or two, who seemed justifiably irritated to be displaced from their usual place of nocturnal shelter! To the credit of the guides, the trek doctor and the trekkers themselves, morale and good humour were maintained.
On the final day the weather improved sufficiently for us to trek down the mountain to join the first road we had encountered for five days. A drive through the Atlas Mountains took us to the wonderful city of Marrakesh, where a well-deserved celebratory dinner and award ceremony took place. The trials and tribulations of our mountain trek had brought us all much closer together, so it was with a tinge of sadness that the Hikers for Hope disbanded and headed for home. The final sum of money raised and the camaraderie and bonding that occurred during the trek made the whole experience so very worthwhile.
A recent editorial in the BMJ by Christopher Parker (Treating prostate cancer. BMJ 2012; 345: e5122)uses the “best available evidence” from the PIVOT study (Wilt TJ, et al) to argue the case for watchful waiting for low risk prostate cancer and question the need to diagnose the condition at all. Unfortunately the PIVOT trial was marred by a number of serious flaws that should make us doubt its conclusions.
The original design of the PIVOT trial included a randomisation of 2000 patients to surgery or observation (Prostate cancer, uncertainty and a way forward. NEJM 2012; 367: 270-1). Unfortunately, this goal was not achieved; the design was modified to justify a randomization goal of only 740 patients. Median survival was assumed to be 15 years in the original study design and 10 years in the updated version. If the median survival of 12 years in the study’s observation group is taken and 7 years for enrollment and 8 years of follow-up assumed, the sample requires 1200 patients in order to detect a 25% relative reduction in mortality with 90% power and a two-sided alpha level of 0.05. With an actual enrollment of only 731 patients, the study was consequently underpowered to detect this relatively large clinical effect. The wide 95% confidence interval around the hazard ratio for death in the treatment group illustrates this point. A relative increase of 8% to a relative reduction of 29% in the risk of death in the prostatectomy group, as compared with the observation group, cannot be excluded with 95% confidence. Only 15% of the deaths were attributed to prostate cancer or its treatment.
Although a “life expectancy of at least 10 years” was an entry criterion, by 10 years almost half the participants had died, leaving only 176 men in the surgery group and 187 in the observation cohort, and by 15 years only 30% were alive. The investigators therefore did not recruit healthy men who would be the normal candidates for surgery and randomize them to observation; instead they recruited elderly and co-morbid men with very limited life expectancy and randomised them to surgery (with one fatality!). Furthermore, the finding that one fifth of patients did not adhere to the assigned treatment further reduces the ability of the trial to discern a treatment effect.
Prostate cancer is a slowly progressive condition which eventually, and after many years, results in a painful death from metastases in a significant number of patients, unless mortality from other causes supervenes. Radical prostatectomy, now usually performed minimally invasively with robotic assistance (Goldstraw MA, et al), prevents disease progression in >80% of well-selected cases. We appear to manage localised prostate cancer in a much more holistic way than our American colleagues and MDT decision-making and robust active surveillance programmes have enhanced this. Others were also outraged by the Parker editorial and the intrinsically flawed results of the PIVOT study should definitely not encourage us to turn our backs on a disease that kills more than 10,000 men per annum in the UK and hundreds of thousands more worldwide.
Roger Kirby, Ben Challacombe and Prokar Dasgupta The Prostate Centre, London W1G 8GT and Guy’s Hospital, King’s College London, King’s Health Partners
Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.
In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.
If you only have time to read one article this week, it should be this one.
Expression patterns of epithelial–mesenchymal transition markers in localized prostate cancer: significance in clinicopathological outcomes following radical prostatectomy
Hosny M. Behnsawy, Hideaki Miyake, Ken-Ichi Harada and Masato Fujisawa
• To analyse the expression patterns of multiple molecular markers implicated in epithelial–mesenchymal transition (EMT) in localized prostate cancer (PC), in order to clarify the significance of these markers in patients undergoing radical prostatectomy (RP).
PATIENTS AND METHODS
• Expression levels of 13 EMT markers, namely E-cadherin, N-cadherin, b-catenin, g-catenin, fibronectin, matrix metalloproteinase (MMP) 2, MMP-9, Slug, Snail, Twist, vimentin, ZEB1 and ZEB2, in RP specimens from 197 consecutive patients with localized PC were evaluated by immunohistochemical staining.
RESULTS
• Of the 13 markers, expression levels of E-cadherin, Snail, Twist and vimentin were closely associated with several conventional prognostic factors.
• Univariate analysis identified these four EMT markers as significant predictors for biochemical recurrence (BR), while serum prostate-specific antigen, Gleason score, seminal vesicle invasion (SVI), surgical margin status (SMS) and tumour volume were also significant.
• Of these significant factors, expression levels of Twist and vimentin, SVI and SMS appeared to be independently related to BR on multivariate analysis
• There were significant differences in BR-free survival according to positive numbers of these four independent factors. That is, BR occurred in four of 90 patients who were negative for risk factors (4.4%), 21 of 83 positive for one or two risk factors (25.3%) and 19 of 24 positive for three or four risk factors (79.2%).
CONCLUSION
• Measurement of expression levels of potential EMT markers, particularly Twist and vimentin, in RP specimens, in addition to conventional prognostic parameters, would contribute to the accurate prediction of the biochemical outcome in patients with localized PC following RP.
Emily A. Matuszak and Natasha Kyprianou
Departments of Toxicology, Urology and Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA
Radical prostatectomy is among the most successful treatment modalities for patients exhibiting clinically localized prostate cancer. Despite this, roughly one-third of all radical prostatectomy patients will experience biochemical recurrence following prostatectomy. Curing prostate cancer requires a greater understanding of distinct biological events that differentiate prostate cancer from advanced life-threatening disease. Thus, a current challenge facing the clinical management of prostate cancer is the need for novel prognostic biomarkers capable of predicting biochemical recurrence to direct therapeutic interventions at earlier disease stages.
The oncogenic epithelial–mesenchymal transition (EMT) plays a critical role in metastatic prostate cancer progression [1]. EMTs engender coordinated molecular and genetic events which provoke phenotypic transformations that are indicative of the acquisition of mesenchymal characteristics which yield altered cellular behaviours [2]. Such altered behaviours may include but are not limited to enhanced migratory capability, increased invasive capacity, heightened resistance to apoptosis and conferred stem-like properties [3,4]. Conversion of an epithelial-derived prostate cancer cell to a more mesenchymal-like state has recently been implicated in prostate tumourigenesis as a mechanism facilitating the progression to metastatic castration-resistant disease [5].While alterations in the expression profiles of numerous EMT-associated transcriptional regulators and their molecular targets have served as biomarkers for studying EMT programmes, less is known about the contributions of EMTs in the emergence of treatment failure and tumour recurrence. Recently, EMT has been suggested to be a programme involved in metastatic disease progression that may also profoundly influence therapeutic outcomes amongst patients. Thus, it may be advantageous to develop predictors for risk assessment among prostate cancer patients that include specific EMT-associated markers in clinical evaluations.
Despite our current lack of knowledge regarding the clinicopathological significance of EMT, the potential value of an EMT marker signature as a prognostic indicator of biochemical recurrence among prostate cancer patients has emerged with some promise. Behnsawy et al. establish an initial path towards estimating the clinical value of assessing EMT marker levels in tandem with conventional clinicopathological prognostic factors in radical prostatectomy specimens from patients with organ confined prostate cancer, without any neoadjuvant therapy. Their evaluation follows a robust profile and results intriguingly reflect a pattern that may facilitate prediction of biochemical recurrence among patients. Using an exhaustive immunohistochemical analysis, the expression patterns of 13 EMT markers were evaluated in 197 radical prostatectomy specimens of which the expression levels of two EMT-associated markers, Twist and vimentin, were the most promising factors for such predictions.
The novel aspect and translational significance of this study are both reflected in the homogeneity of the patient population, in terms of localized organ confined disease. It represents an initial step towards recognizing an expression signature for specific EMT-associated factors in the therapeutic outcome of localized prostate cancer, but not disease progression. While the clinical impact of the reported findings may not be fully apparent, one may begin to speculate the promise of incorporating EMT-associated biomarkers in a clinical setting to facilitate diagnosis, prognosis and/or directing treatment strategies among patients. Primary endpoints of acquisition of an EMT phenotype following androgen axis targeting treatment must be clearly defined in the design of future clinical trials for the treatment of prostate cancer patients, with caution being given to selection of biopsy specimens vs radical prostatectomy specimens at an ‘optimal’ EMT window and in order to mitigate bias in tissue sampling resulting from long duration of therapeutic intervention. Control groups will provide valuable biological material to identify alternative mechanisms of treatment resistance (MAPK signalling). The statistical power in the relatively large cohort analysed enhances our confidence in considering the EMT landscape as an attractive platform for prediction of therapeutic response in future clinical trials. The concern, however, of whether improved prediction of biochemical recurrence by EMT profiling in pretreatment biopsies justifies its integration in the clinicopathological parameters (Gleason score, PSA) remains. Thus high expectations and much promise surround the pathological exploitation of EMT biomarkers (as signatures) in identifying profiles of tumour aggressiveness and providing a significant contribution in our quest towards the development of personalized therapies in prostate cancer patients with advanced disease.
References 1 Matuszak E, Kyprianou N. Androgen regulation of epithelial–mesenchymal transition in prostate tumorigenesis. Expert Rev Endo Metab 2011; 6: 469–82
2 Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial–mesenchymal transition in development and disease. Cell 2009; 139: 871–90
3 Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 2009; 9: 265–73
4 Kalluri R, Weinberg R. The basics of epithelial–mesenchymal transition. J Clin Invest 2009; 119: 1420–8
5 Tanaka H, Kono E, Tran CP et al. Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nat Med 2010; 16: 1414–20
Deep vein thromboses (DVT) and pulmonary embolism (PE) are rare, but potentially devastating, complications of major pelvic surgery. We have performed more than 1000 robot assisted radical prostatectomy (RARP) procedures in Central London (Lessons learned from 1000 RARP operations BJUI 2013;111(1):9-10.) and to date encountered just a couple of DVTs, as well as a single, non-fatal instance of PE. However, in the case of one of us (RK), a close relative passed away as a result of a PE 10 days after a routine hip replacement performed in Oxford, a very sad event which highlighted the very negative impact on the family of this preventable surgical complication.
Guidance from NICE recommends that evidence-based steps be taken to reduce the risk of venous thromboembolism (VTE). Failure to do so therefore renders us open to criticism if a DVT, or worse a PE, does develop. On the other hand, pelvic haematoma and haematuria are troublesome complications of RARP, the risks of which may be exacerbated by anticoagulation.
What therefore should we be doing to reduce the risk of before and after laparoscopic pelvic surgery? Few would disagree that TED stockings should be worn before and after surgery, but how long should they be retained, as many patients do find them rather uncomfortable? Calf compression boots during surgery and for 12 hours or so post-operatively should also be standard practice.
More contentious is the duration of use of low molecular weight heparin (LMWH). Some surgeons use a single dose immediately prior to the operation; we have used 5000 Units of Clexane post-operatively for 2-3 days. Orthopaedic surgeons are increasingly continuing LMWH for 28 days at home after joint replacement surgery, which carries a significant risk of VTE. Should we follow their lead? A simpler alternative from the patients’ viewpoint is daily use of one of the new oral anti-coagulants such as dabigatran.
Perhaps the most sensible approach clinically is to perform a risk assessment of all RALP candidates pre-operatively. A calf compression device and TED stockings should be used for all patients, together with LMWH, while in hospital. Those considered especially at risk with, for example, a BMI >30 (Becattini CA) (See Box 1), should usually go home for a month with either LMWH injections or daily oral dabigatran, or equivalent oral anticoagulant agent.
We would be most interested in the views, experiences and current practice of the readers of this piece. Please do post your own response.
Roger Kirby, Ben Challacombe and Prokar Dasgupta The Prostate Centre, London W1G 8GT and Guy’s Hospital, King’s College London, King’s Health Partners
+ Metastatic prostate cancer – it’s getting complicated…
2012 was a year of hope for metastatic prostate cancer patients. First, Enzalutamide (also known as MDV3100), in the context of a phase III RCT, was shown to prolong the survival of men with metastatic prostate cancer after chemo. And just when we thought the year was over, Abiraterone, which was previously shown to improve survival in patients with metastatic prostate cancer after chemotherapy, was found to be beneficial even in chemo-naive patients. All this translates into more complicated algorithms for castrate-resistant prostate cancer. That said, my question is the following: what happens if these drugs are effective at treating localized prostate cancer? It seems that some medical oncologists are trying to figure that out. Prostatectomists, murky waters lie ahead! Oh wait, I’m part of that group.
+ The changing landscape of surgical education
Times They Are a-Changin’. Residents are working less but don’t sleep more. 16-hour work day restrictions. More women are admitted into surgical fields. Protected nap (sleep) time during calls. Residents not covering floor consults during the day (those are actually the rules where I work). Most trainees now value quality of life above anything else, possibly even the quality of their training (do read this beautiful piece by a Urologist in JAMA: ‘Considering Life Before Lifestyle‘. Yet, the amount of knowledge a resident needs to consolidate during residency is at least 10-fold greater than what the old geezers had to learn back in the days (the current Campbell-Walsh is 134 chapters, 4320 pages). Whether or not you agree with any of the above (which is irrelevant anyways, because it’s happening whether you like it or not), attending surgeons and urologists are finding it hard to adapt or understand. “Honey, things were much harder back when I was a resident…” How do we evolve as a sub-specialty without compromising surgical education (or lengthening residency)? Status quo is not an option.
+ Radiotherapy for prostate cancer – what’s up with that?
+ Urology at the forefront of the social media revolution
As a group, we should be proud of how we embraced social media in 2012. In the field of medicine, where anything novel is usually met with smirk and mockery (see: surgery, robot-assisted), social media has been surprisingly well received, thanks to a tight-knit community of twitter champions (if you’re new to twitter, you should definitely follow urologymatch.com’s list of key opinion leaders (KOLs) in Urology. Moreover, the first International Urology Journal Club was held in November 2012 and has been a global success ever since. I’m sure that 2012 was only the start. It will be exciting to see the role of social media in upcoming international meetings such as the EAU, AUA and BAUS. Virtual high-five everyone!
+ Be inspired.
OK, so this one has nothing to do with Urology, or Medicine for that matter. Here’s a toast to the events that shook 2012, and let’s hope that 2013 will be a great year!
Quoc-Dien Trinh is a minimally-invasive urologist and co-director of the Cancer Prognostics and Health Outcomes Unit. His research focuses on patterns of care, costs and outcomes in prostate cancer treatment.
I remember distinctly when the penny dropped for me. It was about 2am on a warm summer’s night in early January 2012 (apologies to those of you shivering in the Northern Hemisphere). I had my one-week old son in one arm, swinging between sleeping and spewing, and an iPad in my other hand, providing distraction between nappy changes and feeds. The sleep-deprivation had dulled my senses considerably and my brain was capable of no more than light reading.
It was then I read a piece in the New York Times online about the power of Twitter in medical communication. Previously, I thought Twitter was the domain of Lady Gaga, Justin Bieber, Kim Kardashian (Kim who?) and various narcissistic cricket and football players. It seemed like puerile nonsense for a generation that I no longer belonged to. However, reading this opinion piece made me think again. It was clear that there is a whole generation of significant academic clinicians, researchers and publishers who have embraced social media and who use Twitter, in particular, to disseminate their work with a speed and reach that is simply unachievable through any other medium. I was struck by various examples of how key scientific publications are first flagged on Twitter and how within hours, responses are made by key opinion leaders and these responses are again disseminated rapidly around the Twittersphere. And although none of the examples were based around urology, it was clear to me that oncologists and surgeons were getting on board the social media rollercoaster.
So between nappy changes and having wiped some baby vomit off my iPad, I logged onto Twitter and created a username. I searched for prostate cancer and urology and quickly found my way to a few key resources and super-users who seemed to have a very active Twitter presence and who were tweeting content that immediately appeared of interest to me. Within a few minutes I had identified a few highly valuable Twitter users to follow and within their lists of followers and those who they were following, I quickly built up a useful stream of tweets dropping into my timeline. And then of course, a few of these Twitterers started following me back, which was mildly exciting. Within a few days and having posted a few tweaks, I began to feel part of the Twittersphere.
As the weeks went by, I continued to be astounded by just how fast information travels on Twitter. While I get emails with the table of contents for the various journals that I subscribe to, these only drop in my inbox every few weeks. Also, because there are a number of significant journals that I do not subscribe to (non-urological mostly), there are many papers published out there that do not come immediately to my attention. Depending on which Twitter sites you follow, all key papers related to your area of interest find their way into your timeline instantaneously as soon as they are published. Not just that, very interesting comment from others also gets to you very quickly. For example, key findings in prostate cancer tend to be picked up by the major US news sites who then invite comment from key leaders in major cancer centres. A typical example is that of the PSA screening recommendations made by the United States Preventive Services Taskforce in June 2012, which provoked huge controversy. Twitter came to life and key opinion leaders such as Matt Cooperberg (@cooperberg_ucsf) helped drive the conversation through Twitter and blogs (e.g.The Huffington Post blog) at lightning speed. These comments get tweeted out and responses to these comments also get blogged and within hours of a paper being published you have news of the paper, expert comment and wider reaction…… all in 140 characters or less!
And while none of us have much time in the day to add an extra task, I find that waiting for my coffee in the morning or while the resident puts an arterial line in my next patient, there are a few spare moments in the day where the Twitter app on my iPhone comes to life. Twitter is perfectly suited to the smart phone user and that is where the majority of tweets around the world are generated from. It is also perfectly suited for one of the other very exciting areas in which I have seen Twitter play a very useful role – that of conferencing. At the EAU in Paris, a small but energetic group of Twitter users started tweeting content from various sessions at this large meeting and started engaging with other Twitter users around the world. For me, I believe conferencing is about to be transformed by the power of social media but more about that soon.
For now, at the new BJUI, we want to grow the audience and get you all to join the conversation. Through Twitter, blogging, Facebook, YouTube and other social media platforms, we are building for the future of communication in urology. The next generation of trainees will be deeply embedded in all of these platforms and will expect to be engaged through them. We are entering a new generation of medical communication – come join the conversation.
Declan Murphyis Honorary Clinical Associate Professor at the Department of Surgery, University of Melbourne, St Vincent’s Hospital and Director of Robotic Surgery at the Peter MacCallum Cancer Centre. He had previously been consultant urological surgeon at Guys & St Thomas’ NHS Foundation Trust in London.
Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.
In addition to the article itself, there is an accompanying blog written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.
Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video of John Eifler and Alan Partin discussing their paper.
If you only have time to read one article this week, it should be this one.
An updated prostate cancer staging nomogram (Partin tables) based on cases from 2006 to 2011
John B. Eifler, Zhaoyang Feng, Brian M. Lin, Michael T. Partin, Elizabeth B. Humphreys, Misop Han, Jonathan I. Epstein, Patrick C. Walsh, Bruce J. Trock, Alan W. Partin
• To update the 2007 Partin tables in a contemporary patient population.
PATIENTS AND METHODS
The study population consisted of 5,629 consecutive men who underwent RP and staging lymphadenectomy at the Johns Hopkins Hospital between January 1, 2006 and July 30, 2011 and met inclusion criteria.
• Polychotomous logistic regression analysis was used to predict the probability of each pathologic stage category: organ-confined disease (OC), extraprostatic extension (EPE), seminal vesicle involvement (SV+), or lymph node involvement (LN+) based on preoperative criteria.
• Preoperative variables included biopsy Gleason score (6, 3+4, 4+3, 8, and 9–10), serum PSA (0–2.5, 2.6–4.0, 4.1–6.0, 6.1–10.0, greater than 10.0 ng/mL), and clinical stage (T1c, T2c, and T2b/T2c).
• Bootstrap re-sampling with 1000 replications was performed to estimate 95% confidence intervals for predicted probabilities of each pathologic state.
RESULTS
• The median PSA was 4.9 ng/mL, 63% had Gleason 6 disease, and 78% of men had T1c disease.
• 73% of patients had OC disease, 23% had EPE, 3% had SV+ but not LN+, and 1% had LN+ disease. Compared to the previous Partin nomogram, there was no change in the distribution of pathologic state.
• The risk of LN+ disease was significantly higher for tumors with biopsy Gleason 9–10 than Gleason 8 (O.R. 3.2, 95% CI 1.3–7.6).
• The c-indexes for EPE vs. OC, SV+ vs. OC, and LN+ vs. OC were 0.702, 0.853, and 0.917, respectively.
• Men with biopsy Gleason 4+3 and Gleason 8 had similar predicted probabilities for all pathologic stages.
• Most men presenting with Gleason 6 disease or Gleason 3+4 disease have <2% risk of harboring LN+ disease and may have lymphadenectomy omitted at RP.
CONCLUSIONS
• The distribution of pathologic stages did not change at our institution between 2000–2005 and 2006–2011.
• The updated Partin nomogram takes into account the updated Gleason scoring system and may be more accurate for contemporary patients diagnosed with prostate cancer.
Erratum:
A typographical error was identified in Table 2, for the cell corresponding to the probability for EPE in a man with clinical stage T1c, PSA >10, and biopsy Gleason 4+3. The cell should read “38 (32-45)” rather than “28 (32-45).” Also, in the third paragraph of the Results section, the fourth sentence should be changed to “In contrast, the predicted risk of LN+ is no more than 3% for T1c tumours with biopsy Gleason score <9 for an PSA below 10.”
