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Editorial: Is zero sepsis alone enough to justify transperineal prostate biopsy?

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The landscape of infectious complications after TRUS-guided biopsy of the prostate has changed dramatically. While sepsis after TRUS-guided prostate biopsy has always been a concern for urologists performing this very common procedure, in the past couple of years a number of factors have added to these pre-existing concerns for urologists and patients alike.

First, key papers have reported the true incidence of sepsis and hospital re-admission after TRUS biopsy and have shown that these rates are increasing. Loeb et al. [1] reported that the 30-day re-admission rate in a Surveillance, Epidemiology and End Results (SEER)-Medicare population was 6.9% and that this rate is increasing. Nam et al. [2] similarly reported a 3.5-fold increase in hospital admissions after prostate biopsy in the previous 10 years, principally attributable to infection-related complications. These reports have been replicated around the world and there is consensus that this is a growing problem.

Second, there are increasing concerns about the emergence of resistant organisms, in particular, extended spectrum beta lactamase (ESBL), in regions where antibiotic use has contributed to the emergence of these strains [3]. Media attention has focused on this issue and has led to increased concerns among urologists and patients alike. It has also led to a requirement for extra precautions when assessing patients for prostate biopsy such that in some regions, rectal swabs are being taken to identify ESBL-carriers ahead of time. In a contemporary series, Taylor et al. [4] report that 19% of men undergoing transrectal prostate biopsy in Canada carry ciprofloxacin-resistant coliforms in rectal swabs. The thought of passing a needle through this flora into the prostate is somewhat disturbing; rectal swabs may become mandatory when offering a TRUS-guided biopsy to any patient and should absolutely be taken if planning a TRUS biopsy in someone who has travelled to South-East Asia in the preceding 6 months.

The Bloomberg News, in a well-researched report into antibiotic use in India and the emergence of resistant strains of Escherichia coli, reported some startling statistics about the overuse of antibiotics in that country, and described how the ‘perfect storm’ of antibiotic overuse, poverty and poor sanitation (half of the country’s 1.2 billion residents defaecate in the open), is contributing to the emergence of superbugs colonizing the gut of dwellers and visitors to India [5]. It is clear that even walking through a puddle in New Delhi puts a visitor at high risk of harbouring ESBL organisms in the rectum for many months after.

In this month’s BJUI, Vyas et al. [6] describe a consecutive series of 634 patients undergoing prostate biopsy at Guy’s Hospital in London using a transperineal template-guided approach, and report a sepsis rate of zero. They also report other notable factors including a 36% cancer detection rate in men who had previously undergone transrectal prostate biopsy with no evidence of malignancy and, in men on active surveillance for Gleason 6 prostate cancer, they observed upgrading to Gleason ≥7 cancer in 29% of cases after immediate re-staging biopsy using a transperineal approach. An even larger contemporary study from Pepe et al. [7] reports zero sepsis in a consecutive series of 3000 men undergoing transperineal prostate biopsy.

It is quite impossible to imagine such large series of prostate biopsies with no episodes of sepsis if performed using a transrectal approach. The documented increasing levels of ESBL and high levels of asymptomatic gut colonization, especially for those resident or travelling through South-East Asia, mean that adequate risk assessment and counselling of patients before TRUS biopsy is more important than ever before. A careful history regarding recent antibiotic use is also essential as previous recent use of quinolones is also a risk factor for infection after a transrectal biopsy [8].

While widespread adoption of a transperineal approach to prostate biopsy would have considerable resource and logistic issues, and inevitably would not be accepted by all urologists, the rising rate of infectious complications and of resistant organisms colonizing the rectum may mean that continuing with a transrectal approach becomes too risky and therefore unacceptable to patients and clinicians alike. While a transperineal approach also appears to add value in terms of more accurate staging and also facilitates the emerging interest in MRI fusion-guided biopsies and focal therapy, zero sepsis alone may be enough to convince many that a transrectal approach should no longer be preferred.

Read the full article

Declan G. Murphy*†, Mahesha Weerakoon† and Jeremy Grummet‡

*Division of Cancer Surgery, University of Melbourne, Peter MacCallum Cancer Centre, †Australian Prostate Cancer Research Centre, Epworth Richmond Hospital, and ‡Department of Urology, The Alfred Hospital, Melbourne, VIC, Australia

References

  1. Loeb S, Carter HB, Berndt SI, Ricker W, Schaeffer EM. Complications after prostate biopsy: data from SEER-Medicare. J Urol 2011; 186: 1830–1834
  2. Nam RK, Saskin R, Lee Y et al. Increasing hospital admission rates for urological complications after transrectal ultrasound guided prostate biopsy. J Urol 2010; 183: 963–968
  3. Williamson DA, Masters J, Freeman J, Roberts S. Travel-associated extended-spectrum beta-lactamase-producing Escherichia coli bloodstream infection following transrectal ultrasound-guided prostate biopsy. BJU Int 2012; 109: E21–22
  4. Taylor S, Margolick J, Abughosh Z et al. Ciprofloxacin resistance in the faecal carriage of patients undergoing transrectal ultrasound guided prostate biopsy. BJU Int 2013; 111: 946–953
  5. Gale JN, Narayan A. Drug-defying germs from India speed post-antibiotic era. 2012; Available at: https://www.bloomberg.com/news/2012-05-07/drug-defying-germs-from-india-speed-post-antibiotic-era.html. Accessed June 2014
  7. Pepe PA, Aragona F. Morbidity after transperineal prostate biopsy in 3000 patients undergoing 12 vs 18 vs more than 24 needle cores. Urology 2013; 81: 1142–1146
  8. Patel U, Dasgupta P, Amoroso P, Challacombe B, Pilcher J, Kirby R. Infection after transrectal ultrasonography-guided prostate biopsy: increased relative risks after recent international travel or antibiotic use. BJU Int 2012; 109: 1781–1785

 

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Editorial: Penile vibratory stimulation (PVS) a novel approach for penile rehabilitation post nerve sparing radical prostatectomy

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The reported incidence of erectile dysfunction (ED) after nerve-sparing radical prostatectomy (NS-RP) varies in the literature from 30 to 80% [1]. This can be explained by the state of neuropraxia which affects the cavernosal nerves, even if the nerves are anatomically intact. During this period there is a lack of nocturnal tumescence which leads to tissue hypoxia and ischaemic damage to the cavernosal smooth muscles leading to smooth muscle necrosis and fibrosis, which in turn causes veno-occlusive dysfunction (VOD). A study by Mulhall et al. [2] showed that, at 12 months after NS-RP, 50% of patients will have VOD and ED. The role of penile rehabilitation, therefore, is to maintain adequate tissue oxygenation until the cavernosal nerves recover with the return of the spontaneous nocturnal tumescence; thus, penile rehabilitation should not be confused with ED treatment. If you see yourself as religious, addiction may make you feel guilty or get you to feel isolated among your friends at your religious organization. A spiritual Christian rehab center in Orlando may be the right choice for you. Not only do you get to meet like-minded people to share your experiences in your journey to sobriety, but the process may also help you to rediscover your faith in God. Legacy Healing Center Tampa offer programs that make spiritual guidance an important part of every type of addiction treatment. Orange County law enforcement has taken steps to make sure the drugs are not as easily available as they once were. This has helped manage Orlando’s drug problem and kept it from turning worse. As important as prevention is to saving lives, however, to the hundreds who are already addicted, rehab is what helps. If you are religious or spiritual, faith-based drug rehab can be the answer to the challenges that you face. It’s important to remember that faith-based rehab only works well for those who are deeply spiritual or religious. Trying faith-based rehab when you are ambivalent about religion can work against you. You may find that you aren’t able to accept what you’re asked to practice, and you may find yourself rebelling. It’s important to choose a treatment approach that you can go along with in good conscience.

Several lines of treatment, including phosphodiesterase 5 inhibitors, intracavernous injection of alprostadil and vacuum pump therapy, have been used in penile rehabilitation but an agreed rehabilitation programme in terms of agents used, timing and duration of therapy does not yet exist [1].

The present study by Fode et al. [3] reports a novel approach to penile rehabilitation using penile vibratory stimulation (PVS). The study looked into the effect of PVS on postoperative erection and continence. The Ferticare® vibrator (Fig. 1) was used at an amplitude of 2 mm and a vibration frequency of 100 Hz and applied to the frenulum once daily, with a sequence consisting of 10 s of stimulation followed by a 10-s rest and repeated 10 times.

The results showed a trend towards better erection in the PVS group (n = 30) compared with the control group (n = 38) as evidenced by the higher International Index of Erectile Function (IIEF) score, but the difference was not significant (P = 0.09). After 1 year, 16 patients (53%) in the PVS group had an IIEF score ≥18 compared with 12 (32%) patients in the control group (P = 0.07). The results did not show any effect of treatment on continence; at 12 months, 90% of the PVS group achieved continence compared with 94.7% of the control group (P = 0.46), although the PVS group had a significantly higher preoperative LUTS score which may explain the results.

The theory postulated is that application of PVS activates the parasympathetic erectile spinal centre (S2–S4), which in turn leads to activation of the cavernosal nerves, enhancing the healing process, and recovery from neuropraxia and restoration of spontaneous erections. Also this would lead to stimulation of the somatic S2–S4 spinal centre, which controls the pelvic floor muscles via the pudendal nerve, leading to the recovery of continence. Although this has been shown in patients with spinal cord injury as the authors mentioned; this may not be the case in post NS-RP with the nerves in a state of neurapraxia, whereas in patients with spinal cord injury the nerves are intact. It would have been of great value to conduct neurophysiological tests on these patients to demonstrate that, despite the cavernosal nerves being in a state of neurapraxia, nerve activity in response to PVS was actually present.

The rehabilitation protocol used in the present study started early but only continued for 6 weeks postoperatively. Studies have shown that the potential recovery time of erectile function after NS-RP is 6–36 months, with the majority recovering within 12–24 months [1,4]. The results might have shown statistical significance in favour of PVS, had treatment continued for a longer period. Starting PVS treatment in the early postoperative period may not be suitable in all patients; in this study six out of 36 patients (16.6%) were non-compliant with the protocol; four had prolonged catheterization and two experienced pain. Furthermore, neurophysiological testing is required to show that in the early postoperative period the cavernosal nerves are actually intact and therefore respond to PVS.

Although the results of the present study did not reach significance, they are encouraging, as there was a trend in favour of treatment with regard to erectile function. Further studies involving larger numbers of patients are warranted to investigate this new line of rehabilitation.

Read the full article

Amr Abdel Raheem*† and David Ralph†
*Andrology Department, Cairo University Hospital, Cairo, Egypt, and †St. Peter’s Andrology Centre, Institute of Urology, London, UK

References

  1. Mulhall JP, Bivalacqua TJ, Becher EF. Standard operating procedure for the preservation of erectile function outcomes after radical prostatectomy. J Sex Med 2013; 10: 195–203
  2. Mulhall JP, Slovick R, Hotaling J et al. Erectile dysfunction after radical prostatectomy: hemodynamic profiles and their correlation with the recovery of erectile function. J Urol 2002; 167: 1371–5
  3. Fode M, Borre M, Ohl D, Lichtbach J, Sønksen J. Penile vibratory stimulation in the recovery of urinary continence and erectile function after nerve-sparing radical prostatectomy: a randomized, controlled trial. BJU Int 2014; 114: 111–7
  4. Rabbani F, Schiff J, Piecuch M et al. Time course of recovery of erectile function after radical retropubic prostatectomy: does anyone recover after 2 years? J Sex Med 2010; 7: 3984–90
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A new take on GPS navigation? Summary of the June #urojc twitter debate.

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The diagnosis and management of prostate cancer continues to rapidly evolve, with heavy debates at each stage of the evolution process. The key trade off between avoiding the over diagnosis and overtreatment of low risk indolent tumours, versus failing to diagnose and act on what may progress to aggressive disease, is an on going theme in the debate.

Research into various diagnostic tools to help both the patient and clinician stratify individual risk is on going, however the heavy consequence of undertreating perhaps leads more into active treatment than clinically necessary.

The June #urojc twitter debate focused on the new and hugely important paper by Klein E et al, to which we were given open access to courtesy of European Urology.  The authors of this US study focus on the potential underuse of Active Surveillance (AS), and propose a Genomic Prostate Score in order to help risk stratify patients considering both surveillance and active therapy. Based on three studies, a prostatectomy study, a biopsy study, and a validation study, a 17-gene assay was created which was shown to predict both high stage and high grade disease at diagnosis.

The debate kicked off with the suggestions from the hosts that at genomics may make their way into AS protocols

 

Which was rapidly agreed

However inevitably the issue of cost was raised

Parth Modi praised the study design and results, however raised a valid question

And the further issue of logistics of samples provided for genomic testing was debated

With the possibility of low disease volume in samples contributing

Which launched a debate as to whether for those with low volume disease, the discussion of opting for genomics was a discussion too far

Alternatives to genomics in predicting progressive disease were discussed. However again the cost of these tests were debated – although generally thought to be less expensive than genomic testing.

 

Followed by perhaps an early contender for best tweet…

 

The host again posed an on point question

With responses suggesting there remains room for further work until genomics plays a role in day-to-day treatment plans

David Canes helped to put the debate into real terms by using an example case for discussion, which raised the point of interpretation of results being dependent on likely treatment decision, not necessarily treatment decision based fully on results

Which raised some slightly more pragmatic suggestions

GPS results however are not necessarily clear-cut. Like all prognostic indicators, they can be interpreted in variable ways. Is there a possibility that they could add to the quagmire in the decision making process for patients?

Ultimately the theme of the debate was summed up excellently by Matt Cooperberg. GPS is not offering a definitive strategy to decide who will and will not progress, or who should decide on active treatment. It does however mark a movement into individualised care, which may well be the future for prostate cancer treatment

Congratulations to David Canes for winning the Best Tweet prize which is a complimentary manuscript to Research Reports in Urology published by @DovePress.

Many thanks to all of those who participated in the debate. We look forward to next month’s #urojc discussion!

Sophia Cashman is a first year urology trainee working in the East of England region, UK. Her main areas of interest are female and functional urology. @soph_cash

 

Editorial: Cryosurgery for clinical T3 prostate cancer

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There are limited data available on the outcomes of cryosurgery for clinical T3 prostate cancer, and as such, the role of cryosurgery for clinical T3 disease is currently undetermined [1]. Modern cryosurgery of the prostate, utilizing gas-based third-generation technology, a real-time monitoring system with ultrasonography and thermocouples, is associated with a low complication rate [7], although comparative outcomes of the different treatment modalities and long-term follow-up data remain to be seen.

Several aspects of cryosurgery can make it difficult to adequately control locally advanced prostate cancer. First, cryosurgery for clinical T3 cancer requires unique surgical expertise to control local disease while minimizing side-effects. Secondly, staging of locally advanced prostate cancer is challenging – it is difficult to accurately identify the extent of extracapsular extension, seminal vesicle involvement and/or lymph node metastasis. Thirdly, challenges in managing clinical T3 disease include the requirement of a more extensive ablation technique to appropriately target the extraprostatic disease and seminal vesicle involvement as well as treatment for possible microscopic metastasis, which might not be clinically detectable.

Two recent randomized trials compared outcomes of external beam radiation therapy with those of cryosurgery (including cT3 diseases with use of neo-adjuvant androgen deprivation therapy [ADT]), with contrasting results [2, 3]. Chin et al. [2] reported superiority of biochemical disease-free survival favouring external beam radiation therapy in relatively more advanced (bulky) disease, while Donnelly et al. [3] reported significantly fewer positive biopsy rates favouring cryosurgery in the relatively less advanced disease. These findings could suggest that more advanced bulky cases that require wider local control of bulky extraprostatic diseases are not suitable for cryosurgery, while in appropriately selected cases with fewer extraprostatic diseases, cryosurgery is an acceptable option (when combined with neo-adjuvant ADT). Although appropriately extended cryo-lesions that achieve lethal temperatures can control extraprostatic disease, there is a certain limitation in the extension of cryo-lesions without injury to vital peri-prostate organs, such as the urinary sphincter, rectal wall, bladder wall and ureters.

Evolving accuracy of preoperative diagnostic imaging to assess extraprostatic disease can enhance outcomes, and staging tissue sampling from suspected extraprostatic disease could also identify actual microscopic extension of the extraprostatic disease [4]. A recently updated nomogram predicting lymph node invasion [5] suggests that the probability of lymph node invasion in patients with cT3, PSA level >10 ng/mL, and biopsy primary Gleason grade 4 is 20% or greater. Clearly, the preoperative risk assessment of lymph node involvement using such a modern calculator is pertinent for appropriate patient selection. Finally, management decision should be made by a multidisciplinary team.

When combined with radiotherapy, neo-adjuvant ADT for high-risk and locally advanced prostate cancer has been associated with clinical benefit; however, when combining neo-adjuvant ADT with prostatectomy, there is pathological down-staging and reduction in the surgical positive margin but minimal improvement in overall or disease-free survival [6]. The role of neo-adjuvant and adjuvant ADT when combined with cryosurgery is still unknown. Clearly, a prospective study is needed to determine the optimal duration and method of ADT (whether to use LHRH analogue or combined blockade) and to analyse the side-effects, the quality of life and the cost-effectiveness of a combination of cryosurgery with ADT for cT3a and cT3b prostate cancer.

Osamu Ukimura, Andre Luis de Castro Abreu, Andrew J. Hung and Inderbir S. Gill
USC Institute of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Read the full article

References

  1. Babaian RJ, Donnelly B, Bahn D et al. Best practice statement on cryosurgery for the treatment of localized prostate cancer. J Urol 2008; 180: 1993–2004
  2. Chin JL, Al-Zahrani AA, Autran-Gomez AM, Williams AK, Bauman G. Extended followup oncologic outcome of randomized trial between cryoablation and external beam therapy for locally advanced prostate cancer (T2c-T3b). J Urol 2012; 188: 1170–1175
  3. Donnelly BJ, Saliken JC, Brasher PM et al. A randomized trial of external beam radiotherapy versus cryoablation in patients with localized prostate cancer. Cancer 2010; 116: 323–330
  4. Ukimura O, Coleman JA, de la Taille A et al. Contemporary role of systematic prostate biopsies: indications, techniques, and implications for patient care. Eur Urol 2013; 63: 214–230
  5. Briganti A, Larcher A, Abdollah F et al. Updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node dissection: the essential importance of percentage of positive cores. Eur Urol 2012; 61: 480–487
  6. Shelley MD, Kumar S, Wilt T, Staffurth J, Coles B, Mason MD. A systematic review and meta-analysis of randomised trials of neo-adjuvant hormone therapy for localised and locally advanced prostate carcinoma. Cancer Treat Rev 2009; 35: 9–17
  7. Ward JF, DiBlasio CJ, Williams C, Given R, Jones JS. Cryoablation for locally advanced clinical stage T3 prostate cancer: a report from the Cryo-On-Line Database (COLD) Registry. BJU Int 2014; 113: 714–718

 

Not So Watchful Waiting?

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SPCG-4 of Robotic Prostatectomy versus WW: April #urojc summary

This month’s twitter based international urology journal club, found by using #urojc, kicked off with the highly anticipated 20 year follow-up of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4). This article had twitter buzzing in mid-March when it was published in the New England Journal of Medicine making it an ideal article for April’s journal club. This paper became an instant urology “classic.”

Bill-Axelson et al. published this 18 year follow up of a randomized control trial which separated individuals with early prostate cancer into two groups: watchful waiting or radical prostatectomy. Notable results of the study included a relative risk reduction of 44% from prostate cancer for those who underwent a radical prostatectomy compared to with watchful waiting with the NNT = 8, decreased use of androgen-deprivation therapy in this group, and the benefit of surgery being the most prominent in men <65 years with a 55% decrease in the relative risk of death due to prostate cancer.

Given that these results contradict the well known results of the Prostate Cancer Intervention versus Observation Trial (PIVOT), which started after the advent of PSA screening – the discussion of this article was particularly interesting. They are however, very different studies in terms of era and the populations studied.

During the 48 hour discussion period, key topics discussed were:

  • The applicability of these findings given the many advances in prostate cancer screening, diagnosis, and treatment since the 1990’s
  • The factors that influence the NNT
  • The impact of androgen deprivation therapy within both groups
  • How to weigh the impact of adverse effects including erectile dysfunction and urinary incontinence especially in the context of today’s treatment which includes radiation therapy, an option not addressed in this SPCG-4 study
  • The importance of this study should we face the possibility of shifting back to a pre-PSA era with the new USPSTF recommendations regarding PSA screening

As soon as the discussion opened, a question was posed if this was considered a contemporary cohort:

However, this thought was countered by:

The conversation continued to include the importance of time in NNT as pointed out Stacy Loeb. The point was later made, that the NNT might actually be lower with today’s advents of management in high-risk cancer patients.

There was a brief discussion on the statistic that 60% of the participants in the watchful waiting group underwent ADT treatment versus only 40% in the radical prostatectomy group.

Impact of adverse effects was also briefly discussed. The article stated that 84% of prostatectomy patients had ED versus 80% of the patients in WW.  However, incontinence was only present in 11% of the watchful waiting group versus 40% of the surgery group. These statistics are interesting to compare, when the third option of radiation therapy is introduced. With RT being a viable alternative today compared to the 1990’s when the initial enrollment for the SPCG-4 study was done, weighing the risk/benefits of treatment becomes much more complicated.

The importance of weighing QOL was not forgotten during this discussion.

Finally, there was some great conversation alluding to the relevance of this study in the future given the new guidelines of the USTPSF which recommend against using PSA to screen for prostate cancer in healthy men of all ages on the account that there is no realized benefit.

Overall the importance of this study can be easily summarized as follows:

We welcomed a new member!

A huge thank you to the American Urological Association who supported the Best Tweet prize of a video box set. The winner is Fardod O’Kelly for the following tweet:

Thank you to everyone who joined the discussion. We look forward to seeing you at the May #urojc! 

Meena Davuluri is a 3rd year medical student at Upstate Medical University in Syracuse, NY. She is interested in pursuing a career in Urology. Her interests include cost-effective decision analysis and health policy regarding healthcare delivery models. Follow her on Twitter @MeenaDavuluri.

 

Editorial: Nationwide prostatectomy practice

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Surgical management of prostate cancer is one of the most frequently performed urological procedures [1]. Available data suggests that surgeons’ experience is correlated with both oncological and functional outcome [2]. These initial observations stress the importance of concentration of prostatectomy in high-volume institutes. This centralisation could improve documentation and monitoring of outcome. The data presented by Røder et al. [1] from Denmark show a rapid increase in registered prostatectomy procedures in recent years in six institutes. It remains to be studied whether this is caused by centralisation and better registration or the results of an increased overtreatment. For that, data on the incidence of low-risk disease over time in their series needs analysis.

At least one-third of the population was treated since 2008. The relatively short follow-up and associated few events, and high number of low-risk patients (47% had biopsy Gleason ≤6) make outcome analysis of less value. It is therefore not surprising that in their analysis low- and intermediate-risk tumors had similar outcome. On the other hand, despite prostatectomy, one-third of deaths during follow-up were prostate cancer related in their population. Consistent with reported data at 15 years after prostatectomy more patients died from prostate cancer than from other causes [3]. But still a considerable number of men died from prostate cancer. This also seems the case in the group of men often soothed for having indolent, low-risk disease. At 15 years Røder et al., reported 8.9% of these men with low-risk disease still dying from prostate cancer in Denmark, despite prostatectomy. And although this percentage was lower than that of the prostatectomy group in the Scandinavian Prostate Cancer Group Study Number 4 (SCPG-4) study (14.6%) [4], most men will still find it disturbingly high and it is three-times higher than the 3% life-time risk of dying from prostate cancer for all men. In other words, it may be perceived that prostatectomy does only partly reverse the risk of dying from prostate cancer, even in men with low-risk disease.

The data from Røder et al. [1] can, with longer follow-up, set the standard for oncological outcome on a national level. Of interest is the observation that, although not significant in the multivariate analysis, variation among institutes for outcome seems to exist but not clearly dependent on institutes volume. Variations of case-mix and patient selection could be topics of further study. With the short follow-up available we are also looking forward to data on functional outcome and perioperative complications that may be more mature. Comparison with now also available registries in Belgium and the Netherlands would be of interest.

It always strikes me that prostate cancer seems to be a systemic disease from the start even in assumed ‘low-risk’ disease, yet surgical management is only focused at loco-regional control. Perhaps the mortality improvement shown in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) trial by prostatectomy is merely caused by disease delay provided by local control even in the presence of systemic disease. Initial encouraging data from an ongoing study evaluating the role of radiotherapy to the prostate in the presence of bone metastases seem supportive of this notion. Is prostatectomy a debulking management of a systemic disease at most, and an unneeded cure for many, or is there this sub-sub group of men that is eventually fully benefiting from the intervention reversing not only death but also the debilitating effects of androgen ablation.

Henk G. van der Poel
Department of Urology, Netherlands Cancer Institute, Amsterdam, the Netherlands
Read the full article

References

  1. Røder MA, Brasso K, Christensen IB et al. Survival after radical prostatectomy for clinically localised prostate cancer: a population-based study. BJU Int 2014; 113: 541–547
  2. Vickers A, Savage C, Bianco F et al. Cancer control and functional outcomes after radical prostatectomy as markers of surgical quality: analysis of heterogeneity between surgeons at a single cancer center. Eur Urol 2011; 59: 317–322
  3. Shikanov S, Kocherginsky M, Shalhav AL, Eggener SE. Cause-specific mortality following radical prostatectomy. Prostate Cancer Prostatic Dis 2012; 15: 106–110
  4. Bill-Axelson A, Holmberg L, Ruutu M et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011; 364: 1708–1717

 

Another good week for radical prostatectomy

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The SPCG-4 (Bill-Axelson) study updated again in NEJM

In this week’s edition of the NEJM, Anna Bill-Axelson and the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) investigators have written an impressive update to their famous study comparing radical prostatectomy (RP) to watchful waiting (WW) in a setting of mostly clinically detected prostate cancer. In 2002, the group reported in NEJM at a median 8 years of follow-up that RP reduces disease specific mortality, overall mortality, and risk of metastasis and local progression. The declines in prostate cancer specific mortality were 8.6% for RP versus 14.4% for WW. In 2011, they published again with a median 12.8 years of follow-up and the differences were 14.6% versus 20.7%, but the benefit was impressively driven by men under age 65. Now in 2014, the median follow-up time is 13.4 years with up to 23.2 years at the high end, and overall 64% of the cohort has died by end of 2012 — specific to prostate cancer in 17.7% vs. 28.7%. The number needed to treat is 8. 

What stands out in the latest edition of this famous trial? Although previous reports describe differences in metastatic and progressive disease in WW, this report nicely shows that RP reduces metastatic disease burden, androgen deprivation therapy, and palliative treatments across all age groups — even if mortality comparisons are still more notable in younger cohorts. So the paper has evolved into a key lesson in the natural history of prostate cancer and localized curative intervention (side debate — this paper is not really about radical prostatectomy itself, but rather intervention, and I would assume many similar benefits possible with radiation approaches). Prostate cancer outcomes are more complex than simple cure fractions. Patients can suffer from relapsed disease, multiple treatments, long-term androgen deprivation, and, yes, actual prostate cancer mortality that apparently takes a committee of experts to decipher from competing sources. I think the impact of the study will be that healthy men between the ages of 65-75 may benefit from treatment of lethal potential prostate cancer — but perhaps as measured by endpoints other than mortality. This is especially relevant with the evolving library of treatment options for castrate resistant prostate cancer — it may take a lot longer to actually die of prostate cancer, but who really wants to spend their last 5-10 years of life heavily medicated compared to a more effective localized intervention at an earlier time? Between earlier versions of this study and the PIVOT trial, I think we already believe in the benefits of curative therapy for men <65 years with intermediate to high-risk disease. On the other end of the spectrum, the paper still supports the concept of active surveillance for low risk cancer, although more is to be learned from other accruing cohorts of patients who will undergo selective delayed intervention. 

Overall, I found this to be a highly citable paper with a new set of figures destined for use in many PowerPoint talks to come. The overall message is that RP at the right time and right patient can prevent mortality and disease progression. A comprehensive prostate cancer program should start with such biology-based discussions with patients and then carefully integrate active surveillance in the lower risk end and clinical trials of combination therapy at the higher end. Finally, I wonder if the findings of reduced metastatic events in older patients might re-challenge the screening guidelines that are encouraging less screening after age 70?

John W. Davis, MD
Associate Editor, BJUI

Read the NEJM article

Radiation within urology: challenges and triumphs

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As gatekeepers urologists remain at the frontline of urological oncology in a position of trust that they have held since Charles Huggins, Nobel Laureate in Urology, pioneered the use of hormone manipulation to treat prostate cancer. However, radiation within urology is an important adjunctive, palliative and even primary treatment method for many urological malignancies. However, within many spheres, particularly internationally regarding prostate cancer, tensions appear to have been simmering between urologists and radiation oncologists. Fortunately, this does not appear to be the case in Australia and New Zealand but it is an important time to reflect on such issues as we move ever forward in the multimodality era.

In the USA the use of self-referral by urologists of men for adjuvant radiotherapy (RT) has come under scrutiny. Some urology groups have integrated intensity modulated RT (IMRT), a RT treatment carrying a high reimbursement rate, into their practice. This was highlighted in a recent New England Journal of Medicine article where the rate of IMRT use by urologists working at National Comprehensive Cancer Network centres remained stable at 8% but increased by 33% among matched self-referring urology groups [1]. This study has been criticised for bias but nonetheless captured political and academic attention. Certainly this situation has not arisen in our hemisphere but it remains important we think critically of what treatments we offer our patients and ensure patient’s best interests are maintained.

Clearly more research is required as to who should be receiving adjuvant RT and at what stage. In the latest issue of the BJUI USANZ supplement we highlight the Radiotherapy – Adjuvant vs Early Salvage (RAVES) trial for prostate cancer biochemical failure and high-risk disease [2]. There is no doubt this is an important trial because to date we have been unable to establish exactly which patients should receive adjuvant RT and when. Recruitment has been challenging as patients doing well after surgery often do not want additional treatment and a very small subset who are still recovering want to be enrolled but due to timing missing eligibility. Enthusiastic patients also may demand treatment rather than be randomised. Critics would also argue that the trial can never really answer the question because many men not requiring adjuvant RT will receive it [3]. Ongoing support of all parties should achieve accrual and in time, robust data. Excitingly imaging with MRI and other modalities will ensure further trials to assist in identifying disease in the salvage setting making choices easier based on more objective data [4].

 

Read the USANZ Supplement

Consumerism has driven robotic surgery [5] and is doing the same for RT but descriptions of treatment would be better placed to remain generic. The use of the term ‘radiosurgery’ has highlighted the shift away from the term ‘radical radiotherapy’. Of course the term ‘robot’ has become synonymous with radical prostatectomy but the ‘radical’ contribution remains and interestingly the term ‘robot’ has been trialled by radiotherapists: ‘image-guided robotic radiosurgery’ or its other more commonly used term Cyberknife® (Accuracy Incorporated, Sunnyvale, CA, USA). Certainly this would be more accurately known as stereotactic body RT (SBRT). It is these terminology changes and continual shifts in treatment regimens that rankles many, with the old argument that RT treatment was done with inferior technology so results should be ignored receives disproportionate use at conferences. All groups need to acknowledge treatments have improved rather than disowning data from older treatment regimes. On the counter side one example from brachytherapy [6] concluded that despite the hype of improving dosimetry and reducing complications, the preoperative condition regarding erectile function and LUTS are the most important factors regarding postoperative outcome. This is almost certainly true for surgery as well. Comparison of side-effects appears unfair with grading of radiation toxicities more lenient than Clavien listed complications – an even playing field for comparison of complications is warranted.

Multimodality treatment for high-risk disease is becoming the standard of care. Urologists are beginning to embrace this regime of planned surgery with likely RT and ultimately systemic therapies. However, radiation oncologists often prefer to use radiation and hormonal manipulation and consider this ‘modified monotherapy’. Some men receive different modes of RT with concerns this leads to significantly more complications and in combination with androgen deprivation comes with all of the secondary effects of such therapy. An ideal study for such high-risk patients would randomise men to RT and androgen deprivation vs a graded multimodality treatment starting with surgery and then progressing to RT and systemic therapies when required (as some men will have T2 or T3a disease with clear margins that can be observed for a PSA rise necessitating treatment).

Complications do develop after any therapy and urologists are expertly placed to deal with them. Yet, there is a belief that RT and its long-term effects are real and these are often underplayed. This is contributed by a paucity of follow-up data beyond 5 years with primary RT. Major problems from surgery are generally able to be repatriated. However, the same may not be stated for RT complications: cystitis, stricture disease, permanent catheter drainage and chronic pain syndromes although uncommon, are not rare events and not easily remedied due to the altered tissues. Urologists are able to assist with these conditions but some feel that their efforts are unrecognised and that they share too much of the burden from somewhat surprised patients when situations are not able to be satisfactorily resolved. This reinforces the involvement by enthusiastic urologists with the patient selection and follow-up of brachytherapy and even other RT treatments being the cornerstone for ideal patient management and success.

Other areas worthy of engagement are with patients who develop a recurrence after RT treatment where the available data are sparse, making a decision even more difficult [3]. The perceived reluctance to refer RT failures to urologists in a timely fashion meaning many men are not offered salvage surgery or other options [7]. Occasionally urologists do the same with surgical failures but with multi-disciplinary teams, this is a rare event.

Communication remains a key to a multidisciplinary approach. Against the successes and strains, there are newer developments that will conspire to bring teams closer together, such as newer systemic therapies and the consideration of RT in men with oligometastatic disease. Also, based on Surveillance, Epidemiology and End Results (SEER) data, it appears that patients with limited metastatic disease may benefit from having treatment of the primary disease with a significant decrease in mortality (slightly more pronounced with surgery than radiation) [8]. This will ensure further debate on how far we stretch our primary treatment boundaries for the betterment of patients. Finally, use of fiducial markers and spacers will hopefully minimise morbidity and these are discussed in this supplement [9].

Just like any long-term relationship, the balance will shift at times and there has to be give and take on both sides. Many of the points in this editorial could be switched the other way with urologists at fault, so we must always be careful to be global, and not focal in our approaches. With everyone working together we have improved outcomes and survival of many with many urological malignancies. Overall, there is still harmony but room for even greater communication and collaboration as we strive towards better outcomes in future decades.

Nathan Lawrentschuk
University of Melbourne, Department of Surgery and Ludwig Institute for Cancer Research, Austin Hospital and Peter MacCallum Cancer Centre, Department of Surgical Oncology, Melbourne, VIC, Australia

Read the USANZ Supplement

References

  1. Mitchell JM. Urologists’ use of intensity-modulated radiation therapy for prostate cancer. N Engl J Med 2013; 369: 1629–1637
  2. Pearse M, Fraser-Browne C, Davis ID et al. A Phase III trial to investigate the timing of radiotherapy for prostate cancer with high-risk features: background and rationale of the Radiotherapy – adjuvant versus Early Salvage (RAVES) trial. BJU Int 2014; 113: 7–12
  3. Chen RC. Making individualized decisions in the midst of uncertainties: the case of prostate cancer and biochemical recurrence. Eur Urol 2013; 64: 916–919
  4. Thompson J, Lawrentschuk N, Frydenberg M, Thompson L, Stricker P. The role of magnetic resonance imaging in the diagnosis and management of prostate cancer. BJU Int 2013; 112 (Suppl. 2): 6–20
  5. Alkhateeb S, Lawrentschuk N. Consumerism and its impact on robotic-assisted radical prostatectomy. BJU Int 2011; 108:1874–1878
  6. Meyer A, Wassermann J, Warszawski-Baumann A et al. Segmental dosimetry, toxicity and long-term outcome in patients with prostate cancer treated with permanent seed implants. BJU Int 2013; 111: 897–904
  7. de Castro Abreu AL, Bahn D, Leslie S et al. Salvage focal and salvage total cryoablation for locally recurrent prostate cancer after primary radiation therapy. BJU Int 2013; 112: 298–307
  8. Cheng J. Would you really do a radical prostatectomy on a man with known metastatic prostate cancer? BJU Int BLOG posted 09 December 2013. Available at: https://www.bjuinternational.com/bjui-blog/would-you-really-do-a-radical-prostatectomy-on-a-man-with-known-metastatic-prostate-cancer/. Accessed January 2014
  9. Ng M, Brown E, Williams A, Chao M, Lawrentschuk N, Chee R. Fiducial markers and spacers in prostate radiotherapy: current applications. BJU Int 2014; 113: 13–20
 

Surgery or Radiation in Prostate Cancer?

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I am sure many of you are familiar with the clinical situation I see every week of a man with newly-diagnosed prostate cancer asking me about his options. While we steer many men with low risk prostate cancer towards surveillance nowadays, for those with intermediate or high risk disease intervention is usually their best option, especially if they have a long life expectancy. This gives us the dilemma of whether to recommend surgery or radiotherapy.

In Oxford, we have a long and pioneering history of evidence-based medicine, and I lament the lack of RCTs in this field. The only one, ProtecT, which is being led also by Oxford, will not report before 2016, and will at least in part be subject to volunteer bias. Now, the question of surgery or radiotherapy for prostate cancer is not a new question. Millions of men have undergone these treatments across the globe and over the decades, and many other investigators have evaluated this question.

Most of these previous studies suggest that surgery in indeed superior but the main problem with them is inadequate control for selection bias (what we term in the trade as confounding by indication) – i.e. that men undergoing surgery are fitter and have better prognosis from their cancer point of view than men undergoing radiotherapy, and thus it’s not a fair comparison. Another problem with these previous studies is that the datasets used are not very comprehensive – not all men are included, and we don’t know all their important risk factors. All this makes it difficult to be confident in their results.

What is different about the BMJ study (https://www.bmj.com/content/348/bmj.g1502) is that the dataset and the statistics were top-notch. More than 98% of men diagnosed with prostate cancer in Sweden from 1998 onwards were included, and virtually all important data points were recorded with <2% incomplete data. Men were followed for up to 15 years and 4 different sets of statistical models were done to balance the surgery and radiotherapy groups with each other.

Remarkably, all sets of models came up with the same answer: that surgery led to better survival results than radiotherapy, especially for the men with intermediate and high risk prostate cancer and even more so if they had a long life expectancy. If I were a barrister, I would say this study provides strong evidence to build the case that surgery is a better option in survival terms for the majority of men who need treatment for localized prostate cancer.  Medicine, like law, is never about absolutes, it’s about risk and probability. Can I prove that surgery is better than radiotherapy from this study – no; but there certainly seems a strong case to argue.

The current BJUI Article of the Week is another excellent article on the same subject (https://www.bjuinternational.com/article-of-the-week/prostate-cancer-sun-shines-light-on-surgical-survival/)

You can download Drs Sooriakumaran & Wiklund’s slideshow on their article by clicking here (1.5mb)

Prasanna Sooriakumaran is a robotic prostate & bladder cancer surgeon and academic at Oxford and Karolinska. @PSooriakumaranu

 

Editorial – Prostate cancer surgery vs radiation: has the fat lady sung?

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The current article by Sun et al. [1] representing a number of institutions involved in prostate cancer treatment provision is thought-provoking and hypothesis-generating. The authors contention when mining Surveillance, Epidemiology and End Results data for 67 000 men who had localized prostate cancer between 1988 and 2005 is that those with a life expectancy >10 years had less likelihood of prostate cancer death when treated with surgery rather than by radiotherapy or being left to observation. The Scandinavians have already shown, in the randomized study by Hugosson et al. [2], that if you have your prostate cancer removed you have less likelihood of symptomatic local recurrence, lower likelihood of metastasis and progression, and a 29% reduced likelihood of prostate cancer death. The current study asks the question ‘Is radiation therapy less likely to provide a long-term cure for prostate cancer than surgery?’ and gives an answer in the affirmative.

The current paper, in its way, neatly encapsulates the contemporary angst generated in the community when prostate cancer screening, diagnosis and therapy are discussed. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) trial [3] allegedly shows no benefit from treatment over observation and contends perhaps that we surgeons and radiation oncologists are harm-workers, not life-savers. The PLCO has a 52% PSA contamination in its control arm [3]. That flawed trial compared screening with de facto screening and produced, in my view, a null hypothesis. How do we explain the paradox of a 44% reduction in prostate cancer-specific mortality between 1993 and 2009? How do we explain the disconnect between these trials and the facts? What do we do with the data not yet considered by the expert panels showing that early PSA testing at age <50 years is highly predictive of subsequent lethal prostate cancer? [4]

Clinicians are rapidly moving to an era of judicious risk assessment. This can only be done after biopsy is performed. We now frequently enrol patients with apparently indolent prostate cancer into surveillance protocols [5]. So the question should be ‘If the disease found on biopsy is moderate to high risk, and potentially lethal for that man, should we remove his prostate surgically or radiate it with intensity-modulated radiation therapy, brachytherapy, proton therapy, +/- hormone therapy?’.

As a surgeon I have an inherent dislike of combining hormone therapy in primary treatment. At least 50% of men in high-risk prostate cancer cohorts who receive radiation therapy also receive hormone therapy as adjuvant or neoadjuvant treatment [6]. Hormone therapy has a myriad of side effects. Even if the playing field was level between surgery and radiation therapy, the avoidance of hormone therapy as a first-line treatment gives surgery a seductive advantage.

The authors of the current report show a significant survival advantage in the cohort for surgery over radiation therapy and observation. There will never be a randomized trial between the two potentially curative treatment methods surgery and radiation. The scourge of commercial interest with spurious claims of superiority of one form of therapy over another, proton beam vs intensity-modulated radiation therapy, robotics vs high-intensity focused ultrasonography, means that we risk having our decisions regarding appropriate therapy formed by multibillion dollar technology companies with powerful marketing capacity. The current paper confirms what is self-evident: untreated localized prostate cancer can be lethal. Surgery and radiation therapy lower the morbidity and mortality from prostate cancer. Which is the better method of curative therapy is moot, but we do know that cure is very much predicated on the expertise and location of the practitioner.

We know mostly when and who to treat and what treatments work well. In my view, the prostate cancer testing debate resonates with the contemporary discussion about childhood immunization for infectious diseases. Some parents now, who clearly cannot remember the devastating epidemics of polio and other childhood illnesses, refuse to immunize their children. Prostate cancer practitioners who did not live in the quite recent era where the initial presentation of prostate cancer was bone metastasis +/− crush fracture to the vertebra and sometimes paraplegia, may be unknowingly steering us backwards.

At the recent 2013 AUA meeting, Adams et al. [7] reported on the fate of men not screened for prostate cancer, i.e. those men who presented with a PSA >100 ng/mL. There was a 3-year survival rate of 9.7%, a 19.7% cord compression rate and a 64% hospitalization rate. Those who do not learn the lessons of history are condemned to repeat them.

Anthony J. Costello
Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia

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References

  1. Sun M, Sammon JD, Becker A et al. Radical prostatectomy vs radiotherapy vs observation among older patients with clinically localized prostate cancer: a comparative effectiveness evaluation. BJU Int 2014; 113: 200–208
  2. Hugosson J, Carlsson S, Aus G et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 2010; 11: 725–732
  3. Andriole GL, Crawford ED, Grubb RL 3rd et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst 2012; 104: 125–132
  4. Vickers AJ, Ulmert D, Sjoberg DD et al. Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40–55 and long term risk of metastasis: case-control study. BMJ 2013; 346: f2023
  5. Evans SM, Millar JL, Davis ID et al. Patterns of care for men diagnosed with prostate cancer in Victoria from 2008 to 2011. Med J Aust 2013; 198: 540–545
  6. Cooperberg MR, Vickers AJ, Broering JM, Carroll PR. Comparative risk-adjusted mortality outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for localized prostate cancer. Cancer 2010; 116: 5226–5234
  7. Adams W, Elliott CS, Reese JH. The fate of men presenting with PSA over 100 ng/mL: what happens when we do not screen for prostate cancer? AUA 2013. Abstract 2696

 

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