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Editorial: Hot topic of cancer survivorship and the ‘seven deadly sins’

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Cancer survivorship has become a hot topic as overall mortality for most cancer patients continues to decrease, the worldwide population continues to age and as patients become more information savvy [1-3]. Gavin et al. [4] provide a data-rich population-based patient survey of seven of the most common physical symptoms after prostate cancer treatment. While we, as urologists and prostate cancer providers, may not be able to recount the seven deadly sins or the seven dwarfs, we do know these seven symptoms: impotence; incontinence; bowel problems; fatigue; hot flushes; loss of libido; and breast symptoms. Urological surgeons and radiation oncologists talk to patients every day about the ‘big three’ of these: impotence, incontinence and bowel problems. Gavin et al. provide the striking statistic that ~1.6% of the male population over the age of 45 years is a prostate cancer survivor currently living with one of the seven.

The paper describes mailed survey results from a population-based cohort of 3 348 prostate cancer survivors 2–15 years after diagnosis with a response rate of 54%. The average age of respondents was 64.9 years, 64% had localized disease at presentation, 65% had Gleason 5–7 disease, and 48, 32 and 20% were surveyed 2–4.9, 5–9.9 and >10 years after diagnosis, respectively. The paper is chock full of descriptive statistics about rates of past and ongoing side effects of the various treatments and essentially has ‘something for everyone’. For example, at baseline before treatment, 51.2% of respondents reported urinary frequency, 18.8% reported impotence and 14.7% reported loss of libido. These data may be useful for estimating population-based general men’s health disease. After treatment, radical prostatectomy (RP) had the highest rates of impotence (76% current) and incontinence (current 28%; ever 70%); however, the authors examined radiation plus hormonal therapy and found impotence rates of 64% and rates of hot flushes, breast changes and bowel problems in the 20–27% range. Table 3 and Figs 3 and 4 in the paper are particularly useful to further examine the seven side effects with treatment.

On the one hand, these data could be useful in educating patients about treatment options for prostate cancer and what they might expect should they choose one treatment over another. Ideally, this education would occur in the multidisciplinary clinic setting [5]. On the other hand, these data could also be used in the wrong way. For example, an aggressive surgeon could selectively present the ‘deadly downsides’ of radiation while downplaying the ‘surgical sins’, whereas a radiation oncologist could do just the opposite to try to influence his or her patients. This highlights the limitations of the present study. While the authors are to be congratulated for a wonderful population-based survey, no control group was surveyed and, more importantly, the authors do not address satisfaction and regret. In other words, the seven side effects must be placed into the patient’s overall satisfaction regarding cancer control and the patient’s ‘trade-offs individualized internal assessment’. For example, our group examined satisfaction and regret after open and robot-assisted RP, finding an ~80–85% satisfaction rate despite levels of impotence and incontinence slightly lower but similar to those in the present population-based survey [6]. While patients who underwent open RP enjoyed more satisfaction and less regret, we attributed much of this to the ‘used car salesman’ approach to ‘selling’ robot-assisted RP in the last decade [7]. In other words, we hypothesized that patients undergoing robot-assisted RP were misled into believing the robot would lessen or eliminate the surgical sins while those undergoing open RP were counselled more realistically. Also, we found that in multivariable analysis, African-American patients exhibited more regret [6]. These data point to the fact that the present study from Ireland may not be applicable to other populations, particularly those with a mixed or different ethnic make-up. Another limitation to population-based data is the impact of centres of excellence and highly experienced treatment providers. The impact of high-volume surgeons/providers on treatment outcomes is now being recognized as a critical variable that is rarely accounted for in case series, multicentre studies or population data as seen here.

Overall, Gavin et al. are to be commended for a very rich source of side effect data for a large population-based cohort of prostate cancer survivors. The ‘seven deadly sins’ of possible side effects/complications of prostate cancer treatment should be shared openly and honestly with our patients. Furthermore, physicians and healthcare systems must be encouraged to collect provider and system-specific data to better fine-tune our pre-treatment counselling that will ultimately improve the satisfaction of our cancer survivors.

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Judd W. Moul
Duke Cancer Institute, Durham, NC, USA

 

References

1 Resnick MJ, Lacchetti C, Bergman J et al. Prostate cancer survivorship care guideline: American society of clinical oncology clinical practice guideline endorsement. J Clin Oncol 2015; 33: 1078–85

2 Skolarus TA, Wolf AM, Erb NL et al. American Cancer Society prostate cancer survivorship care guidelines. CA Cancer J Clin 2014; 64: 225–49; Erratum in: CA Cancer J Clin. 2014; 64: 445

3 Gupta S, Peterson AC. Stress urinary incontinence in the prostate cancer survivor. Curr Opin Urol 2014; 24: 395–400

4 Gavin A, Drummond F, Donnelly C, O’Leary E, Sharp L, Kinnear H. Patient reported ‘ever had’ and ‘current’ long-term physical symptoms following prostate cancer treatments. BJU Int 2015.

5 Stewart SB, Ba~nez LL, Robertson CN et al. Utilization trends at a multidisciplinary prostate cancer clinic: initial 5-year experience from the Duke Prostate Center. J Urol 2012; 187: 103–8

6 Schroeck FR, Krupski TL, Sun L et al. Satisfaction and regret after open retropubic or robot-assisted laparoscopic radical prostatectomy. Eur Urol 2008; 54: 785–93

7 Schroeck FR, Krupski TL, Stewart SB et al. Pretreatment expectations of patients undergoing robotic assisted laparoscopic or open retropubic radical prostatectomy. J Urol 2012; 187: 894–8

 

Video: Patient-reported long-term physical symptoms after prostate cancer treatments

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Patient reported “ever had” and “current” long term physical symptoms following prostate cancer treatments.

To investigate the prevalence of physical symptoms that were ‘ever’ and ‘currently’ experienced by survivors of prostate cancer at a population level, to assess burden and thus inform policy to support survivors. The study included 3 348 men surviving prostate cancer for 2-18 years after diagnosis. A cross-sectional, postal survey of 6 559 survivors diagnosed 2-18 years ago with primary, invasive prostate cancer (ICD10-C61) identified via national, population-based cancer registries in Northern Ireland and Republic of Ireland. Questions included symptoms at diagnosis, primary treatments and physical symptoms (erectile dysfunction [ED]/urinary incontinence [UI]/bowel problems/breast changes/loss of libido/hot flashes/fatigue) experienced ‘ever’ and at questionnaire completion (‘current’). Symptom proportions were weighted by age, country and time since diagnosis. Bonferroni corrections were applied for multiple comparisons.

Adjusted response rate 54%; 75% reported at least one ‘current’ physical symptom (‘ever’ 90%), with 29% reporting at least three. Prevalence varied by the diverse treatments found at https://www.ukmeds.co.uk/finasteride. Overall, 57% reported current ED and this was highest after radical prostatectomy (RP, 76%) followed by external beam radiotherapy with concurrent hormone therapy (HT, 64%). UI (overall ‘current’ 16%) was highest after RP (‘current’ 28%; ‘ever’ 70%). While 42% of brachytherapy patients reported no ‘current’ symptoms, 43% reported ‘current’ ED and 8% ‘current’ UI. ‘Current’ hot flashes (41%), breast changes (18%) and fatigue (28%) were reported more often by patients on HT.

Anna T. Gavin, Frances J. Drummond*, Conan Donnelly, Eamonn O’Leary*, Linda Sharp† and Heather R. Kinnear

Northern Ireland Cancer Registry, Centre for Public Health, Queen’s University Belfast, Mulhouse Building, Belfast Northern Ireland, UK, *National Cancer Registry Ireland, Building 6800, Airport Business Park Cork, Ireland, and †Institute of Health and Society, Newcastle University, Richardson Road, Newcastle upon Tyne, NE2 4AX, England, UK

 

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OBJECTIVE

To investigate the prevalence of physical symptoms that were ‘ever’ and ‘currently’ experienced by survivors of prostate cancer at a population level, to assess burden and thus inform policy to support survivors.

PATIENTS AND METHODS

The study included 3 348 men surviving prostate cancer for 2–18 years after diagnosis. A cross-sectional, postal survey of 6 559 survivors diagnosed 2–18 years ago with primary, invasive prostate cancer (ICD10-C61) identified via national, population-based cancer registries in Northern Ireland and Republic of Ireland. Questions included symptoms at diagnosis, primary treatments and physical symptoms (erectile dysfunction [ED]/urinary incontinence [UI]/bowel problems/breast changes/loss of libido/hot flashes/fatigue) experienced ‘ever’ and at questionnaire completion (‘current’). Symptom proportions were weighted by age, country and time since diagnosis. Bonferroni corrections were applied for multiple comparisons.

RESULTS

Adjusted response rate 54%; 75% reported at least one ‘current’ physical symptom (‘ever’ 90%), with 29% reporting at least three. Prevalence varied by treatment. Overall, 57% reported current ED and this was highest after radical prostatectomy (RP, 76%) followed by external beam radiotherapy with concurrent hormone therapy (HT, 64%). UI (overall ‘current’ 16%) was highest after RP (‘current’ 28%; ‘ever’ 70%). While 42% of brachytherapy patients reported no ‘current’ symptoms, 43% reported ‘current’ ED and 8% ‘current’ UI. ‘Current’ hot flashes (41%), breast changes (18%) and fatigue (28%) were reported more often by patients on HT.

CONCLUSION

Symptoms after prostate cancer treatment are common, often multiple, persist long-term and vary by treatment method. They represent a significant health burden. An estimated 1.6% of men aged >45 years are survivors of prostate cancer and currently experiencing an adverse physical symptom. Recognition and treatment of physical symptoms should be prioritised in patient follow-up. This information should facilitate men and clinicians when deciding about treatment as differences in survival between radical treatments is minimal.

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Here comes the sun

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BJUI-on-the-beach

Sun, sea, sand and stones: BJUI on the beach.

Welcome to this month’s BJUI and whether you are relaxing on a sun-drenched beach or villa somewhere having a hard-earned break, or back at your hospital covering for everyone else having their time off, we hope you will enjoy another fantastic issue. After an action packed BAUS meeting with important trial results, innovation, social media and the BJUI fully to the fore, this is a great moment to update yourself on what is hot in urology. This is probably the time of year when most urologists have a little extra time to take the BJUI out of its cover or open up the iPad and dig a little deeper into the articles, and we do not think you will be disappointed with this issue, which certainly has something for everyone.

In the ‘Article of the Month’, we feature an important paper from Egypt [1] examining factors associated with effective delayed primary repair of pelvic fractures that are associated with a urethral injury. Do be careful whilst you are travelling around the world, as most of the injuries in this paper were due to road traffic accidents. They reported 76/86 successful outcomes over a 7-year period. When a range of preoperative variables was assessed, four had particular significance for successful treatment outcomes. The paper really highlights that in the current urological world of robotics, laparoscopy and endourology, in some conditions traditional open surgery with delicate and precise tissue handling and real attention to surgical detail are the key components of a successful outcome.

Whilst you are eating and drinking more than usual over the summer, we have some food for thought on surgery and metabolic syndrome with one of our ‘Articles of the Week’. This paper contains an important message for all those performing bladder outflow surgery. This paper by Gacci et al. [2] from an international group of consecutive patients clearly shows that men with a waist circumference of >102 cm had a far higher risk of persistent symptoms after TURP or open prostatectomy. This was particularly true for storage symptoms in this group of men and should influence the consenting practice of all urologists carrying out this common surgery.

Make sure you drink plenty of Drink HRW to stay well hydrated on your beach this August, as the summer months often lead to increased numbers of patients presenting to emergency departments with acute ureteric colic, so it seems timely to focus on this area.To this end I would like to highlight one of our important ‘Guideline of Guidelines’ series featuring kidney stones [3] to add to the earlier ones on prostate cancer screening [4]and prostate cancer imaging [5]. This series serve to assimilate all of the major national and international guidelines into one easily digestible format with specific reference to the strength of evidence for each recommendation. Specifically, we look at the initial evaluation, diagnostic imaging selection, symptomatic management, surgical treatment, medical therapy, and prevention of recurrence for both ureteric and renal stones. Quite how the recent surprising results of the SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial will impact on the use of medical expulsive therapy remains to be seen [6].

So whether you are sitting watching the sunset with a drink in your hand or quietly working in your home at night, please dig a little deeper into this month’s BJUI on paper, online or on tablet. It will not disappoint and might just change your future practice.

 

References

1 Koraitim MM, Kamel MI. Perineal repair of pelvic fracture urethral injury: in pursuit of a successful outcome. BJU Int 2015; 116: 265–70

 

2 Gacci M, Sebastianelli A, Salvi M et al. Central obesity is predictive of persistent storage lower urinary tract symptoms (LUTS) after surgery for benign prostatic enlargement: results of a multicentre prospective study. BJU Int 2015;116:271–7

 

3 Ziemba JB, Matlaga BR. Guideline of guidelines: kidney stones. BJU Int 2015; 116: 184–9

 

4 Loeb S. Guideline of guidelines: prostate cancer screening. BJU Int 2014; 114: 323–5

 

5 Wollin DA, Makarov DV. Guideline of guidelines: prostate cancer imaging. BJU Int 2015; [Epub ahead of print]. DOI: 10.1111/bju.13104

 

6 McClinton S, Starr K, Thomas R et al. Use of drug therapy in the management of symptomatic ureteric stones in hospitalized adults (SUSPEND), a multicentre, placebo controlled, randomized trial of a calcium-channel blocker (nifedipine) and an a-blocker (tamsulosin): study protocol for a randomized controlled trial. Trials 2014; 15: 238

 

Ben Challacombe
Associate Editor, BJUI 

 

Article of the Month: Perineal repair of PFUI – In pursuit of a successful outcome

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

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

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

Perineal repair of pelvic fracture urethral injury – In pursuit of a successful outcome

 

Mamdouh M. Koraitim and Mohamed I. Kamel*

 

Department of Urology and *Occupational and Enviromental Medicine, College of Medicine, University of Alexandria, Alexandria, Egypt

 

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OBJECTIVE

To determine perioperative factors that may optimize the outcome after delayed perineal repair of a pelvic fracture urethral injury (PFUI).

PATIENTS AND METHODS

In all, 86 consecutive patients who underwent perineal repair of a PFUI between 2004 and 2011 were prospectively enrolled in this study. The mean (range) patient age was 23 (5–50) years. The mean (range) follow-up was 5.5 (2–8) years. We examined seven perioperative variables that might influence the outcome including: prior failed treatment, condition of the bulbar urethra, displacement of the prostate, excision of scarred tissues, fixation of the mucosae of the two urethral ends, and the number and size of sutures used for urethral anastomosis. Univariate and multivariate analyses were used to identify factors that influence postoperative outcome.

RESULTS

Of the patients, 76 (88%) had successful outcomes and 10 (12%) were considered treatment failures. On univariate analysis, four variables were significant factors influencing the outcome: excision of scarred tissues, prostatic displacement, condition of the bulbar urethra and fixation of the mucosae. On multivariate analysis only two remained strong and independent factors namely complete excision of scarred tissues and prostatic displacement in a lateral direction.

CONCLUSIONS

Meticulous and complete excision of scar tissue is critically important to optimise the outcome after perineal urethroplasty. This is particularly emphasised in cases associated with lateral prostatic displacement. Six sutures of 3/0 or 4/0 polyglactin 910 are usually sufficient to create a sound urethral anastomosis. Prior treatment and scarring of the anterior urethra do not affect the outcome.

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Editorial: Specialty within a specialty – posterior urethroplasty

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Posterior urethral distractions occur in up to 25% of cases of blunt force pelvic fractures. Proper repair of these pelvic fracture urethral injuries (PFUI) is an art that requires exquisite attention to technique and tissue handling. Koraitim and Kamel [1] recently reported their single-surgeon series of PFUI repairs on 86 patients, with the specific aim of characterizing risk factors for treatment failure. Success was defined subjectively as absence of urinary symptoms and normal postoperative urethrography. Requirement for repeat procedures constituted failure. At a mean 5.5 years of direct follow-up, 88% of patients were considered to have had successful treatment. Multivariate logistic regression showed that incomplete scar excision and lateral prostatic displacement (as opposed to superior or no displacement) were predictive of treatment failure (odds ratios 122 and 34, respectively). All other factors analysed, including previous treatment, relative bulbar urethral scarring, mucosal fixation, suture size and number of sutures, were not significant predictors of urethral outcomes.

Large patient series of posterior urethroplasty report treatment success rates of 86–97%, although follow-up has been short in general [2-4]. The present report by Koraitim and Kamel compares favourably with these series, despite longer patient follow-up. This suggests that late failures after posterior urethral repair are rare. The authors should be commended for their desire to ascertain risk factors for failure after repair of these urethral injuries; however, several factors that probably affect outcomes were not evaluated and may at least partially explain some of their treatment failures.

Erectile dysfunction (ED) is known to occur in ~5% of men after pelvic fracture, and to increase to a mean of 42% in those with a concomitant urethral injury [5]. A portion of these men with ED will have arterial insufficiency and will be at increased risk of bulbar necrosis and ischaemic stenosis. Before urethral reconstruction, men with ED should be evaluated with penile duplex ultrasonography and, if arteriogenic ED is suggested, pelvic angiogram. In those with bilateral complete obstruction of the deep internal pudendal or common penile arteries, revascularization should be offered before urethral reconstruction. In this patient population, penile revascularization has been shown to reverse arterial insufficiency, leading to both improved erections and enhanced tissue perfusion for optimum outcomes after posterior urethral reconstruction [6].

A progressive perineal approach has been popularized by Webster and Ramon [4] and generally accepted by those regularly performing posterior urethral reconstruction. While the present authors report extensively on relative excision of fibrosis and number, type and location of suture utilization, they do not provide insight into the number of ancillary measures necessary for a tension-free repair. While some argue that the importance of crural separation and infrapubectomy are overstated [3], these techniques are essential in some patients in order to achieve a tension-free anastomosis. Given that fibrosis was incompletely excised in 15% of patients in this cohort, some of these same patients may also have had some degree of tension of the urethral anastomosis. Alternatively, these adjunctive procedures may be independent predictors of treatment success or failure and their role in this series would be interesting to note.

It is our experience, and surely that of others, that direct long-term follow-up after urethroplasty at a tertiary referral centre is often difficult or non-existent. These authors should be applauded for their ability to follow their patients for a mean 5.5 years in this series. They have provided much needed extended outcome data after posterior urethral reconstruction. The challenge going forward will be for high-volume centres of reconstruction to design studies prospectively that answer specific questions using standardized instruments and objective results.

Read the full article
Jack M. Zuckerman, Kurt A. McCammon and Gerald H. Jordan

 

Department of Urology, Eastern Virginia Medical School, Norfolk, VA, USA

 

References

 

1 Koraitim MM, Kamel MI. Perineal repair of pelvic fracture urethral injury: in pursuit of a successful outcome. BJU Int 2015; 116: 265–70

 

2 Cooperberg MR, McAninch JW, Alsikafi NF, Elliott SP. Urethral reconstruction for traumatic posterior urethral disruption: outcomes of a 25-year experience. J Urol 2007;178:2006–10; discussion 10

 

3 Kizer WS, Armenakas NA, Brandes SB, Cavalcanti AG, Santucci RA, Morey AF. Simplified reconstruction of posterior urethral disruption defects: limited role of supracrural rerouting. J Urol 2007;177:1378–81; discussion 81–2

 

4 Webster GD, Ramon J. Repair of pelvic fracture posterior urethral defects using an elaborated perineal approach: experience with 74 cases. J Urol 1991;145:744–8

 

5 Gomez RG, Mundy T, Dubey D et al. SIU/ICUD consultation on urethral strictures: pelvic fracture urethral injuries. Urology 2014;3(Suppl):S48–58

 

6 Zuckerman JM, McCammon KA, Tisdale BE et al. Outcome of penile revascularization for arteriogenic erectile dysfunction after pelvic fracture urethral injuries. Urology 2012;80:1369–73

 

Article of the Month: Targeted microbubbles in the treatment of kidney stones

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

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 from Dr. Krishna Ramaswamy, discussing his paper. 

Targeted microbubbles: A novel application for treatment of kidney stones

Krishna Ramaswamy, Vanessa Marx*, Daniel Laser†, Thomas Kenny‡, Thomas Chi, Michael Bailey§, Mathew D. Sorensen §, Robert H. Grubbs* and Marshall L. Stoller 

 

Department of Urology, University of California, San Francisco, *Department of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, †Wave 80 Biosciences, San Francisco, ‡Department of Mechanical Engineering, Stanford University, Stanford, CA, and §Department of Urology, University of Washington School of Medicine, Seattle, WA, USA 

 

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ABSTRACT
Kidney stone disease is endemic. Extracorporeal shockwave lithotripsy was the first major technological breakthrough where focused shockwaves were used to fragment stones in the kidney or ureter. The shockwaves induced the formation of cavitation bubbles, whose collapse released energy at the stone, and the energy fragmented the kidney stones into pieces small enough to be passed spontaneously. Can the concept of microbubbles be used without the bulky machine? The logical progression was to manufacture these powerful microbubbles ex vivo and inject these bubbles directly into the collecting system. An external source can be used to induce cavitation once the microbubbles are at their target; the key is targeting these microbubbles to specifically bind to kidney stones. Two important observations have been established: (i) bisphosphonates attach to hydroxyapatite crystals with high affinity; and (ii) there is substantial hydroxyapatite in most kidney stones. The microbubbles can be equipped with bisphosphonate tags to specifically target kidney stones. These bubbles will preferentially bind to the stone and not surrounding tissue, reducing collateral damage. Ultrasound or another suitable form of energy is then applied causing the microbubbles to induce cavitation and fragment the stones. This can be used as an adjunct to ureteroscopy or percutaneous lithotripsy to aid in fragmentation. Randall’s plaques, which also contain hydroxyapatite crystals, can also be targeted to pre-emptively destroy these stone precursors. Additionally, targeted microbubbles can aid in kidney stone diagnostics by virtue of being used as an adjunct to traditional imaging methods, especially useful in high-risk patient populations. This novel application of targeted microbubble technology not only represents the next frontier in minimally invasive stone surgery, but a platform technology for other areas of medicine.

 

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Article of the Month: Choline-PET/CT radical PCa treatment

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

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

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

Clinical utility of 18F-fluorocholine positron-emission tomography/computed tomography (PET/CT) in biochemical relapse of prostate cancer after radical treatment: results of a multicentre study

Sonia Rodado-Marina, Mónica Coronado-Poggio, Ana María García-Vicente*,
Jose Ramón García-Garzón†, Juan Carlos Alonso-Farto††, Aurora Crespo de la Jara‡, Antonio Maldonado-Suárez§ and Antonio Rodríguez-Fernández

 

Department of Nuclear Medicine, La Paz Universitary Hospital and §Quirón Universitary Hospital, Madrid, *Department of Nuclear Medicine, Universitary Hospital, Ciudad Real, †CETIR Unitat PET Esplugues, Barcelona, ††Gregorio Marañón Universitary Hospital, Madrid, ‡Department of Nuclear Medicine, Quirón Hospital, Torrevieja, and Department of Nuclear Medicine, Virgen de las Nieves Universitary Hospital, Granada, Spain

 

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OBJECTIVE

To evaluate 18F-fluorocholine positron-emission tomography (PET)/computed tomography (CT) in restaging patients with a history of prostate adenocarcinoma who have biochemical relapse after early radical treatment, and to correlate the technique’s disease detection rate with a set of variables and clinical and pathological parameters.

PATIENTS AND METHODS

This was a retrospective multicentre study that included 374 patients referred for choline-PET/CT who had biochemical relapse. In all, 233 patients who met the following inclusion criteria were analysed: diagnosis of prostate cancer; early radical treatment; biochemical relapse; main clinical and pathological variables; and clinical, pathological and imaging data needed to validate the results. Criteria used to validate the PET/CT: findings from other imaging techniques, clinical follow-up, treatment response and histological analysis. Different statistical tests were used depending on the distribution of the data to correlate the results of the choline-PET/CT with qualitative [T stage, N stage, early radical prostatectomy (RP) vs other treatments, hormone therapy concomitant to choline-PET/CT] and quantitative [age, Gleason score, prostate-specific antigen (PSA) levels at diagnosis, PSA nadir, PSA level on the day of the choline-PET/CT (Trigger PSA) and PSA doubling time (PSADT)] variables. We analysed whether there were independent predictive factors associated with positive PET/CT results.

RESULTS

Choline-PET/CT was positive in 111 of 233 patients (detection rate 47.6%) and negative in 122 (52.4%). Disease locations: prostate or prostate bed in 26 patients (23.4%); regional and/or distant lymph nodes in 52 (46.8%); and metastatic bone disease in 33 (29.7%). Positive findings were validated by: results from other imaging techniques in 35 patients (15.0%); at least 6 months of clinical follow-up in 136 (58.4%); treatment response in 24 (10.3%); histological analysis of lesions in 17 (7.3%); and follow-up plus imaging results in 21 (9.0%). The statistical analysis of qualitative variables, corresponding to patients’ clinical characteristics, and the positive/negative final PET/CT results revealed that only whether or not early treatment with RP was done was statistically significant (P < 0.001), with the number of positive results higher in patients who did not undergo a RP. Among the quantitative variables, Gleason score, Trigger PSA and PSADT clearly differentiated the two patient groups (positive and negative choline-PET/CT: P = 0.010, P = 0.001 and P = 0.025, respectively). A Gleason score of <5 or ≥8 clearly differentiated positive from negative PET. Trigger PSA: mean of 8 ng/mL for positive PET/CT vs 2.8 ng/mL for negative PET/CT; PSADT: mean of 8 months for positive vs 12.6 months for negative. The optimal threshold values were: 3 ng/mL for Trigger PSA level and 6 months for PSADT (Youden index/receiver operating characteristic curve). Analysing these two variables together showed that PSADT was more conclusive in patients with lower Trigger PSA levels. Analysing variables by location showed that only PSADT was able to differentiate between those with disease confined to the prostate compared with the other two locations (lymph nodes and bone), with shorter PSADT in these two, which was statistically significant (P < 0.002). In the patient group with a PSA level of <1.5 ng/mL, 30.8% had the disease, 7% of whom had metastatic bone disease. In the multivariate logistic regression, the risks factors that were clearly independent for those with positive PET/CT were: PSA level of >3 ng/mL, no early RP, and Gleason score of ≥8.

CONCLUSIONS

Our results support the usefulness of 18F-fluorocholine PET/CT in biochemical relapse of prostate cancer after radical treatment, with an overall disease detection rate close to 50%, and it can be recommended as first-line treatment. As mentioned above, besides Trigger PSA levels, there are other clinical and pathological variables that need to be considered so as to screen patients properly and thus minimise the number of nodular lesions and increase the diagnostic accuracy of the examination.

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Editorial: Choline-PET/CT in relapsing prostate cancer patients

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18F-choline positron emission tomography (PET)/C T has become a modern imaging technique in men with prostate cancer and biochemical relapse after local treatment with curative intent (radical prostatectomy, external beam/intensity-modulated radiation therapy, brachytherapy) in order to differentiate between local, locoregional and systemic relapse. Although 18F-choline PET/CT will probably be replaced by prostate-specific membrane antigen-PET/CT in the near future, the present paper by Rodada-Marina et al. [1] is important for daily routine because the authors attempt to define the current role of 18F-choline PET/CT in the diagnostic algorithm of men with relapsing PSA and to define specific patient cohorts in whom 18F-choline PET/CT might have a significant impact in the decision-making process regarding the most appropriate treatment.

Two issues are important to me when discussing the potential indication for performing new imaging studies in my patients with relapsing PSA: (1) whether the method is sensitive enough to detect a metastatic deposit at a given PSA serum concentration and (2) whether a positive finding using this imaging method would change my treatment recommendation. In this context, the current recommendation is 18F-choline PET/CT at a PSA serum concentration >1 ng/mL if a therapeutic consequence will be drawn [2]. If the patient would not be a candidate for a secondary local treatment option, such as salvage radiation therapy or salvage radical prostatectomy, but he would be treated with androgen deprivation therapy anyhow, none of the modern imaging studies would make sense.

In the present paper, a total of 233 patients from six different institutions were included in a retrospective study. One of the most important findings of this paper is that the detection rate was only 47.6%, despite relatively high mean and median trigger PSA serum levels of 5.3 and 2.8 ng/mL, respectively. The detection rates varied between 23.5 and 38.2% in men with PSA serum levels between <1 and 2–3 ng/mL and the detection only increased to 67% in men with PSA levels ≥3 ng/mL. Moreover, the authors identified that the best threshold for the trigger PSA level was 3.5 ng/mL, with a sensitivity and a specificity of 64 and 76%, respectively. With regard to PSA doubling time (PSA-DT), the best threshold was < 6 months, with a sensitivity and a specificity of 58% only. Based on these very high PSA serum levels at the time of imaging studies, which had the potential intent to select the most appropriate therapy, the majority of patients were already beyond the scope of secondary local therapy with curative intent [2, 3]. Furthermore, it was shown that patients with a Gleason score 8–10 and a PSA-DT of <6 months have a higher probability of having systemic disease – a fact which is well known already.

What do these data mean for clinical practice? There might be three clinical scenarios in which imaging studies might exert a significant impact on further treatment: (1) salvage radiation therapy in men with PSA relapse after radical prostatectomy (RP) [2, 3], (2) salvage RP after radiation therapy of the prostate [4] and (3) salvage pelvic lymphadenectomy in men with PSA relapse after RP or radiation therapy of the prostate [5]. In my view, the data underline the fact that imaging with 18F-choline PET/CT is not helpful in the first clinical scenario, early or late PSA relapse after RP. The clinician needs to start local salvage therapy, such as percutaneous radiation therapy, at a serum PSA concentration well below 0.5 ng/mL if a curative intent is the focus of treatment [2, 3]. Based on the current data, only one fifth of the patient cohort had a positive 18F-choline PET/CT finding even when considering aggressive biological features such as a high Gleason score, a rapid PSA-DT and a high PSA nadir after RP; therefore, PET/CT does not add significant additional diagnostic information in the individual patient so that it does not appear useful to perform 18F-choline PET/CT in men with low PSA levels at time of relapse. 18F-choline PET/CT might be helpful in the second clinical scenario to identify patients who will benefit from salvage RP. It has been shown that a PSA < 10 ng/mL and a PSA-DT >12 months at time of surgery are the most significant prognosticators for identifying organ-confined disease [4]. A positive detection rate for metastatic foci would be >75% in this scenario, underlining the indication for performing choline PET/CT. With regard to the third clinical scenario, it has been shown that a serum PSA <4 ng/mL and a slow PSA-DT represent prognostic markers for selecting men who most probably have locoregional relapse in the small pelvis and who will benefit the most from salvage lymphadenectomy [5]. Again, choline-PET/CT is indicated to exclude retroperitoneal or systemic disease and it should be performed before any salvage procedure.

In conclusion, the retrospective study performed by Rodado-Marina et al. [1] provides significant and clinically useful information with regard to the definition of a patient cohort that would benefit most from the performance of a choline PET/CT. This information should be considered when counselling patients with regard to the need for new imaging methods at the time of PSA relapse.

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Axel Heidenreich,

 

Department of Urology,Uniklinik RWTH University Aachen, Aachen, Germany

 

References

 

1 Rodado-Marina S, Coronado-Poggio M, Garcia-Vicente A et al. Clinical utility of 18F-flourocholine PET-CT in biochemical relapse of prostate cancer after radical treatment. Results of a multicentre study. BJU Int 2015. [Epub ahead of print]. doi: 10.1111/bju.12953

 

2 Heidenreich A, Bastian PJ, Bellmunt J et al. EAU guidelines on Prostate Cancer. Part 2: screening, diagnosis, and local treatment with curative intent – update 2013. Eur Urol 2014; 65: 467–79

 

3Pfister D, Bolla M, Briganti A et al. Early salvage radiotherapy following radical prostatectomy. Eur Urol 2014; 65: 1034–43

 

4 Heidenreich A, Richter S, Th€uer D, Pfister D. Prognostic parameters, complications, and oncological and functional outcome of salvage radical prostatectomy for locally recurrent prostate cancer after 21rst-century radiotherapy. Eur Urol 2010; 57: 437–45

 

5 Rigatti P, Suardi N, Briganti A et al. Pelvic/retroperitoneal salvage lymph node dissection for patients treated with radical prostatectomy with biochemical recurrence and nodal recurrence detected by [11C]choline positron emission tomography/computed tomography. Eur Urol 2011; 60: 935–43

 

Article of the Month: Have TRP channels fulfilled their promise in LUTS?

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

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

Finally, the third post under the Article of the Month heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Wouter Everaerts, discussing his paper. 

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

Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms (LUTS): myth or reality?

Yves Deruyver*‡¶, Thomas Voets†¶, Dirk De Ridder*‡¶ and Wouter Everaerts*§¶

 

*Laboratory of Experimental Urology, Department of Development and Regeneration,† Laboratory for Ion Channel Research, Department of Molecular Cell Biology, KU Leuven, ‡University Hospitals Leuven, TRP Research Platform Leuven (TRPLe), Leuven, Belgium, and §Royal Melbourne Hospital, Melbourne, Australia

 

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Transient receptor potential (TRP) channels belong to the most intensely pursued drug targets of the last decade. These ion channels are considered promising targets for the treatment of pain, hypersensitivity disorders and lower urinary tract symptoms (LUTS). The aim of the present review is to discuss to what extent TRP channels have adhered to their promise as new pharmacological targets in the lower urinary tract (LUT) and to outline the challenges that lie ahead.

  • TRP vanilloid 1 (TRPV1) agonists have proven their efficacy in the treatment of neurogenic detrusor overactivity (DO), albeit at the expense of prolonged adverse effects as pelvic ‘burning’ pain, sensory urgency and haematuria.
  • TRPV1 antagonists have been very successful in preclinical studies to treat pain and DO. However, clinical trials with the first generation TRPV1 antagonists were terminated early due to hyperthermia, a serious, on-target, side-effect.
  • TRP vanilloid 4 (TRPV4), TRP ankyrin 1 (TRPA1) and TRP melastatin 8 (TRPM8) have important sensory functions in the LUT. Antagonists of these channels have shown their potential in pre-clinical studies of LUT dysfunction and are awaiting clinical validation.
Read more articles of the week

Editorial: TRP channel – a reality that still requires many years of scientific efforts

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Seventeen years have elapsed since the capsaicin receptor was first cloned by Caterina et al. [1] and the excellent review with an unusual provocative title by Deruyver et al. [2] was written. The capsaicin channel, re-named transient receptor potential (TRP) vanilloid receptor subtype 1 (TRPV1), is now commonly referred to as the founding member of the TRP family, as it currently includes 28 related channels, a number difficult to foresee in those early years [3].

TRP channels have been extensively studied in the lower urinary tract (LUT) with the aim of clarifying their role in micturition control and in the generation of LUTS. It is well accepted that TRP receptors have neuronal and non-neuronal expression [3, 4]. TRPV1 is fundamental to bladder hyperactivity and pain associated with LUT inflammation [3], while TRPV4 may participate in the generation of the normal sensation to void [5]. Another group of TRP receptors may even participate in bladder oncogenesis, which seems to be a role of TRPV2 [3]. The main substance of all this information is not a myth; rather it represents a large body of very solid scientific data.

There are certainly still many obscure areas. The distribution of TRP receptors in the bladder is certainly one of them. However, I disagree that a substantial part of available technical and financial resources have been allocated to study this matter. One should not forget that other matters, like the role of many TRP channels for bladder function, remain elusive. Broadly speaking, in my opinion, future key studies should tackle three very relevant but still unclear points. The importance of most TRP channels for bladder function is difficult to predict at the moment [3]. Just as an example, TRPA1 and TRPM8, which are sensitive to cold temperatures, are expressed in the bladder. However, the bladder, as all internal organs, is conserved at very constant physiological temperatures, making it difficult to understand the relevance of cold receptors to its function. Then, we need to find what the endogenous agonists for TRP receptors are in the LUT. Anandamide has been largely explored as an endogenous agonist for TRPV1 in the bladder [6], a fruitful observation as drugs able to manipulate endogenous levels of anandamide are currently being explored in clinical trials. The same holds true for the other members of the TRP family. TRPA1 may respond to infections due to its capacity to react to hydrogen sulphide [3]. But for the large majority of the TRP family endogenous agonists remain unknown. Finally, TRP antagonists that are simultaneously effective and safe must be generated. Most available TRPV1 antagonists, produced to date, although able to control bladder dysfunction in models of cystitis and spinal cord injury [3], cause hyperthermia and have been associated with an enlargement of ischaemic areas of the heart after coronary artery obstruction [3]. TRPV4 antagonists look very promising for controlling frequency but a compound safe for human use is still eagerly awaited [2]. Eventually the combination of antagonists for more than one of these receptors may prove effective at very low doses, so low that they do not generate serious adverse effects [7].

In conclusion, TRP receptors are a reality that still needs an enormous amount of work and dedication before becoming therapeutically useful. And that may take more time than we anticipate at the moment.

 

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Francisco Cruz
Department of Urology, Al. Hernani Monteiro, Porto, Portugal

 

References

 

1 Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389: 816–24

 

2 Deruyver Y, Voets T, De Ridder D, Everaerts W. Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms: myth or reality? BJU Int 2015; 115: 686–97

 

3 Avelino A, Charrua A, Frias B et al. Transient receptor potential channels in bladder function. Acta Physiol (Oxf) 2013; 207: 110–122

 

4 Birder LA, Kanai AJ, de Groat WC et al. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci U S A 2001; 98: 13396–401

 

5 Gevaert T, Vriens J, Segal A et al. Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding. J Clin Invest 2007; 117: 3453–62

 

6 Dinis P, Charrua A, Avelino A et al. Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in cystitis. J Neurosci 2004; 24: 11253–63

 

7 Charrua A, Cruz C, Jansen K, Rozenberg B, Heesakkers J, Cruz F. Co- administration of transient receptor potential vanilloid 4 (TRPV4) and TRPV1 antagonists potentiates the effect of each drug in a rat model of cystitis. BJU Int 2014; [Epub ahead of print] doi: 10.1111/bju.12861

 

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