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Final Analysis of RT+ADT versus ADT alone in locally advanced CaP

March 23, 2015/by Chris Hillary

The March 2015 international urology journal club #urojc twitter discussion focused on a paper by Mason et al [1]. This article, published in the Journal of Clinical Oncology (Feb 2015), reports on the preplanned final analysis of the randomized trial of radiotherapy (RT) and androgen deprivation therapy (ADT) versus ADT alone in patients with locally advanced prostate cancer between 1995 and 2005.

The authors have previously reported on the survival benefits of RT added to ADT in this cohort of patients and the final analysis demonstrates a sustained longer-term survival outcomes of RT+ADT over a median follow-up of 8 years as compared to ADT alone.

As ever the discussion was lively with some polarized views. The feed commenced at 12:00pm PST on Sunday 1^st March 2015 for a 48-hour period. Initially debate focused on staging and the under-reporting of DRE findings:

Which was perhaps addressed by issues during the screening process…

Despite this, other aspects of staging were discussed, particularly the methods for node staging:

For N staging, the authors included either a clinical assessment (70.5% of patients), Imaging (8.5%) or surgical dissection (2.4%). Meanwhile, the accuracy of ‘clinical’ nodal staging was questioned.

Consideration of the patient inclusion criteria was followed by a discussion over the use of ADT in this patient cohort

In this context, ADT consisted of either BSO or lifelong LHRH agonists

However, the question was asked of ADT in addition to RT ‘is lifelong ADT appropriate?’

While for high-risk disease, evidence suggests that long-term (2-3 years) ADT should be used following RT [2, 3], for intermediate risk cancers, 8 weeks of adjuvant ADT remains the standard of care as highlighted in the recent RTOG 9910 data [4].

The rationale behind RT and ADT was noted:

While the results of the study came as no shock to some:

The addition of RT to ADT significantly improved OS and DSS. The study reports that ‘there was no evidence of any differences in deaths from other causes’, however, the issue of secondary malignancies with RT was ‘highlighted’:

Ultimately, the role of surgery for these patients was questioned. A point highlighted in the paper was not shared by some:

To conclude the March #urojc, some final comments were provided by @_TheUrologist:

Thanks to all those who participated in this months discussion. We look forward to the April #urojc.

References

[1] Mason, M.D., W.R. Parulekar, M.R. Sydes, et al., Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer. J Clin Oncol 2015;.

[2] Horwitz, E.M., K. Bae, G.E. Hanks, et al., Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 2008;26:2497-504.

[3] Bolla, M., G. Van Tienhoven, P. Warde, et al., External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 2010;11:1066-73.

[4] Pisansky, T.M., D. Hunt, L.G. Gomella, et al., Duration of androgen suppression before radiotherapy for localized prostate cancer: radiation therapy oncology group randomized clinical trial 9910. J Clin Oncol 2015;33:332-9.

Chris Hillary @chrisjhillary

Clinical Fellow in Urology, Sheffield, UK

EAU 2015 Review Days 1 and 2

March 23, 2015/1 Comment/by Rebecca Tregunna

The 30^th anniversary EAU congress is currently taking place in the beautiful but rainy city of Madrid with over 12,000 delegates attending. The opening Friday proved a monumental day with the start of the congress as well as personally as I gave into the pressure of social media, and joined Twitter. This is being heavily promoted by the EAU this year and with multiple engaging sessions going on at the same time this seemed to be the best way to have my cake and eat it and enjoy highlights from different parts of the meeting.

The second ESO prostate cancer observatory was well attended and led to interesting debates about PSA screening and informed consent due to risks of over-detection and subsequent overtreatment of indolent disease. Indeed Andrew Vickers also highlighted that the results of the much anticipated ProtecT trial should be interpreted with caution given the high number of Gleason 6 patients that have been randomised.

In the evening the opening ceremony took place with an emotional final introduction to the congress by Per Anders Abrahamsson as he steps down and hands over to Chris Chapple as EAU Secretary General (photo courtesy @uroweb).

The EAU also gave out a number of awards including the Crystal Matula award for promising young urologist which was given to Morgan Roupret.

The scientific programme on Saturday started with the main plenary session on controversies in bladder and kidney cancer. It is difficult to draw conclusions regarding lymphadenectomy in upper tract tumours due to a lack of randomised data but certainly based on retrospective data a benefit is seen both in terms of staging and cancer specific survival. A hot topic lecture on molecular profiling in bladder cancer gave a thrilling insight into how agents will be able to target pathways based on specific mutations and Professor Studer, in his last ever plenary session, led to an interesting debate on robotic vs. open radical cystectomy. This has caused much controversy recently with the Bochner randomised controlled trial and this debate will surely run and run. Maybe most importantly, as Studer concluded “The surgeon makes the difference not the instrument”. This was highlighted on the front cover of the congress news with a more downbeat headline on robotic cystectomy.

Next came an intriguingly titled talk “What would Charles Darwin make of renal cell carcinoma?” with discussion about the heterogeneity of renal tumours making it difficult to identify specific targeted treatments based on renal biopsy alone.
Multiple section meetings then ensued. From the EAU section of urolithiasis (EULIS) meeting it seems that PCNLs are increasingly being miniaturised with development to mini, ultra-mini and micro procedures. The issues behind “diabesity” and stones were discussed with Professor Reis Santos predicting an epidemic of stones either due to uric acid stone formation from obesity or calcium oxalate formation from malabsorbative bariatric procedures. There was also a recurring theme with poster and podium sessions on “ESWL – is there still a role?” While the argument is made for ESWL there is no doubt that worldwide treatment rates for ESWL are falling.
As the EAU Section of Female and Functional Urology there was an excellent series of talks on mesh and mesh complications. There was a fantastic review of dealing with these complications through a variety of approaches and techniques and whether all these should all be dealt with in high volume centres. Unfortunately, no one knows what high volume means for this. Interestingly the terminology is changing, moving away from ‘erosion’ to ‘exposure’ and ‘perforation’. Removing the mesh only relieves associated pain in 50% of cases and these dedicated centres need to offer multimodality treatments to deal with pain and ongoing continence issues.
In the parallel EAU section meeting of Genito-urinary Reconstructive Surgeons, Professor Mundy gave a personal 30 year series of 169 patients treated with both clam cystoplasty and artificial sphincter. The majority of complications were related to the sphincter. The largest subgroup was patients with Spina Bifida but were the patients with the best outcomes.
David Ralph in the EAU Section of Andrology stated that shunts were ineffective after 48 hours after priapism and that a prosthesis instead should be inserted to prevent corporal fibrosis.
The EAU section of Oncological Urology also heard that 68Ga-S+PSMA-PET improves detection of metastatic lymph nodes in prostate cancer and can be used intra-operatively in radioguided surgery for targeted lymph node dissection.
Overall the organisers have done a fantastic job with a well organised meeting and a great venue despite the disappointing weather. There were sessions that people could not get in to as the rooms were full.

However, with live TV screens outside those rooms and transmission to an adjacent overflow room this didn’t seem to matter too much. Much to look forward to for the rest of the conference #EAU15.

Rebecca Tregunna, Speciality Trainee, Burton Hospitals NHS Foundation Trust, West Midlands Deanery. @RebeccaTregunna

Matthew Bultitude, Consultant Urologist, Guy’s and St. Thomas’ Foundation Trust; Web Editor BJU International. @MattBultitude

Editorial: The robot to the rescue!

March 18, 2015/by Ben Challacombe

Fortunately injuries to the urinary tract remain rare in obstetric and gynaecological surgery. Their potential for causing serious morbidity, not to mention the substantial medico-legal implications ensure that it remains a highly researched and evocative area [1].

Iatrogenic urinary tract injuries can be broadly divided into two groups; acute complications, such as bladder and ureteric lacerations or ligation and more chronic complications, such as vesicovaginal or ureterovaginal fistulae and ureteric strictures. Historically, iatrogenic trauma to the urinary tract most commonly followed open, abdominal hysterectomy with the most frequent complication being direct bladder injury. Gross bladder injuries are generally both detected and treated intraoperatively. In contrast, the management of more complex ureteric injuries and their long-term sequelae, such as fistula, pose greater surgical challenges. The complexity of these injuries is often further compounded by delay in diagnosis. It is generally accepted that, if possible, immediate repair provides the optimal treatment. However, when diagnosis is delayed, there is little consensus on the best management approach, although the current tendency is towards early repair [2].

The multicentre, retrospective study of robotic repair of 49 iatrogenic genitourinary injuries by Gellhaus et al. [3] should therefore serve to reassure gynaecologists with respect to the incidence of this feared complication. This paper, mainly looking at ureteric re-implants and fistula repairs, constitutes the largest cohort of robotic reconstructions to date. A zero conversion rate to open surgery suggests excellent case selection by the robotic surgeons. Four cases had undergone previous failed open or endoscopic management and this is clearly a challenging cohort. Yet, with the absence of total numbers of urology referrals received for such injuries, it is important to remember that it may not be a panacea for all.

There has been a considerable shift in the management of urological trauma from open to laparoscopic techniques. While the repair of basic injuries has been proven to be effective, less data is available to support the management of more complex injuries, such as ureteric transections or fistulae [4]. Numerous techniques for repairing ureteric injuries and fistulae have been described; nonetheless, the surgery remains technically challenging even for experienced laparoscopic surgeons and is generally limited to high-volume centres [5].

In comparison, this article [3] provides strong evidence for the effectiveness of robot-assisted (RA) repairs, even for complex injuries. The enviable 95.9% success rate from 47 operations is complemented by short recovery times and low complication rates. These results are especially impressive in view of the mean 23.5-month delay time to repair. But the authors do not report the reasons for these delays. Immediate robotic repair of RA injuries is clearly feasible especially in larger units. Whether immediate RA repair should be performed for other iatrogenic injuries needs further discussion. Is it realistic to convert to the robot in the case of laparoscopic trauma or should RA repairs remain a planned return to theatre?

The demand for RA reconstructive surgery and experienced robotic pelvic surgeons is likely to rise in the near future. As the authors note, the continued expansion of minimally invasive procedures is likely to lead to a shift in the patterns of complications from more straightforward bladder injuries to complex ureteric injuries. As mentioned previously these types of injury are more likely to be initially undetected.

Whilst rates of surgical complications involving the urinary tract remain low, obstetrical and gynaecological procedures account for 75% of these injuries. This article provides robust evidence for the key role that RA surgery can play in the management of these complex and feared injuries. When faced with such situations, Gellhaus et al. [3] have shown that it is increasingly likely that the robot saves the day.

Read the full article

Nicholas Raison and Ben Challacombe

Department of Urology, Guy’s and St Thomas’ Hospital,London, UK

References

1 Preston JM. Iatrogenic ureteric injury: common medicolegal pitfalls. BJUInt 2000; 86: 313–7

2 El-Tabey NA, Ali-el-Dein B, Shaaban AA et al. Urological trauma aftergynecological and obstetric surgeries. Scand J Urol Nephrol 2006; 40:225–31

3 Gellhaus PT, Bhandari A, Monn MF et al. Robotic management ofgenito-urinary injuries from obstetrical and gynecological operations: amulti-institutional report of outcomes. BJU Int 2015; 115: 430–6

4 De Cicco C, Ussia A, Koninckx PR. Laparoscopic ureteral repairin gynaecological surgery. Curr Opin Obstet Gynecol 2011; 23:296–300

5 Rassweiler J, Pini G, Gözen AS, Klein J, Teber D. Role of laparoscopy inreconstructive surgery. Curr Opin Urol 2010; 20: 471–82

Editorial: On the Mark? Is AP a surrogate for BMD in hypogonadal men?

March 11, 2015/by Ronald Wiehle

The current issue of the BJUI contains a paper by Dubaja et al. [1] that may be of interest to physicians who have patients with hypogonadism. The authors speak to an unappreciated aspect of low testosterone; namely, the loss of bone in men and the possible recovery with treatment. Their retrospective study looked at 140 men with hypogonadism treated with exogenous testosterone replacement or clomiphene citrate testosterone enhancement. These men were also assessed for bone mineral density (BMD) markers at 6, 12 and 24 months after initial treatment. Importantly, dual-energy X-ray absorptiometry (DEXA) was performed a second time after 2 treatment years for a subset of these men. DEXA showed that there was a gain in BMD and a loss of serum alkaline phosphatase (AP) for all the men over time. The loss of AP was rapid but stabilized at 6 months. Testosterone and free testosterone increased as expected but there were no changes in vitamin D, calcium, parathyroid hormone or sex hormone-binding globulin. There was a correlation between AP and testosterone. The authors recognized poor bone density at baseline in those men with testosterone levels

Bone mineral density is the best way to predict osteoporosis and fragility fractures [2]. Women loose BMD after menopause and that is accompanied by many changes, including gains in AP [3]. The decline in serum oestrogens is a factor for women, and oestrogen replacement therapy historically has been used to prevent that loss. Not all men undergo a similar loss, i.e. andropause is not recognized in the same way as menopause. Even though osteoporosis is less common in men, the associated comorbidity may be more significant.

There is an age-related decline in testosterone and an acute loss for some men such that they approach their physicians with symptoms. The underlying cause of bone loss in men and women may be the same: serum oestrogen loss. Men who lose testosterone are also losing oestrogen because testosterone is the precursor via aromatase. Repros Therapeutics is developing a way to treat men with secondary hypogonadism. An ongoing 1-year DEXA study recruited eligible men. Key inclusion factors were age < 60 years and body mass index > 25 kg/m2. Remarkably 24% of men failed the screening test because of osteopenia, despite the fact that few of them were old or underweight.

The present paper by Dubaja et al. suggests that a readily available serum test may be able to monitor men on testosterone therapies for gain in BMD. Given the relatively low incidence of osteoporosis, screening every man by DEXA is not cost-efficient. The 1 year or more needed to find BMD loss by DEXA also wastes time and resources. Quantitative CT is more costly and is accompanied by high radiation exposure. The use of AP, as suggested in the present study, may represent a reasonable alternative.

The paper is not without its weaknesses. There was no indication of whether these men had primary or secondary hypogonadism. Transdermal testosterone should raise testosterone and oestrogen in both groups of men whereas clomiphene citrate works through changes in LH and FSH and requires an intact hypothalamic-pituitary-gonadal axis (useful in men with secondary hypogonadism only). Indeed, the two kinds of treatment will have the opposite effect on LH and FSH [4]. The authors recognized the importance of Leydig cells in producing testosterone, yet the effects of a transdermal testosterone would be to shut down testosterone production. We commend their suggestion that other factors that contribute to both bone and Leydig cell function, insulin-like 3 [5] and osteocalcin [6] should be studied in relation to AP. The loss of subjects throughout the 2 years was troubling, but it is known that men on transdermal treatments discontinue with disturbing frequency despite satisfaction [7]. If those who stayed in the present study were those with the best outcomes in terms of testosterone and BMD, potential bias may exist. If men can be encouraged to continue therapy through positive effects on BMD being detected as early as 6 months, AP monitoring may improve patient compliance. Only DEXA can give that assurance now. The authors noted the need for a larger prospective trial. Nevertheless, their paper provides a rationale for monitoring men on testosterone therapies that can be implemented with minimal cost or the need for new diagnostics.

Read the full article

Martin C. Michel

Department of Pharmacology, Johannes Gutenberg University, Mainz, German

References

1 Dabaja A, Bryson C, Schlegel P, Paduch D. The eﬀect of hypogonadism and testosterone-enhancing therapy on alkalinephosphatase and bone mineral density. BJU Int 2015; 115: 3

2 NIH Consensus Development Panel. Osteoporosis prevention, diagnosis and therapy. JAMA 2001; 285: 785–95

3 Biver E.Use of bone turnover markers in clinical practice. Curr O pin Endocrinol Dia betes Obes 2012; 19: 468–73

4 Kaminetsky J, Werner M, Fontenot G, Wiehle RD. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel. JSexMed2013; 10: 1628–35

5 Ivell R, Anand-Ivell R. Biology of insulin-like factor-3 in human reproduction. Hum Reprod Update 2009; 15: 463–76

6 Karsenty G. Bone endocrine regulation of energy metabolism and male reproduction. CRBiol2011; 334: 720–4

7 Kovac J, Rajanahally S, Smith R, Coward R, Lamb D, Lipshultz L. Patient satisfaction with testosterone replacement therapies: the reasons behind the choices. JSexMed2014; 11: 553–62

Editorial: Enzalutamide withdrawal syndrome: is there a rationale?

March 4, 2015/by Alessandra Mosca

Enzalutamide is a second generation non-steroidal antiandrogen (AA), which significantly improved overall survival (OS) and progression-free survival (PFS) after docetaxel (AFFIRM study), and OS and radiographic PFS before chemotherapy (PREVAIL study) in patients with metastatic castration-resistant prostate cancer (mCRPC) [1].

Being a potent androgen receptor (AR) antagonist, an enzalutamide withdrawal syndrome (EWS) appeared unlikely [2,3]. In contrast with this position, and considering the well-known AR structural alterations in CRPC, very recent preclinical and clinical data support the possibility of the existence of an EWS after the discontinuation of this drug, in a castration-resistant setting.

In patients with mCRPC progressing on androgen-deprivation therapy (ADT), the AAWS, due to the interruption of first generation AAs (flutamide, bicalutamide, nilutamide, cyproterone acetate and megestrol acetate), often pursues as a further hormonal manipulation, although no level one studies supported its efficacy. AAWS leads to a PSA reduction in 15–30% of patients, with concomitant symptomatic relief and radiographic responses in some cases, without impacting on survival [1]. The molecular mechanisms of the AAWS are still unclear. One of the possible mechanisms responsible for the AAWS is the mutation of the AR. In vitro models showed that bicalutamide may switch from antagonist to agonist in LNCaP-cxD cell lines, due to an additional AR mutation in codon 741 during bicalutamide treatment [4]. Similarly, preclinical in vitro and in vivo studies demonstrated that initially enzalutamide exerts its AR antagonist activity, but during the treatment enzalutamide potently induces an AR mutation, leading to the mutant ARF876L, which confers agonism to enzalutamide, and resistance to enzalutamide therapy [1]. In the clinical setting, the first evidence of possible EWS has begun to appear. Phillips [5] observed EWS in one patient, 40 days after enzalutamide discontinuation. Rodriguez-Vida et al. [1] showed EWS in three of 30 (10%) patients with mCRPC after the drug cessation, although none of the 17 factors examined were statistically significant predictors of PSA decline after enzalutamide interruption. Considering the clinical characteristics of the three patients showing EWS, interestingly all of them were aged <70 years, had Gleason score ≥7, had bone and/or lymph node metastases without visceral sites of disease, and had had previous treatments with bicalutamide and docetaxel. In all three patients, EWS seems to have no correlation with: prostate cancer staging at diagnosis (M0 vs M1), PSA value before enzalutamide, PSA decline on enzalutamide treatment, LHRH analogues and enzalutamide therapy duration. Similarly to bicalutamide WS, in all three patients no symptomatic improvement was recorded during EWS.
Focusing on patient 1, interestingly he displayed initially a PSA response during enzalutamide and later a further PSA decline plus radiological response after enzalutamide interruption (i.e. EWS), showing a sensitivity either to initial enzalutamide antagonism and to subsequent agonism, and exhibiting an EWS not preceded by a bicalutamide WS. This supports previous data concerning different AR mutations for the two different AAs, without subsequent clinical correlations between the two different AAWSs. A LHRH analogue duration treatment (5 months) shorter than a subsequent enzalutamide duration therapy (21.4 months) suggests different tumoral cells sensitivity to different ADTs, in different stages (hormone naïve and castration-resistant prostate cancer), likely related to several AR structural alterations collected along the disease. Intriguingly, patient 3 discontinued enzalutamide after only 1.2 months, maybe due to primary resistance [6]; nevertheless, he showed a PSA
response after enzalutamide interruption, suggesting that EWS, characterised by the switch from enzalutamide antagonism to agonism, could occur even in prostate cancer patients primary resistant to this drug. Limitations of the two first clinical reports related to EWS include a restricted sample size, a reduced number of EWS events and a short duration of follow-up after enzalutamide discontinuation. Furthermore, preclinical studies on EWS and published data concerning AAWS described more frequently early stage mCRPC, while the two papers considered heavily pretreated patients with mCRPC, in whom EWS incidence could be reduced due to several previous treatments, which probably produced various AR alterations.

In conclusion, the preclinical models have demonstrated one possible plausible mechanism responsible for EWS and enzalutamide resistance. First clinical reports suggest the possibility of EWS in a minority of patients after enzalutamide discontinuation in mCRPC. Further studies are needed to confirm and detail the EWS, before translating these data into clinical practice.

Read the full article

Alessandra Mosca
Medical Oncology, ‘Maggiore della Carità’ University Hospital, Novara, Italy

References

1 Rodriguez-Vida A, Bianchini D, Van Hemelrijck M et al. Is there an antiandrogen withdrawal syndrome with enzalutamide? BJU Int 2015; 115: 373–80

2 von Klot CA, Kramer MW, Böker A et al. Is there an anti-androgen withdrawal syndrome for Enzalutamide? World J Urol 2014; 32: 1171–6

3 von Klot CA, Kuczyk MA, Merseburger AS. No androgen withdrawal syndrome for enzalutamide: a report of disease dynamics in the postchemotherapy setting. Eur Urol 2014; 65: 258–9

4 Hara T, Miyazaki J, Araki H, Yamaoka M, Kanzaki N, Kusaka M. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res 2003; 63: 149–53

5 Phillips R. An enzalutamide antiandrogen withdrawal syndrome. Nat Rev Urol 2014; 11: 366

6 Efstathiou E, Titus M, Wen S et al. Molecular characterization of Enzalutamide-treated bone metastatic castration-resistant prostate cancer. Eur Urol 2015; 67: 53–60

Racing ahead

March 3, 2015/1 Comment/by Declan Murphy

Since the new Editorial team assumed the reins here at the BJUI in January 2013, we have worked hard to embrace social media as the transformative communication technology it clearly is. While our priority is to only publish papers of the highest quality, we have also ensured that the reach and engagement of these papers are maximised using our social media platforms – Twitter, Facebook, YouTube, Instagram and Blogs@BJUI.

In this month’s BJUI, there are two intriguing papers that deal with this area but that deliver contrasting messages. The first from Nason et al. analyses the Twitter activity of all urology journals over a recent 6-month period. It is clear that the major journals have adopted Twitter as a preferred social media platform and it is gratifying to see how well the BJUI performs when assessed using the metrics in this paper. However, Fuoco and Leveridge report that most urologists in a Canadian survey believe that ‘social media integration into medical practice is impossible’ and attitudes towards the professional role of social media were ‘generally negative’.

Nevertheless, the power of social media in enhancing our personal and professional communication is undeniable and we at the BJUI expect more and more urologists to embrace social media in the coming years. We will continue to evolve our social media strategy to ensure the BJUI is a highly ‘social’ experience.

On another note, the BJUI is pleased to support an excellent conference taking place in Dublin in April in the memory of our previous Editor-in-Chief, Professor John Fitzpatrick, who passed away suddenly last year. The Inaugural John Fitzpatrick Irish Prostate Cancer Conference takes place from 23–24th April 2015 and has attracted an outstanding International Faculty of colleagues and friends who look forward to exploring the most challenging areas in prostate cancer in his memory. Details here https://www.globalteamwork.ie/prostate.html.

Declan G. Murphy – BJUI Associate Editor – Social Media

Department of Urology, University of Melbourne, Melbourne, VIC, Australia

Twitter @declangmurphy

Am I normal? Review Analyzes Data on Flaccid and Erect Penis Lengths in Men

March 3, 2015/9 Comments/by admin Z.9

Press Release

A new analysis provides insights on what’s considered “normal” for penis length and circumference in men. The findings in BJU International may be helpful when counseling men who are worried about their size, or when investigating the relationship between condom failure and penile dimensions.

Some men are concerned about their penis size, and those who are preoccupied and severely distressed with the size of their penis may even be diagnosed with Body Dysmorphic Disorder. There have been no formal systematic reviews of penile size measurements and no attempts to create a graphical diagram, or nomogram, that depicts the distribution of the size of a flaccid or erect penis. Here you will get best penile traction therapy, do visit us. People who are experiencing a lack of desire and interest in lovemaking may find sex toys and games to be beneficial in resolving their problems. Using games for sexual stimulation or arousal is considerably cheaper and easier than using other drugs. You can vists site for the best sex toy for your sexual life.

Dr. David Veale, of King’s College London and the South London and Maudsley NHS Foundation Trust, and his colleague from King’s College Hospital NHS Foundation Trust, set out to create such a nomogram of male penis size measurements across all ages and races. A search of the medical literature revealed 17 studies with up to 15,521 males who underwent penis size measurements by health professionals using a standard procedure. The nomograms revealed that the average length of a flaccid penis was 9.16 cm, the average length of a flaccid stretched penis was 13.24 cm, and the average length of an erect penis was 13.12 cm. The average flaccid circumference was 9.31 cm, and the average erect circumference was 11.66 cm. There was a small correlation between erect length and height.

“We believe these graphs will help doctors reassure the large majority of men that the size of their penis is in the normal range. We will also use the graphs to examine the discrepancy between what a man believes to be their position on the graph and their actual position or what they think they should be” said Dr. Veale.

Article: “Am I normal? A systematic review and construction of nomograms for flaccid and erect penis length and circumference in up to 15,521 men.” David Veale, Sarah Miles, Sally Bramley, Gordon Muir, and John Hodsoll. BJU International; Published Online: March 3, 2015 (DOI: 10.1111/bju.13010).

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Editorial: Malignant medication? Testosterone and cancer

February 25, 2015/by Alexander Pastuszak

Testosterone therapy (TTh) in men with hypogonadism is becoming more commonplace among urologists, endocrinologists and even primary practitioners. While the definition of hypogonadism remains a moving target, the literature reflects very clear benefits of TTh in appropriately selected patients. As with any drug, the adverse effect profile helps to dictate the risk:benefit ratio and, over the past several years, numerous, primarily retrospective, analyses have provided mixed insights into the impact of TTh on cardiovascular disease and cancer, specifically prostate cancer.

Eisenberg et al. [1] take a step back from the focus on prostate cancer and evaluate the impact of TTh on general cancer incidence in a cohort of men treated in a single, large-volume andrology practice over 20 years. The authors found no difference in either overall cancer incidence or in the prostate cancer incidence in men on TTh in comparison with men not on TTh. This finding is significant as it supports the hypothesis that testosterone does not harmfully affect either hormonally responsive (prostate cancer) or non-hormonally responsive malignancies. Interestingly, the authors also observe a lower rate of all cancers in men on testosterone therapy. While not statistically significant, this finding is consistent with that of at least one other study focused on prostate cancer, in which men with high-risk prostate cancer receiving exogenous testosterone had a lower recurrence rate than a matched control group [2]. If borne out in future studies, a protective relationship between TTh and cancer would indeed reflect a novel benefit of treatment.

Nevertheless, at this time the jury remains out on a definitive assessment of the effects of TTh on both cancer as well as cardiovascular disease, and will probably continue to do so until controlled, prospective studies are completed. Numerous, mostly retrospective studies have examined the effects of endogenous testosterone and of the administration of exogenous testosterone, primarily on prostate cancer. While the details of these studies are beyond the scope of the present editorial, their findings have varied with regard to whether testosterone does or does not have effects on cancer incidence, biopsy findings, grade, recurrence rates and margin status, preventing a clear perspective on the effects of testosterone on cancer. Similarly, studies evaluating the impact of TTh on cardiovascular disease have also widely varied in their conclusions [3, 4]. Several recent large retrospective studies have found a detrimental relationship between TTh and cardiovascular disease in specific male populations, but have come under withering criticism from the community, with significant doubts cast regarding the veracity of their findings [5, 6].

The growing popularity of TTh has subjected it to a level of scrutiny applied to few other medications, resulting in a slew of peer-reviewed publications of varying quality and conclusions. In the effort to safeguard patients, investigators have hurriedly carried out retrospective data evaluation, which, by design, limits compensation for confounding factors and unfortunately results in an overall murky understanding of long-term adverse events related to TTh. Nevertheless, the clinical benefits of TTh are clear, and many patients are satisfied with the results of treatment. While physicians should remain the stewards of patient care, informed consent and a patient’s acceptance of both the known as well as the unknown risks of testosterone treatment should continue to be an integral part of the initiation and continuation of TTh, until additional high-quality data from clinical trials become available in the coming years.

Read the full article

Alexander W. Pastuszak

Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

References

1 Eisenberg ML, Li S, Betts P et al. Testosterone therapy and cancer risk. BJU Int 2015; 115: 317–21

2 Pastuszak AW, Pearlman AM, Lai WS et al. Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy. J Urol 2013; 190: 639–44

3 Basaria S, Coviello AD, Travison TG et al. Adverse events associated with testosterone administration. NEnglJMed2010; 363: 109–22

4 Shores MM, Smith NL, Forsberg CW et al. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012; 97: 2050–8

5 Vigen R, O’Donnell CI, Baron AE et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013; 310: 1829–36

6 Finkle WD, Greenland S, Ridgeway GK et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS ONE 2014; 9: e85805

Editorial: How active should active surveillance be?

February 18, 2015/1 Comment/by Scott Eggener

Many investigators, including those from Johns Hopkins University (JHU) and the Prostate cancer Research International: Active Surveillance project (PRIAS), have provided meaningful data to strongly support the increasing use of active surveillance (AS) across the world. There are a multitude of strategies to minimise excessive rates of prostate cancer over detection and overtreatment. After the diagnosis of prostate cancer, the single best is AS for appropriately selected men.

For decades, the concept of not treating a prostate cancer in otherwise healthy men, even if low-grade and low-volume was typically considered nihilistic and heretical, particularly in the USA. Thankfully, data have largely made this line of thinking anachronistic. The era of sensibly applied AS is upon us, and single-institution series with intermediate-term follow-up are excellent, with exceedingly low rates of metastasis or cancer-related death. However, we await longer-term (>10 years) outcomes from the contemporary PSA screening era.

The ‘success’ of AS is largely dependent on the entry criteria, follow-up strategies, and indications for curative intervention. Highly restrictive inclusion criteria, rigorous biopsy based follow-up and strict definitions of reclassification triggering treatment have produced superb outcomes. Critics appropriately argue these criteria exclude a significant proportion of men with a low rate of requiring treatment or having metastases, if allowed on AS. Conversely, other programmes with looser entry criteria, more lax follow-up, and relaxed indications for intervention will be more inclusive and have lower rates of immediate or delayed intervention but must be counterbalanced against the expected higher rate of metastases or death.

The current study [1] evaluates two different AS follow-up strategies from JHU and PRIAS. In general, JHU uses annual biopsies with progression defined as a new PSA density >0.15 ng/mL/mL or increasing tumour volume or grade beyond a certain threshold, while PRIAS recommends less frequent biopsies (years 1, 4, and 7) while relying on serological (PSA doubling time, PSADT) alongside histological indicators for defining progression and recommending treatment.

Not surprisingly, different strategies lead to varying expected outcomes. Among the JHU patients, 38% were reclassified at a median of 2.1 years. Nearly two-thirds of the reclassified would have been identified at the PRIAS year 1 or triennial biopsies with 16% identified between PRIAS biopsies at a median delay of 1.9 years. The unanswerable but incredibly important question is whether this delay is essentially a non-issue, perhaps a favourable attribute (more AS time without compromising cure rates), or clinically disastrous (patients no longer curable).

PRIAS relies heavily on PSA kinetics, which can be a double-edged sword. Among men in the JHU programme with >5 years follow-up, 11% would have delayed reclassification compared with PRIAS at a median time of 4.7 years. Additionally, 12% would have undergone intervention due to PRIAS-defined PSADT but not progressed based on the JHU protocol. It is convenient and perhaps intuitive that PSA kinetics should predict progression and meaningful clinical events for men on AS; however, the data from multiple studies have simply not supported this concept [2, 3].

The JHU programme has restrictive entry rules compared with most other programmes, a rigorous biopsy based follow-up protocol, and strict criteria to treat, which is exactly why no metastasis or death have been reported among 769 men, some with up to 15 years follow-up[4]. Guidelines are needed but should not be overly prescriptive or rigid. For example, a surveillance biopsy showing a single core of Gleason 6 encompassing 60% of the total core or three cores of Gleason 6 with total cancer length of 3 mm would lead to a recommendation of treatment according to published JHU criteria. Many of us would not be phased with these biopsy reports and comfortably recommend ongoing AS.

Data from AS series are very encouraging but it is highly likely we can do even better. For example, 10-year cancer-specific survival is 97% in the Sunnybrook AS experience and all five cancer-related deaths occurred in patients that would not meet most contemporary AS entry criteria [5, 6]. I am hopeful and confident that emerging data incorporating MRI imaging, serum biomarkers (e.g. prostate health index), or tissue-based biomarkers (e.g. Prolaris, Oncotype Dx) will provide us with a more comprehensive understanding of these men’s cancer such that tailored, evidence-based recommendations can be even more accurate.

There is much yet to be learned about AS and this study [1] adds to our knowledge. Surveillance for prostate cancer is definitely active, but it is also dynamic and evolving.

Read the full article

Scott Eggener

Associate Professor of Surgery, University of Chicago, Chicago, IL, USA

References

1 Kates M, Tosoian JJ, Trock BJ, Feng Z, Carter HB, Partin AW. Indications for intervention during active surveillance of prostate cancer:

a comparison of the Johns Hopkins and Prostate Cancer Research International Active Surveillance (PRIAS) protocols. BJU Int 2015; 115: 216–22

2 Whitson JM, Porten SP, Hilton JF et al. The relationship between prostate speciﬁc antigen change and biopsy progression in patients on active surveillance for prostate cancer. J Urol 2011; 185: 1656–60

3 Fall K, Garmo H, Andrén O et al. Prostate-speciﬁc antigen levels as a predictor of lethal prostate cancer. JNatlCancerInst2007; 99: 526–32

4 Tosoian JJ, Trock BJ, Landis P et al. Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. J Clin Oncol 2011; 29: 2185–90

5 Klotz L, Zhang L, Lam A, Nam R, Mamedov A, Loblaw A. Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol 2010; 28: 126–31

6 Krakowsky Y, Loblaw A, Klotz L. Prostate cancer death of men treated with initial active surveillance: clinical and biochemical characteristics. J Urol 2010; 184: 131–5

The Death of the Junior Surgeon

February 16, 2015/6 Comments/by Jonathan Glass

I think I attended a meeting recently at which I fear, after many years of being slowly deprived of oxygen by various organisations, a component of a profession which I love and to which I have devoted so much of my life, finally started to give up the fight and started to die.

I am involved in training as a training programme director as well as being a local trainer. As a TPD I have had to watch the separation of the London and KSS training programmes. This has happened, despite sitting in a room of thirty to forty senior trainers who all voiced the opinion that this is detrimental to the future of urology training for our trainees. The trainees also voiced an opinion that this was wrong but still it went ahead.

Recently, I sat in a room where, again, a group of thoughtful intelligent doctors spoke about the future of junior doctor training. We are about to impose a change in the training of foundation year doctors imposed upon our excellent organisation from what for most of us is a faceless organisation with whom we will never interact directly. We will be moving them into community-based jobs that no senior doctor round the table believed was in their interests or in the interests of the future of Britain’s healthcare, but we will still oversee that process.

And what test is being applied to what our junior doctors should be doing to justify these changes? The question – do the jobs they are doing have to be done by a doctor?

I can’t imagine for a second that this question can be critically applied to the new foundation year jobs in community work and answered affirmatively.

Furthermore when the role of any of our jobs is deconstructed, how much of that role needs to be done by a doctor? We can give up prescribing to a pharmacist, blood taking to a phlebotomist, ward based care to a physician’s assistant, outpatient follow-up (assuming it will be permitted in the future) to a nurse specialist, diagnostic procedures to a radiographer, diagnostics to a nurse consultant, audit to a data manager, construction and development of the department to an administrator, training programme planning to deanery educationalists, perioperative support to a clinical psychologist, etc, etc, etc.

How much of the work of a junior doctor has ever had to be that of a doctor? The job of the junior doctor has always been all of these, whilst learning from and being inspired by the beauty of a carefully constructed ward consultation by a senior clinician who understood the subtleties of human interaction and the tensions and uncertainties of the patient lying in the bed in front of him or her. The junior doctor didn’t mind devoting much of his or her young life and many hours of hard work, including performing some menial tasks, because the new recruit was intelligent enough and committed enough to realise that hours spent on the wards and in clinic would turn themselves, currently a piece of apparently formless clay, into a fine piece of highly polished china. They would, yes with hard work, hours spent studying, and arguably obsessional attention to detail and a constant desire to improve, become a fantastic diagnostician, a remarkable clinician and, in some cases, a technically brilliant surgeon and the most wonderful observer of the human condition.

Which of any of our jobs must be done by a doctor? That is not a reasonable question to apply to much of what any doctor, or indeed I suspect what any professional, does in their day to day work. It is the totality of what they do that defines their role, not the minutely dissected individual parts of their job. When dismembered, no organism has the functional beauty of its form when complete, nor is it able to survive when it is disassembled.

I fear that that is true of our glorious profession. What would Bright, Hodgkin or Astley-Cooper say if they could guide us now?

I am no Luddite. I work in a branch of medicine that has thrived in the technological development of its specialty, in a department that has led the way in introducing new ways of working, new ways of thinking about how care should be provided with a better understanding of patient processing and what frustrates patients when they access healthcare. We as a group have demonstrated how we are willing to embrace change when we perceive it to be for the benefit of our patients.

I have sat and watched changes being introduced, as have many of us over the years, suspicious that not all changes are really in the interests of the future of medical care. However, I sat down after attending the meeting to which I referred earlier and found myself asking these questions.

In Judaism, at a burial and for a year after the death of a close relative, we recite kaddish, the memorial prayer. Is it now time to recite kaddish for the role of the junior surgical hospital doctor?

Jonathan Glass – Consultant Urologist, Guy’s & St Thomas’ NHS Foundation Trust