Tag: Article of the Week

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Editorial: Should we worry about positive surgical margins in prostate cancer?

February 24, 2016/by Stanley Yap

The debate on the impact of positive surgical margins (PSMs) after radical prostatectomy (RP) continues. The study by Mithal et al. [1] in the present issue contributes further data to an extensive and growing body of literature addressing the clinical significance of a PSM after RP, and ultimately alludes to the question of how to manage these patients.

The authors [1] use the SEARCH database, a large dataset comprised of patients from multiple Veterans Affairs Medical Centers across the USA, to collect and report data on oncological outcomes of PSMs after RP. After adjusting for demographic and pathological confounders, use of adjuvant therapy, and the competing risk of non-prostate-cancer-related death, PSMs were significantly associated with an increased hazard of biochemical recurrence (BCR; hazard ratio 1.99, 95% CI 1.76–2.26), but not castrate resistant prostate cancer (CRPC), metastases, or mortality (prostate-cancer specific or overall). The current study [1], takes such analysis a step further and reports that PSMs were not associated with a negative impact on hard clinical outcomes (CRPC, metastasis, and prostate cancer-specific mortality [PCSM]) in those subgroups at the highest risk of disease progression (high Gleason stage, T-stage, and PSA level). These findings are not necessarily novel, but rather consistent with much of the prior literature. The detrimental impact of PSMs on BCR is well documented [2]. However, the impact of PSMs on hard clinical outcomes such as CRPC, metastasis, and PCSM has not been well demonstrated, despite multiple studies with large cohorts and extensive follow-up.

The negative consequence of a PSM on long-term patient outcome is a very intuitive concept, as it indicates cancer has been inadequately resected or ‘left behind’. Furthermore, the negative impact of a PSM on hard clinical outcomes is well established in many surgically treated malignancies. However, in prostate cancer there remains a disconnect between PSMs and hard clinical outcomes. The authors of the current study [1] provide further evidence to reiterate that the course of this disease after a PSM is not absolute, immediate, or even necessarily concerning (at least in the intermediate follow-up). A PSM after RP may increase the likelihood of BCR but this does not necessarily equal imminent progression and/or death.

PSMs are reported in 10–31% of patients undergoing RP, thus emphasising the clinical importance of this question [3, 4]. Despite the current findings [1], PSMs should not be dismissed. The management of a PSM after RP remains complicated. A proportion of patients will progress and succumb to this disease and, furthermore, therapeutic interventions with shown benefit are available to address such concerns. The decision on how aggressively to manage PSMs may involve an understanding of the patient (comorbidities, lifestyle, and preferences) along with an informed discussion. Furthermore, other pathological details not captured in this study [1] (tumour margin extent and location) [5, 6], along with longer follow-up may be important in identifying drivers for this disease and how to better stratify patients. As with many clinical questions, the approach to PSMs after RP is not necessarily clearly defined and may not apply similarly to all patients across the board. This study [1] may not answer whether or not we should worry about PSMs in prostate cancer, but contributes to our ability to develop clinical algorithms and informed decisions in these patients.

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Stanley A. Yap

Department of Urology, University of California Davis Medical Center, 4860 Y Street, Suite 3500, Sacramento, CA, 95817,

USA

References

Mithal P, Howard LE, Aronson WJ et al. Positive surgical margins in radical prostatectomy patients do not predict long-term oncological outcomes: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort. BJU Int 2015; 117: 244–48

2 Karakiewicz PI, Eastham JA, Graefen M et al. Prognostic impact of positive surgical margins in surgically treated prostate cancer: multi- institutional assessment of 5831 patients. Urology 2005; 66: 1245–50

3 Boorjian SA, Karnes RJ, Crispen PL et al. The impact of positive surgical margins on mortality following radical prostatectomy during the prostate speciﬁc antigen era. J Urol 2010; 183: 1003–9

4 ChalﬁnHJ, Dinizo M, Trock BJ et al. Impact of surgical margin status on prostate-cancer-speciﬁc mortality. BJU Int 2012; 110: 1684–9

5 Brimo F, Partin AW, Epstein JI. Tumor grade at margins of resection in radical prostatectomy specimens is an independent predictor of prognosis. Urology 2010; 76: 1206–9

6 Fontenot PA, Mansour AM. Reporting positive surgical margins after radical prostatectomy: time for standardization. BJU Int 2013; 111: E290–9

Video: PSMs in RP patients do not predict long-term oncological outcomes

February 24, 2016/by admin Z.9

Positive Surgical Margins in Radical Prostatectomy Patients Do Not Predict Long-term Oncological Outcomes: Results from SEARCH

Prabhakar Mithal, Lauren E. Howard†‡, William J. Aronson§¶, Martha K. Terris**††, Matthew R. Cooperberg‡‡, Christopher J. Kane§§, Christopher Amling¶¶ and Stephen J. Freedland‡***

Department of Urology, University of Rochester Medical Center, Rochester, NY, †Department of Biostatistics and Bioinformatics, Duke University School of Medicine, ‡Division of Urology, Veterans Affairs Medical Center, Durham, NC, §Urology Section, Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, ¶Department of Urology, UCLA School of Medicine, Los Angeles, CA, **Section of Urology, Veterans Affairs Medical Center, ††Section of Urology, Medical College of Georgia, Augusta, GA, ‡‡Department of Urology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, §§Urology Department, University of California San Diego Health System, San Diego, CA , ¶¶Division of Urology, Department of Surgery, Oregon Health and Science University, Portland, OR , and ***Division of Urology, Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA, USA

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Objective

To assess the impact of positive surgical margins (PSMs) on long-term outcomes after radical prostatectomy (RP), including metastasis, castrate-resistant prostate cancer (CRPC), and prostate cancer-specific mortality (PCSM).

Patients and Methods

Retrospective study of 4 051 men in the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort treated by RP from 1988 to 2013. Proportional hazard models were used to estimate hazard ratios (HRs) of PSMs in predicting biochemical recurrence (BCR), CRPC, metastases, and PCSM. To determine if PSMs were more predictive in certain patients, analyses were stratified by pathological Gleason score, stage, and preoperative prostate-specific antigen (PSA) level.

Results

The median (interquartile range) follow-up was 6.6 (3.2–10.6) years and 1 127 patients had >10 years of follow-up. During this time, 302 (32%) men had BCR, 112 (3%) developed CRPC, 144 (4%) developed metastases, and 83 (2%) died from prostate cancer. There were 1 600 (40%) men with PSMs. In unadjusted models, PSMs were significantly associated with all adverse outcomes: BCR, CRPC, metastases and PCSM (all P ≤ 0.001). After adjusting for demographic and pathological characteristics, PSMs were associated with increased risk of only BCR (HR 1.98, P < 0.001), and not CRPC, metastases, or PCSM (HR ≤1.29, P > 0.18). Similar results were seen when stratified by pathological Gleason score, stage, or PSA level, and when patients who underwent adjuvant radiotherapy were excluded.

Conclusions

PSMs after RP are not an independent risk factor for CRPC, metastasis, or PCSM overall or within any subset. In the absence of other high-risk features, PSMs alone may not be an indication for adjuvant radiotherapy.

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Article of the Week: Differential effects of ENC & ZUC on reproductive tissues in male mice

February 17, 2016/by admin Z.9

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

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

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. Gregory Fontenot, discussing his paper.

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

Differential effects of isomers of clomiphene citrate on reproductive tissues in male mice

Gregory K. Fontenot, Ronald D. Wiehle and Joseph S. Podolski

Repros Therapeutics Inc., The Woodlands, TX, USA

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Objectives

To determine, in a chronic dosing study, the oral toxicity potential of the test substances, enclomiphene citrate (ENC) and zuclomiphene citrate (ZUC), when administered to male mice by oral gavage.

Materials and Methods

Mice were divided into five treatment groups. Group I, placebo; Group II, 40 mg/kg body weight/day ENC; Group III, 4 mg/kg/day ENC; Group IV, 40 mg/kg/day ZUC; Group V, 4 mg/kg/day ZUC. Serum samples and tissues were obtained from each mouse for analysis and body weights were measured.

Results

In this chronic dosing study in mice, profound effects on Leydig cells, epididymis, seminal vesicles, and kidneys were seen, as well as effects on serum testosterone, follicle-stimulating hormone and luteinising hormone levels that were associated with ZUC treatment only. Treatment with the isolated enclomiphene isomer had positive effects on testosterone production and no effects on testicular histology.

Conclusions

The present study suggests that an unopposed high dose of zuclomiphene can have pernicious effects on male mammalian reproductive organs. The deleterious effects seen when administering ZUC in male mice, justifies the case for a monoisomeric preparation and the development of ENC for clinical use in human males to increase serum levels of testosterone and maintain sperm counts.

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Editorial: When two and two don’t make four

February 17, 2016/by Mike Wyllie

Many drugs are chiral, i.e. the enantiomers (isomers) cannot be superimposed on their mirror images. It has long been known that if a drug is chiral, then in biological terms, the isomers invariably differ in activity [1]. One isomer may specifically interact with a cell receptor to produce the desired outcome while the other might have no useful application or might have an unwanted pharmacological or even a toxicological effect through some other interaction.

In the clear-cut example where one isomer of a chiral compound is ‘good’ and the other ‘bad’, there is obvious benefit from developing the drug as the single isomer to enhance its safety and tolerability. The paper in the present issue of BJUI by Fontenot et al. [2] on the differential activity of the enantiomers of clomiphene elegantly exemplifies this in terms of potential toxicity.

Since 1992 the US Food and Drugs Administration and the European Medicines Agency have required manufacturers to research and characterize each enantiomer in all drugs proposed to be marketed as a mixture. The assumption was that a mixture may not manifest clinically as a simple algebraic summation of the biological characteristics of the individual components. From that date, production of new racemates (mixture of enantiomers) ceased to be a rational commercial option and instead became a high-risk route for pharmaceutical companies.

With respect to the enantiomers of clomiphene, it was undoubtedly the differential toxicological profile [2], coupled with relative primary activity as oestrogen antagonists [3], that resulted in the prioritization of Enclomiphene for late stage clinical development. It is this isomer that forms the basis of the submission to the regulatory authorities for the treatment of secondary hypogonadism.

The present paper in some ways reinforces what we already knew; isomers can have differential activity. What is unusual is that what is presented is not pharmacological evidence but clear-cut differences in toxicological profile.

The research raises a specific issue in relation to the treatment of secondary hypogonadism. In general, patients with secondary hypogonadism require restoration of normal testosterone levels while preserving fertility. As such, the use of exogenous testosterone for replacement can be counter-productive as there is a well-documented negative impact on spermatogenesis [4]. As an alternative, ‘off-label’ clomiphene is relatively widely proffered. Assuming approval, Enclomiphene would provide an attractive alternative to its racemic ‘parent’.

Overall, the present paper is a useful reminder of what we think we know; that is, that all racemates are likely to manifest the characteristics of both component enantiomers.

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Michael G. Wyllie

Global Pharma Consulting Ltd, Banbury, UK

Conflict of Interest

The author is an independent director on the board of Repros Therapeutics.

References

1 Smith DF. The stereoselectivity of drug action. Pharmacol Toxicol 1989; 65: 321–31

2 Fontenot GK, Wiehle RD, Podolski JS. Differential effects of isomers of clomiphene citrate on reproductive tissues in male mice.BJU Int 2015; 117: 344–50

3 Murdter T, Kerb R, Turpeinen M et al. Genetic polymorphism of cytochrome P450 2D6 determines oestrogen receptor activity of the major infertility drug clomiphene via its active metabolites.Hum Mol Genet 2012; 21: 1145–54

4 Wiehle RD, Fontenot GK, Wike J et al.Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone.Fertil Steril 2014; 102: 720–7

Video: Effects of clomiphene citrate isomers on mouse reproductive tissues

February 17, 2016/by admin Z.9

Differential effects of isomers of clomiphene citrate on reproductive tissues in male mice

Gregory K. Fontenot, Ronald D. Wiehle and Joseph S. Podolski

Repros Therapeutics Inc., The Woodlands, TX, USA

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Objectives

To determine, in a chronic dosing study, the oral toxicity potential of the test substances, enclomiphene citrate (ENC) and zuclomiphene citrate (ZUC), when administered to male mice by oral gavage.

Materials and Methods

Results

Conclusions

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Article of the Week: Comparison of the efficacy and safety of tolterodine 2 mg and 4 mg combined with an alpha-blocker

February 10, 2016/2 Comments/by admin Z.9

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. Tae Heon Kim, discussing his paper.

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

Comparison of the efficacy and safety of tolterodine 2 mg and 4 mg combined with an alpha-blocker in men with lower urinary tract symptoms (LUTS) and overactive bladder: a randomized controlled trial

Tae Heon Kim*, Wonho Jung†, Yoon Seok Suh*, Soonhyun Yook‡, Hyun Hwan Sung* and Kyu-Sung Lee*‡

*Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, †Department of Urology, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, and ‡Department of Medical Device Management and Research, SAIHST, Sungkyunkwan University, Seoul, Korea Tae Heon Kim and Wonho Jung contributed equally to this work.

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Objective

To evaluate the efficacy and safety of low-dose (2 mg) tolterodine extended release (ER) with an a-blocker compared with standard-dose (4 mg) tolterodine ER with an α-blocker for the treatment of men with residual storage symptoms after α-blocker monotherapy.

Patients and Methods

The study was a 12-week, single-blind, randomized, parallel group, non-inferiority trial that included men with residual storage symptoms despite receiving at least 4 weeks of α-blocker
treatment. Inclusion criteria were total International Prostate Symptom Score (IPSS) ≥12, IPSS quality-of-life item score ≥3, and ≥8 micturitions and ≥2 urgency episodes per 24 h. The primary outcome was change in the total IPSS score from baseline. Bladder diary variables, patient-reported
outcomes and safety were also assessed.

Results

Patients were randomly assigned to addition of either 2 mg tolterodine ER (n = 47) or 4 mg tolterodine ER (n = 48) to α-blocker therapy for 12 weeks. Patients in both treatment groups had a significant improvement in total IPSS score (5.5 and 6.3, respectively), micturition per 24 h (1.3 and
1.7, respectively) and nocturia per night (0.4 and 0.4, respectively). Changes in IPSS, bladder diary variables, and patient-reported outcomes were not significantly different between the treatment groups. All interventions were well tolerated by patients.

Conclusions

These results suggest that 12 weeks of low-dose tolterodine ER add-on therapy is similar to standard-dose tolterodine ER add-on therapy in terms of efficacy and safety for patients experiencing residual storage symptoms after receiving α-blocker monotherapy.

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Editorial: Should we start with low-dose anti-cholinergics when alpha-blockers alone fail?

February 10, 2016/1 Comment/by Arjun Nambiar

Kim et al. [1] asked the question whether we should start by treating men who have persistent storage LUTS despite α-blocker monotherapy, with a low-dose anti-cholinergic as opposed to the standard dose (given the potentially increased risk of side-effects such as acute urinary retention and high discontinuation rates with the standard dose). It is a valid question, for we know that discontinuation rates with standard doses of anti-cholinergics can be as high as 50% in the first 3 months due to a combination of ineffectiveness and side-effects [2]. However, the problem lies in the multifactorial nature of the causes of storage vs voiding LUTS, and the difficulty in assessing and distinguishing them accurately with our current tools.

The authors have conducted a randomised controlled trial of 2 mg vs 4 mg tolterodine added to the participants’ on-going α-blocker regime and selected reduction in total IPSS as their primary outcome measure. They have also assessed IPSS sub-scores, 3-day bladder diary variables, and the Patient Perception of Bladder Condition (PPBC) and Overactive Bladder (OAB-q) questionnaires, as secondary outcomes. As would be expected of a peer-reviewed publication the trial has been seemingly well conducted and fairly well reported. Recruitment met the requirement set by the power calculation based on a clinically significant difference of a 4-point drop in total IPSS, and the authors concluded that 2 mg tolterodine is not inferior to the 4 mg dose in achieving a significant reduction in total IPSS at 12 weeks. They also report no difference in patient perception of treatment benefit or satisfaction at this time point.

These results are interesting, especially considering some of the details of the study. First of all, patients were not on the same α-blocker at baseline; the most common was tamsulosin (62.8%), but alfuzosin, doxazosin, and others were also being used. This in itself may not be a problem because all patients continued on the same α-blocker through the study, and in fact this better represents real-world practice. However, the mean (sd) duration of α-blocker therapy at baseline was 9.1 (19.9) months. We know that α-blocker therapy can improve IPSS by up to 30–40% [3], but the pertinent question for this study is whether these patients had achieved this level of improvement initially then stabilised and improved no further, or whether they had no improvement at all? It could conceivably make a difference to participants approach to the IPSS if they were previously familiar with it and, more importantly, aware of their results. The Hawthorne effect, also known as the observer effect, and the related Heisenberg uncertainty principle, are factors that we must necessarily encounter in clinical trials but we sometimes fail to account for.

Another aspect of the study that warrants consideration is the choice of primary outcome itself. This is a particular bug-bear of mine and indeed has been commented on by many authors including in the European Association of Urology (EAU) guideline on urinary incontinence in relation to anti-muscarinics [4]. Outcomes that lend themselves to easier power calculations and statistically significant results have almost evolved to be ‘un’-naturally selected for the purpose of clinical trial primary outcome measures. Drug trials are especially notorious for this. Here again, the choice of the total IPSS to assess whether an anti-muscarinic will help improve persistent storage LUTS is a case in point. Not least because it renders the significance of all the secondary outcomes dependant on the same power calculation. It is no doubt convenient, but is it appropriate? It is easy to point the finger at trialists for this, but the business-like, ‘bottom-line’ nature of medical publishing and research today is equally, if not more, to blame.

Finally, I would like to call the reader’s attention to the difference in baseline urgency and urgency urinary incontinence (UUI) episodes. The author’s state there was no statistically significant difference, but one might argue that when assessing improvement in storage LUTS, a group with a mean (sd) baseline number of UUI episodes of 3.9 (8.6) may perceive improvement quite differently compared with a group with a baseline of 1.6 (1.1). This has borne out in the difference in the bladder diary outcome of UUI/24 h; significant improvement in the first group (who were wetter at baseline and got 4 mg tolterodine) but no difference in the latter group (comparatively drier and got 2 mg tolterodine). But almost paradoxically this does not seem to have made a difference to the patient-reported outcome measures. One possible explanation for this could be the relatively few patients who were incontinent at baseline.Overall this paper gives us a lot of food for thought. The direct result – should we indeed start men with persistent storage LUTS on low-dose anti-cholinergics rather than standard dose, and then titrate upwards? But it also challenges us to consider whether we simply accept researcher’s and sponsor’s decisions on outcome measures. What do you think? Do we simply sit back and accept what is put before us because statistics scares us a little? Or, as researchers and consumers of medical literature, do we struggle to make the hard choices, risk our results being rejected by the top journals, and stand up for good science?

Conflicts of Interest

The author has received a travel grant to attend an international conference from Ferring pharmaceuticals.

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Arjun K. Nambiar

Clinical Research Registrar
Department of Urology, Morriston Hospital, Abertawe Bro Morgannwg (ABM) University Local Health Board, Swansea, SA6 6NL, UK

References

1 Kim TH, Jung W, Suh YS, Yook S, Sung HH, Lee KS. Comparison of the efficacy and safety of tolterodine 2 mg and 4 mg combined with an a-blocker in men with lower urinary tract symptoms (LUTS) and overactive bladder: a randomized controlled trial. BJU Int 2015; 117: 307–15

2 Lucas MG, Bedretdinova D, Berghmanset LC et al. Guidelines on Urinary Incontinence, Section 4.2.4. In: EAU Guidelines, edition presented at the 30th EAU Annual Congress, Madrid 2015. ISBN 978-90-79754-80-9. Available at: https://uroweb.org/wp-content/uploads/17-Urinary-Incontinence_LR.pdf. Accessed September 2015

3 Gravas S, Bach T, Bachmann A et al. Guidelines on Non-Neurogenic Male LUTS Including Benign Prostatic Obstruction, Section 3C.2. In: EAU Guidelines, edition presented at the 30th EAU Annual Congress, Madrid 2015. ISBN 978-90-79754-80-9. Available at: https://uroweb.org/wp-content/uploads/11-Male-LUTS_LR.pdf. Accessed September 2015

4 Lucas MG, Bedretdinova D, Berghmanset LC et al. Guidelines on Urinary Incontinence, Section 4.2.1. In: EAU Guidelines, edition presented at the 30th EAU Annual Congress, Madrid 2015. ISBN 978-90-79754-80-9. Available at: https://uroweb.org/wp-content/uploads/17- Urinary-Incontinence_LR.pdf. Accessed September 2015

Video: Tolterodine combined with an alpha-blocker in men with LUTS and OAB

February 10, 2016/by admin Z.9

Comparison of the efficacy and safety of tolterodine 2 mg and 4 mg combined with an α-blocker in men with lower urinary tract symptoms (LUTS) and overactive bladder: a randomized controlled trial

Tae Heon Kim*, Wonho Jung†, Yoon Seok Suh*, Soonhyun Yook‡, Hyun Hwan Sung*
and Kyu-Sung Lee*‡

Read the full article

Objective

Patients and Methods

Results

Conclusions

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Article of the Month: DaPeCa-1 – Diagnostic Accuracy of SNB in Penile Cancer

February 3, 2016/2 Comments/by admin Z.9

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. Jakob Jakobsen, discussing his paper.

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

DaPeCa-1: Diagnostic Accuracy of Sentinel Node Biopsy in 222 Penile Cancer Patients at four Tertiary Referral Centres — a National Study from Denmark

Jakob K. Jakobsen*, Kim P. Krarup†, Peter Sommer†, Henrik Nerstrøm†, Vivi Bakholdt‡, Jens A. Sørensen‡, Kasper Ø. Olsen*, Bjarne Kromann-Andersen§, Birgitte G. Toft¶, Søren Høyer**, Kirsten Bouchelouche†† and Jørgen B. Jensen*

*Departments of Urology, **Pathology, ††Nuclear Medicine and PET-Centre, Aarhus University Hospital, Aarhus, †Departments of Urology, ¶Pathology, Copenhagen University Hospital, Copenhagen, ‡Department of Plastic Surgery, Odense University Hospital, Odense, and §Department of Urology, Herlev University Hospital, Herlev, Denmark

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OBJECTIVES

To estimate the diagnostic accuracy of sentinel lymph node biopsy (SNB) in patients with penile cancer and assess SNB complications in a national multicentre setting.

PATIENTS AND METHODS

Retrospectively data were collected from records in four university centres by one medical doctor covering all SNBs performed in Denmark between 1 January 2000 and 31 December 2010. Patients had either impalpable lymph nodes (LNs) in one or both groins, or had a palpable inguinal mass from which aspiration cytology failed to reveal malignancy. Patients were injected with nanocolloid technetium and had a scintigram recorded before the SNB. The primary endpoint was LN recurrence on follow-up. The secondary endpoint was complications after SNB. Diagnostic accuracy was computed.

RESULTS

In all, 409 groins in 222 patients were examined by SNB. The median (interquartile range) follow-up of patients who survived was 6.6 (5–10) years. Of 343 negative groins, eight were false negatives. The sensitivity was 89.2% (95% confidence interval 79.8–95.2%) per groin. Interestingly, four of 67 T1G1 patients had a positive SNB. In all, 28 of 222 (13%) patients had complications of Clavien-Dindo grade I–IIIa.

CONCLUSION

Penile cancer SNB with a close follow-up stages LN involvement reliably and has few complications in a national multicentre setting. Inguinal LN dissection was avoided in 76% of patients.

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Editorial: Penis cancer management – insight into the future

February 3, 2016/by Simon Horenblas

The report of Jakobson et al. [1] assesses the results of the sentinel node procedure for penis carcinoma in Denmark. The sentinel node procedure was done in four university hospitals. In this geographically small country with little more than 5.6 million inhabitants and a case load of 50 patients with penis cancer per year, a distribution of care of patients with penis cancer over four hospitals seems reasonable at first sight.

The results show interesting elements. With a false-negative rate of 10.8%, the figure is in accordance with what is known from other series, albeit at the high end of the range [2]. The authors rightly acknowledge that there is room for improvement. It seems likely that centralising the procedure to two hospitals, as of 2009, will be instrumental in this endeavour.

The authors did not find a learning curve, underscoring the safe introduction of this procedure.

The experience testifies to the reliability of the procedure with a minimum of complications and morbidity. Despite inter-institutional variation no major differences were detected. The authors conclude that 76% of node dissections could be avoided.

More than 15 years after the first publication on the sentinel node procedure in a urological cancer, the debate on how to manage clinically node-negative patients is still not completely settled and the sentinel node procedure in penis cancer is not universally accepted [3].

Why?

There has been no randomised study comparing standard inguinal lymph node dissection to the sentinel node procedure. Comparisons of series with standard node dissection vs the sentinel node procedure have shown improved survival for the latter [4]. Nevertheless, in the absence of randomisation these figures have not convinced the whole urological community.

Advocates of the sentinel node procedure tend to emphasise the avoidance of unnecessary inguinal node dissections. Opponents tend to emphasise the false-negative rates with its ensuing risk of seriously jeopardising the patients, as some of the patient die from disease.

Oncological care has to seek the most rational balance between too much and too little, realising that 100% success does virtually not exist. It is reasonable to assume that if all elements of the chain necessary to deliver state-of-the-art treatment of penis cancer, the figures of false-negative sentinel node procedures should be around 4–5%. With meticulous follow-up, recurrences should be detected at the earliest possible moment, decreasing the risk of a fatal outcome. A 5% risk is a generally accepted figure to avoid a potentially harmful procedure. New tracers give hope that false-negative rates can even be improved, realising again that some failures have to be accepted as a fact of life [5, 6].

Opponents point to the technicalities of the procedure. True as it is, there is no modern hospital without all the equipment and the expertise, accumulated in other areas in oncology, necessary to perform a state of the art sentinel node procedure.

Is there reluctance to refer patients with penis cancer or is there a strong reason to rely on inguinal node dissection only? There can hardly be a financial motive considering the rarity of the disease. Is it fear for degradation of the trade by losing another surgical procedure, infringement of the surgical ego?

The management of penis cancer is exemplary for changes in health care. While initially four university hospitals were involved, this is further scaled down to two hospitals. Earlier in the Netherlands, the management of >75% of the patients with penis cancer in one institution led to the highest survival of these patients worldwide (88.3%) [7].

Introduction of a new procedure in medicine has to date been a more or less individual effort. This will be of the past with current health policy and a wealth of data on the effect of centralisation. A central introduction of a new procedure in a limited number of institutions and more rational distribution of care with dedicated professionals in institutions suited for the procedure will be the rule.

The future of lymph node staging looks bright for any urological cancer. There will be a day where discussions on sentinel node and the extent of the dissection will be of the past. Our successors will look with bewilderment at our discussions on sentinel node, extended, super-extended or minimal dissections and the failures to grasp the exact mechanisms of lymphatic invasion and the true role of surgical removal. Imaging methods will give unprecedented insight in nodes invaded by tumour. Smart molecules will kill specifically nodal metastases and will revert the process of lymphangiogenesis enhanced by effective immunotherapy.

But before we see these times, the treatment of patients with penis cancer will be completely centralised worldwide to the benefit of these patients.

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Simon Horenblas

Department of Urology, Netherlands Cancer Institute, Antonivan Leeuwenhoek Hospital, Amsterdam, The Netherlands

References

1 Jakobsen JK, Krarup KP, Sommer P et al. DaPeCa-1: diagnostic accuracy of sentinel lymph node biopsy in 222 patients with penile cancer at four tertiary referral centres – a national study from Denmark. BJU Int 2015; 117: 235–43

2 Sadeghi R, Gholami H, Zakavi SR, Kakhki VR, Tabasi KT, Horenblas S. Accuracy of sentinel lymph node biopsy for inguinal lymph node staging of penile squamous cell carcinoma: systematic review and meta-analysis of the literature. J Urol 2012; 187: 25–31

3 Horenblas S, Jansen L, Meinhardt W, Hoefnagel CA, de Jong D, Nieweg OE. Detection of occult metastasis in squamous cell carcinoma of the penis using a dynamic sentinel node procedure. J Urol 2000;

163: 100–4

4 Djajadiningrat RS, Graa ﬂand NM, van Werkhoven E et al. Contemporary management of regional nodes in penile cancer-improvement of survival? J Urol 2014; 191: 68–73

5 Brouwer OR, van den Berg NS, Matheron HM et al. A hybrid radioactive and ﬂuorescent tracer for sentinel node biopsy in penile carcinoma as a potential replacement for blue dye. Eur Urol 2014; 65: 600–9

6 Brouwer OR, van den Berg NS, Matheron HM et al. Feasibility of intraoperative navigation to the sentinel node in the groin using preoperatively acquired single photon emission computerized tomography data: transferring functional imaging to the operating room. J Urol 2014; 192: 1810–6

7 Visser O, Adolfsson J, Rossi S et al. Incidence and survival of rare urogenital cancers in Europe. Eur J Cancer 2012; 48: 456–64