Tag: #ProstateCancer

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STAMPEDE at the Dumball rally

March 5, 2016/2 Comments/by Simon Hughes

I’m sure I’m not the only one to board a long haul flight with the aim of catching up on a little CPD reading, only to be led astray by a series of films that later I’ll never admit to watching. Still they can be educational, as having stopped studying History at the age of 12 I’m ashamed to admit that without this educational medium I would never have been aware that the 16^th President of the United States spent his formative years hunting Vampires. So in January 2016 I boarded a 10-hour flight from London to Chennai equipped with the latest publication from the STAMPEDE Study, a Workshop Manual for the Hindustan Ambassador, and a sense of inevitability that I’d be watching Matt Damon land on Mars before we’d finished crossing Kent. Taking a car manual for in-flight entertainment was not a cunning plan to encourage my neighbouring passengers to change seats before I engaged them in conversation. I have an unread copy of Donald Trump’s 2009 tome “Think Like a Champion” that fulfils that role perfectly. The manual was my homework, as I was en route to join the Dumball Rally.

The Dumball Rally is a fancy-dress charity banger rally – that raises money for the Teenage Cancer Trust. Since its inception in 2006 (Amsterdam to Athens) it has raised over £650,000. This year the route was Chennai to Goa, via Kanyakumari (the Southern Tip of India), the Western Ghats, Cochin, and for our team a stapes-shuddering Rock Bar in Mysore. 37 Hindustan Ambassadors awaited us on the start-line, their fully enclosed monocoque chassis based on the Morris Oxford Series III that last rolled off the production line in Cowley in 1959 – just in case you’re thinking I didn’t read the manual.

As a Clinical Oncologist I’m admit to being in one of the more geek-orientated specialities. Who needs a PDE5-inhibitor when a graph depicting a Bragg Peak excites you? So as I read about the history of Hindustan Motors, and the inner workings of my Ambassador, I was struck by the commonality of their significant anniversaries with those of my chosen profession. Hindustan Motors was founded in 1942, the year after Charles Huggins published his seminal paper on Prostate Cancer. The Morris Oxford Series III began production in 1956, the same year that Hertz and Li first described the successful use of cytotoxic chemotherapy (methotrexate) to treat a solid tumour (Choriocarcinoma). The production of the Hindustan Ambassador began in 1958, the year Rosalind Franklin died. The final version of the Ambassador (the Avigo) began production in 2004, the same year Tak327 was published demonstrating a survival advantage for Docetaxel and prednisone in metastatic castrate-resistant prostate cancer. Who said altitude and wine don’t mix well?

The rally began on 10^th January 2016. Our team, dressed as Dick Dastardly and Muttley (wise outfit choices in greater than 30 degrees centigrade heat), were pitted against a range of other themed cars from a fire-engine (with wired-in power washer), a yellow-submarine (broadcasting “Beatles” songs), to the Jungle Book (which continuously grew with foliage collected from the roadside). The Rally results are summarised below, and compared with the results from the STAMPEDE Study (finally read on the return flight).

STAMPEDE is a study assessing the impact of intensifying initial treatment for locally advanced and metastatic prostate cancer. Its novel Multi-Arm Multi-Stage (MAMS) design may prove as important to future cancer care as the results generated by the study itself. Basically MAMs permits multiple different primary questions to be addressed simultaneously and sequentially over a far shorter time period, and with fewer subjects, than would be required to address the questions separately.

Median Overall Survival for the Standard of Care (SOC) arm of STAMPEDE was 71 months, which increased to 81 months with the addition of 6 cycles of Docetaxel Chemotherapy. There was no additional benefit with the use of Zoledronic acid (with or without Docetaxel). Looking at the subset with metastatic disease, Median Overall Survival increased from 45 months to 60 months with the addition of Docetaxel, demonstrating that this should now be standard of care in suitable patients with metastatic disease. Regarding the Median Overall Survival for the Dumball Rally, there were insufficient events (only 1 car had to be abandoned), and follow-up is too short (8 days) to report meaningful data.

Median Failure Free Survival (FFS) for the SOC arm of STAMPEDE was 20 months, which increased to 37 months with Docetaxel. The hazard ratios were similar for both metastatic and non-metastatic subsets. Again there was no additional benefit with the addition of Zolendronic acid. The median FFS for the Hindustan Ambassador was about 6 hours. The passenger seat and seat-belt broke in our car whilst exiting the car-park having just collected it; most cars over-heated daily (interestingly the electrics are located directly beneath the radiator overflow); one engine seized completely; and an axel broke on Dumball 1, the organiser’s car.

Grade 3 + adverse events reported within the first 6 months of the STAMPEDE Study increased from 17% in the SOC arm to 36% with the addition of Docetaxel. Despite this the chemotherapy was well tolerated, with most patients completing all 6 planned cycles with minimal changes in dose or scheduling. Regarding the Rally, ironically it coincided with India’s National Road Safety Week. Their slogan “Hurry leads to worry; Accident brings tears; Safety brings cheers” repeated Orwellian-style in my subconscious as we negotiated the Indian traffic. In India they drive on the left……and sometimes the right, the middle of the road, the pavement –in fact wherever they want! A gentle toot of the horn lets other road users know where they are, and it appears to be the driver’s responsibility to avoid anything in front of them – no matter how late it pulls out. But it works – and everything keeps moving with good humour and smiles. It wasn’t unusual to be horrendously cut-up, only for the “offending driver” to then stop, get out the car and come over for a friendly chat and a photo opportunity. As a result, there were minimal adverse events – other than putting on a few additional Kg in weight eating curry 3 times a day.

Work on next year’s Dumball Rally has already started – rumours are that it may involve Nepal. If anyone is interested in taking part, please look at their website: www.dumball.org

Simon Hughes is a Consultant Clinical Oncologist at Guy’s and St Thomas’, London

New Gleason grading system: Statement from the Editors of six journals

February 24, 2016/4 Comments/by admin Z.9

The International Society of Urologic Pathology (ISUP) has completed a consensus process to modify and clarify the Gleason scoring system for prostate cancers (1). Five grade groups have been defined with tumors of ISUP Grade Group 1 being the least aggressive and having the lowest likelihood of progression, whereas those of ISUP Grade Group 5 have the highest likelihood of early systemic spread. This new system provides clearer guidance for pathologists to classify cancers on the basis of gland morphology, and it aligns better with contemporary management including active surveillance.

The editors of the major uro-oncology journals believe this is a helpful change for clinicians, researchers, and patients alike and are eager to help this system establish itself in the reporting of pathologic grade. To that end we are now asking investigators to use the ISUP system in the reporting of prostate cancers in their publications. As the grade groups correspond largely with current Gleason scores 6, 3+4, 4+3, 8, 9 and 10, the translation should be relatively simple. Over the next one to two years, side-by-side reporting of old and new histology may temporarily be necessary. We do recognize that some institutional and national databases are not set up to make the translation and exceptions will be granted in these cases.

Anthony Zietman MD
International Journal of Radiation Oncology Biology Physics

Joseph Smith MD
Journal of Urology

Eric Klein MD
Urology

Michael Droller MD
Urologic Oncology

Prokar Dasgupta MSc MD FRCS
BJUI

James Catto MBChB PhD FRCS
European Urology

Reference

Epstein JI, Egevad L, Amin MB et al. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference of Gleason Grading of Prostatic Carcinoma. Am. J. Surg. Pathol. 2016, 40: 244-252.

Where we are with screening and risk prediction for prostate cancer in 2016

February 22, 2016/by admin Z.9

The rate of PSA-based screening over the last 35 years can be compared with driving your car from the Netherlands to Italy. It starts with a rather ﬂat drive, perhaps a few hills in the Southern part of the Netherlands, which represents the rate of PSA screening in the late 1980s. Moving with high speed through Germany, one gradually climbs to higher altitudes, i.e. the rate of PSA testing in the 1990s. Then the high (but very difﬁcult to drive) summits and beautiful valleys of Switzerland are there, representing PSA testing practices in the new millennium and the decline in metastatic disease and related mortality [1]. Finally, we descend to Italy’s Po valley, comparable to PSA testing rates, especially in the USA after the recommendations of the USA Preventive Services Task Force [2,3].

The question is what will we do next? Will we take a left turn and slowly disappear into the sea like Venice? That is, returning to a situation where one out of two or three men died from their prostate cancer? [4] Or will we stop our car, look behind, see the beautiful landscape and return taking the Gotthard road tunnel, avoiding spillage of petrol (i.e. unnecessary PSA testing and potentially harmful prostate biopsies) and go straight to the valleys of Switzerland?

The ﬁrst option is obviously not the way to go. Unfortunately, the recommendation to stop the use of the PSA test as a screening tool is a direct consequence of the rapid and uncontrolled uptake of the test, often followed by a random biopsy resulting in over-diagnosis and subsequent overtreatment. However, there are ample tools available to turn this situation around and reduce the negative effects of prostate cancer screening [5,6].

An example of such an approach can be found in the publication of Poyet et al. [7] in this issue of BJUI. In this study, the investigators validated updated versions of two multivariate risk-prediction tools, i.e. prostate cancer risk calculators (RCs), in a cohort of 1996 men all biopsied (6-, 8- or 12-core random biopsy) on the basis of an elevated PSA level or abnormal DRE. The data showed that both RCs outperformed the PSA/ DRE-based strategy in reducing unnecessary testing, and in addition avoided over-diagnosis. As said, this approach is one of the many opportunities to reduce the negative aspects of PSA-based screening all summarised in the different guidelines [8]. Reading these guidelines, it soon becomes clear that it is known that repeatedly testing men with low PSA levels is useless. It is known that screening men with a limited life expectancy will only cause harm, and that simply repeating a prostate biopsy after a negative biopsy result (i.e. no prostate cancer detected) is not the way to go. And yet, this is what we see happening in daily clinical practice [9,10].

So, where are we with prostate cancer screening and risk prediction in 2016? We are in a situation that we know that we can reduce suffering and death from (metastatic) prostate cancer, with early detection and treatment, but that we have to selectively identify men that can actually beneﬁt. The latter is realistic if we start to implement the knowledge we have acquired over recent decades.

Monique J. Roobol

Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands

References

1 Schroder FH, Hugosson J, Roobol MJ et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet 2014; 384: 2027–35

2 Moyer VA; U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012; 157: 120–34

3 Banerji JS, Wolff EM, Massman JD 3rd, Odem-Davis K, Porter CR, Corman JM. Prostate Needle Biopsy Outcomes in the Era of the U.S. Preventive Services Task Force Recommendation against Prostate Speciﬁc Antigen Based Screening. J Urol 2016; 195: 66–73

4 Hsing AW, Tsao L, Devesa SS. International trends and patterns of prostate cancer incidence and mortality. Int J Cancer 2000; 85: 60–7

5 Roobol MJ, Carlsson SV. Risk stratiﬁcation in prostate cancer screening. Nat Rev Urol 2013; 10: 38–48

6 Emberton M. Doubling our precision of risk stratiﬁcation in early prostate cancer: too good to be true? BJU Int 2016; 117: 8–9

7 Poyet C, Nieboer D, Bhindi B et al. Prostate cancer risk prediction using the novel versions of the European Randomised Study for Screening of Prostate Cancer (ERSPC) and Prostate Cancer Prevention Trial (PCPT) risk calculators: independent validation and comparison in a contemporary European cohort. BJU Int 2016; 117: 401–8

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

9 Nordstrom T, Aly M, Clements MS, Weibull CE , Adolfsson J, Gronberg H . Prostate-speciﬁc antigen (PSA) testing is prevalent and increasing in Stockholm County, Sweden, Despite no recommendations for PSA screening: results from a population-based study, 2003-2011. Eur Urol 2013; 63: 419–25

10 Drazer MW, Huo D, Eggener SE. National Prostate Cancer Screening Rates after the 2012 US Preventive Services Task Force recommendation discouraging prostate-speciﬁc antigen-based screening. J Clin Oncol 2015; 33: 2416– 23

Correction: The word “their” was added to this sentence to clarify its meaning: “That is, returning to a situation where one out of two or three men died from their prostate cancer? [4]”

Should radiotherapy be a routine added-treatment for patients with N0,N+ non-metastatic prostate cancer on hormonal therapy?

December 14, 2015/by Irela Soto Troya

Once again we are approaching the end of another productive year in urological research. The final meeting of the year of the International Urology Journal Club #urojc was held from Monday December 7th to Wednesday December 8th AEDT. This month’s topic was a recent paper published in @JAMAOnc by the well-known STAMPEDE group.

In this new analysis of the STAMPEDE trial, the subject was the control arm. The trial’s definitive primary outcome was to evaluate the overall survival when adding radiotherapy (RT) to the cohort of N0 and N+ M0 high risk prostate cancer patients receiving hormonal therapy. The intermediate primary outcome was the failure-free survival (FFS), which was defined as biochemical failure, progression (locally, lymph nodes, or distant metastases) or death from prostate cancer.

The first comments of the discussion were about the satisfaction of a new study evaluating the beneficial effect of RT in addition to ADT in N+M0 disease. For the N0M0 Sub-cohort, 2 year survival was 97% (95% CI, 93%-99%), and 84% (95% CI, 74%-91%) were still alive after 5 years. On the other hand, for the N+M0 sub-cohort, 2 year survival was 93% (95% CI, 88%-96%), and 71% (95% CI, 56%-82%) were still alive after 5 years.

FFS was better with received RT in both groups: In the N0M0 sub-cohort the adjusted HR was 0.25 (95% CI, 0.13-0.49) with 2 year FFS of 96% (95% CI, 90%-98%) in patients receiving RT compared with 73% (95% CI, 57%-84%) in those not reporting RT (Figure). In the N+M0 the results were similar, with an adjusted HR of 0.35 (95% CI, 0.19-0.65), and a 2-year FFS of 89% (95% CI, 77%-94%) and 64% (95% CI, 51%-75%), respectively.

Since this approach to high-risk N0,+ M0 disease is not a standard of treatment, there were some concerns about urologist opinions, and mainly, about the side-effects of pelvic radiation.

This trial showed the adverse effects associated with RT, split by N0M0 and N+M0. The majority (78%) of N+M0 received conventionally fractionated RT to prostate and pelvis, and of the N0M0, 46% received it only to prostate and 42% to prostate and pelvis. The reported adverse effects were similar for patients with and without nodal involvement, with no grade 4 or 5 adverse effects reported.

Another question during the discussion was about the control group and the different baseline characteristics of the patients if comparing to other countries (mainly previous surgery).

Most urologists conclude that this information contributes to the growing evidence of the different modalities of treatment that should be offered to patients with prostate cancer. Every urologist focused on the importance of determining the risk and stage of the patient to give an appropriate treatment. They also mentioned how these results correlate with other treatment outcomes.

The previous published trials about the subject conclude that this combination reduces the risk of prostate cancer death; however, the population of those studies varies. Most patients were low-risk N0M0 prostate cancer and none were N+M0.

Other thoughts were shared, such as the usefulness of ADT for high-risk M0 prostate cancer, the prostate cancer stage and its relation to treatment response, and the needed collaboration of other specialties for study trials.

We still have to remember that the study has some limitations, though: The study population is drawn from a control arm of a clinical trial. There is no randomization of patients, and those planned for radiotherapy were the ones considered fit for it, so there might be an overestimated benefit biased by a better prognosis.

Indeed this is not the last of the STAMPEDE trials. One of the authors, @Prof_Nick_James mentioned redoing analysis of all the arms to evaluate more parameters about the outcomes of the different treatments.

This topic raises many questions about the treatment approaches to high-risk prostate cancer. As the authors expressed “There is a need for randomized clinical trials within the N+M0 population to address questions prospectively”. So far the results shown seem to be of benefit, and support the routine use of radiotherapy in patients with N+M0 prostate cancer. But as usual, we always need more proof.

This is the last meeting of 2015, so I have to finish this summary with a “Merry Christmas and Happy New Year 2016” to all the Urological twitter family!

Irela Soto Troya is a urologist born and trained in the Republic of Panama, and is a Fellow at Severance Hospital/Yonsei Medical Health System, Seoul, South Korea.
Twitter @irela_soto

Does presentation with metastatic prostate cancer matter?

November 16, 2015/by Anthony Noah

November saw the return of the International Urology Journal Club #urojc on Twitter. The annual meetings of the World Congress for Endourology (#WCE2015) and Société Internationale D’Urologie (#SIU15) led to an October break for #urojc. This month’s discussion was based around a recent editorial in the New England Journal of Medicine by Welch et al on the effects of screening on the incidences of metastatic-at-diagnosis prostate and breast cancers. In the three days prior to the start of the discussion the editorial and it’s now well-known graph had been trending amongst medical Twitter users.

The issue of PSA screening for prostate cancer has been a topic of debate amongst urologists for a number of years. PSA and DRE are first line for early detection of prostate cancer. Supporters of PSA screening argue that it leads to a significant fall in prostate cancer specific mortality. Many others believe there is insufficient evidence to support universal PSA screening given the risks of prostate biopsy and potential overtreatment of low risk prostate cancer.

The editorial presented data showing a significant fall in the number of patients first presenting with metastatic prostate cancer (advanced stage incidence) following the introduction of universal screening. However no effect was shown on similar data for breast cancer. Variations in disease dynamics were suggested to play a role.

The conversation started on Sunday 1st November at 20:00 (GMT), marking the beginning of the fourth year of #urojc. The first questions centred around the reasons behind the trends seen in the graph. Being a urology journal club the conversation was based almost exclusively on the prostate cancer aspect of the editorial.

One suggestion for the discrepancy between the two cancers is that PSA is a better detector of metastatic disease, whilst mammography can only detect localised disease.

Based on incidence of metastatic prostate cancer, the article makes a convincing statement in support of universal PSA screening. However, a successful screening programme should result in a reduction in the incidence of advanced cancers, decreased advanced-stage incidence and reduced mortality. Leading to the question of whether looking solely at advanced-stage incidence is useful.

The importance of responsible treatment and active surveillance was mentioned early on.

One of the most important questions of the discussion: What impact and relevance does the image have? Views were polarised. Some contributors were cautious about drawing conclusions from the graph whilst others were satisfied that it justified PSA screening.

The article drew comparison between Halsted’s and Fisher’s descriptions of cancer progression. Halsted suggested cancer originates from a single site and spreads, whereas Fisher’s paradigm proposed that breast cancer is a systemic disease by the time it is detectable.

The United States Preventive Services Task Force (USPSTF) has recommended against universal screening of prostate cancer, suggesting the risks of testing outweighed the benefits. However, many believe this to be based on outdated evidence.

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial results showed a 12% higher incidence of prostate in the screening arm versus control, with no difference in mortality. Yet, the European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown screening to result in a 1.6 fold increase in prostate cancer with a 21% reduction in mortality.

The debate briefly discussed the morbidity and cost of metastatic disease.

The editorial certainly raised a number of interesting points. It seems the topic of universal PSA screening will continue to be debated. There is a significant benefit to screening in the prevention of metastatic prostate cancer. Whether this is due to differing disease dynamics or PSA being a better screening tool than mammography is as yet unclear.

One point we can all agree on is that increasing utilisation of active surveillance with timely biopsies is important in preventing overtreatment of low risk disease and identifying those at risk of disease progression for curative treatment.

Anthony Noah Urology Speciality Trainee, West Midlands, UK
Twitter: @antnoah

Abandoning PSA screening: What is an acceptable price to pay?

October 27, 2015/by Daniel Moon

The PSA screening debate continues to rage with conflicting advice from various bodies as to appropriate guidelines for men considering prostate cancer screening. In Australia the Urological Society of Australia and New Zealand (USANZ) has supported offering screening to men aged 55-69 [Urological Society of Australia and New Zealand Position Statement on PSA testing 2009], as has the Royal Australasian College of Pathologists [Royal College of Pathologists Australia Position Statement on PSA testing 2014], however the guidelines for General Practitioners is yet to endorse this approach. A consensus group gathered by the Cancer Council of Australia, including Urologists, Oncologists, Epidemiologists and consumer advocates have recently put together proposals being considered by the NHMRC that recommend screening in men of an appropriate age with >7 year life expectancy, as long as active surveillance is offered to those diagnosed with low risk disease [Cancer Council Australia: Draft Clinical Practice Guideline PSA Testing and Early Management of Test-Detected Prostate Cancer]. The US Preventative Service Task Force Grade D recommendation against screening has been well documented, yet widely criticized for failing to include Urologists in its deliberations – the very specialists tasked with evaluating and treating localized prostate cancer.

Screening trials have reported conflicting results [Schroder et al, Pinsky et al], however with longer follow-up it becomes easier to demonstrate a survival advantage in men who are screened, and this does not even directly take into account the reduction in morbidity from advanced disease in populations as a result of early detection.

The issue at hand seems inherently very simple – that mass PSA screening will inevitably lead to overdiagnosis and, if a conservative approach is not adopted in low-risk disease or men with significant co-morbidities, overtreatment. Since PSA testing was introduced, the natural history of prostate cancer has become better understood [Albertsen], along with the understanding that many men with prostate cancer harbor “clinically insignificant” disease. Urologists have recognized this internationally and developed active surveillance protocols in response [Kates et al, Klotz]. Here in Australia the Victorian prostate cancer registry now confirms a significant number of men with low-risk disease being managed conservatively [Evans].

In the meantime, however, the pendulum is swinging the other way, and on the back of the USPSTF recommendations we are now seeing evidence of a drop in PSA screening. Confusing the debate is the extrapolation of negative studies to men of an entirely different population (e.g. using the Prostate Cancer Intervention vs Observation Trial [PIVOT], which comprised an average age of 67 to conclude that men in their 50s will not benefit from screening), poor design of the reported screening trials (e.g. the PLCO trial, which formed the backbone of USPSTF recommendations but due to compliance/contamination compared a population of 52% screened vs 85% screened), and the accusations of vested interests, particularly when Urologists take a pro-screening position (just read comment section on BJUI 2013 report of “Melbourne consensus statement on prostate cancer testing”)

What is the end result at a population level? In Victoria, Cancer Council data confirm a drop in prostate cancer screening and diagnosis [FIGURE]. There is no reason to believe that true prostate cancer incidence has suddenly declined, and we can conclude therefore that the negative publicity surrounding PSA screening is having an impact and less men are undertaking screening and diagnosis; a reversal of the jump in incidence that occurred when PSA testing was first introduced. Is this a bad thing though? Could this just be that we are finally reducing the diagnosis of clinically irrelevant cancers that are the bane of a PSA screening programme?

Trends in prostate cancer incidence and PSA testing rates, 2001-2014
Source: Cancer in Victoria: Statistics and Trends 2014. Cancer Council Victoria

My disclosure is that as a Urologist with a subspecialty practice in prostate cancer management, I deal at a personal level with patients, rather than population statistics, and in the last few months alone, multiple patients have highlighted for me the sacrifice we must admit to making if we are to abandon or even discourage PSA testing. A few specific cases are worth sharing as scenarios that GPs could consider including in the risk/benefit discussion required before ordering a PSA test.

Case 1:
64-year-old, well man with no relevant past/family history was referred with a rising PSA from 3.9μg/L in 2010 to 6.6μg/L in 2011. No abnormality was found on rectal examination and a biopsy was advised but refused given contemporary publicity in the lay press outlining the risk of biopsy and harms of overdiagnosis/overtreatment. Over the next 5 years the patient undertook various natural remedies and in 2014 when the PSA was 13.3μg/L, an MRI was performed that demonstrated a PIRADS 4 lesion. It was only until 2015 when the PSA had reached 21.9μg/L that a biopsy demonstrated a significant volume of Gleason 9 adenocarcinoma, with pelvic lymphadenopathy on staging.

Case 2:
A 57-year-old man requested PSA screening in 2013; however, he was advised by his local doctor that this was unnecessary based on current guidelines. In 2015 the patient’s brother was diagnosed elsewhere with prostate cancer and underwent radical prostatectomy. The patient then demanded a PSA, which was performed and found to be 40μg/L. Rectal examination revealed a firm, clinical stage T3 malignancy and biopsy demonstrated extensive Gleason 4+4 prostate cancer.

Case 3:
A 51-year-old man was found in 2010 to have a mildly elevated screening PSA of 4.5μg/L. Despite repeated recalls from the GP to have this repeated and further investigated the patient refused until in 2015 he presented with obstructive voiding symptoms and was found on examination to have a diffusely firm, clinical stage T3 malignant prostate. Repeat PSA was 39μg/L and subsequent investigation confirmed extensive Gleason 9 prostate cancer with positive pelvic lymph nodes.

For these men curative treatment is probably no longer an option. Whilst a small anecdotal group, these are real men seen at a community level who demonstrate the power of PSA screening to identify aggressive, clinically significant disease, at an early, curable stage. This is the coalface that General Practitioners and Urologists work at. When the USPSTF ratifies the Grade D recommendations on the basis of flawed and often misinterpreted trials in the absence of specialists who treat such patients, when Epidemiologists and well-meaning Oncologists who never see or evaluate localized prostate cancer lobby against the harms of overdiagnosis and overtreatment, they are condemning these men, and many others, to suffer and die from a preventable disease.

This risk of increased advanced cancer in a non-screened population has already been foreseen and reported [Scosyrev]. How many such men is it acceptable to sacrifice in the name of preventing overdiagnosis and overtreatment?

Rather than the knee-jerk response to abandon PSA testing, the answer, which is increasingly accepted by Urologists, is clearly to unlink prostate cancer diagnosis from treatment. It is to improve diagnostics as we are seeing with development of multiparametric MRI and molecular/genetic markers to make screening and treatment selection smarter. I fear that if this is not more widely accepted and the current situation continues, it is helpful that so much research is being conducted in the management of men with high-risk, oligometastatic and advanced disease, because it will be more and more of these cancers that we will be treating.

Dr Daniel Moon is Director of Robotic Surgery at the Epworth Healthcare, and a Urologist at the Peter MacCallum Cancer Institute, Melbourne
@drdanielmoon

Clever surgeons and challenging study endpoints

August 18, 2015/by John Davis

Intraoperative in vivo tracking of a periprostatic nerve with multiphoton microscopy in rat model.

In the last 6 months, the BJUI editorial team has evaluated an average of 59 urological oncology papers per month with an average acceptance rate of 16%. We receive additional papers for our ‘Translational Science’ section. Studies with high-quality methods are given the highest priority. Other papers compete well if they are highly applicable to clinical practice (i.e. comparative, multicentre, multi-surgeon design) and/or show us new ideas in surgical technique, re-designed study endpoints, or explore new sources of data. For translational science, the best candidates are studies that look at new diagnostic tests in humans and beyond simple immunostaining techniques. We want to evaluate biomarkers likely to be validated and translated into a clinical test. Clinical impact will be even higher if a biomarker is linked to a therapy outcome rather than just a risk estimate. We want our papers to guide us to better outcomes for our patients, hopefully control healthcare costs, and, yes, be well-cited in the literature.

Our review process is tough but fair, and we congratulate and highlight three authorship groups for acceptance into this month’s issue of BJUI. The theme of ‘clever surgeons and challenging study endpoints’ is well illustrated by all three groups. Zargar et al. [1] report on an exclusive database of high-volume minimally invasive surgeons who have tackled the partial nephrectomy option for small renal masses. The comparison is simple in concept and retrospective in design, but what they have done is to significantly increase the outcome measures into a ‘trifecta’ concept in perioperative outcomes (previously reported) with an even more stringent ‘optimal outcome’ endpoint that includes renal function preservation. With a database of 1185 robotic and 646 laparoscopic cases, the robotic procedures showed superior trifecta results (70% vs 33%), complication rates (14.8% vs 20.9%), positive surgical margin rates (3.2% vs 9.7%), and warm ischaemia time (18 vs 26 min). The optimal outcome endpoint included a minimum 90% estimated GFR (eGFR) preservation and no chronic kidney disease upstaging. Only the robotic cohort had sufficient data available and the rate was 38.5%. The latter figure is an interesting challenge, as defining such a high threshold for success challenges surgical technique and allows more room to identify incremental advancement. This may be the largest study of its kind, but non-randomised and with limitations discussed in peer review such as the learning curve influence, use of eGFR as an endpoint with two kidneys, and incomplete data. The definitions used are of interest and the field could use some uniformity moving forward in measuring perioperative and long-term benchmarks of quality.

Durand et al. [2] give us a glimpse into the future of surgery, a science fiction world of prostate surgery where nerves and prostatic glands can be colour coded and seen at a microscopic level in real time. The pictures stand for themselves, especially Fig. 1. If such imaging can be integrated into technique decisions, and perhaps future instrument designs, then perhaps we will have a whole new wave of studies possible on linking surgical technique to improved functional and oncological outcomes after radical prostatectomy. The paper has a nice depth in detail, methods, results, as well as narratives in solving technical problems with novel technology.

This issue’s ‘Article of the Month’ by Gavin et al. [3] is a different look at the question of morbidity after localised prostate cancer treatments, specific to long-term care at >2 years from treatment. The database is from a cancer registry and they have an impressive 54% response rate from a population that is 2–18 years from diagnosis. Rather than Likert-like scales of symptom severity, they simply look at ‘current’ vs ‘ever had’ symptoms and look at the total burden including multiple/overlapping symptoms. Although this may not be as robust and validated as the Expanded Prostate Cancer Index Composite (EPIC) instrument, the simple phrasing of ‘current’ vs ‘ever had’ is probably capturing a very high proportion of symptoms rather than dismissing them if minor or in the past. Again, we see more erectile dysfunction after radical prostatectomy and radiation with hormonal therapy, and more bowel symptoms after radiation therapy. Hormone therapy patients have hot flashes and fatigue, and watchful-waiting patients have some advantages but are certainly not free of symptoms. The burden of symptoms is interesting, nine of 10 reported at least one of seven key symptoms at some point and three of four are current. Therefore, as the authors indicate, ≈75% of prostate cancer survivors will have ongoing symptoms needing follow-up care. This is a significant database resource adding to our understanding of long-term outcomes of patients with prostate cancer and supporting the significance of the Durand et al. [2] study that may show the way forward towards reducing such burdens of disease treatment.

References

1 Zargar H, Al laf ME, Bhayani S et al. Trifecta and optimal perioperative outcomes of robotic and laparoscopic partial nephrectomy in surgical treatment of small renal masses: a multi-institutional study. BJU Int 2015; 407–14

2 Durand M, Jain M, Aggarwal A et al. Real-time in vivo periprostatic nerve tracking using multiphoton microscopy in a rat survival surgery model: a promising pre-clinical study for enhanced nerve-sparing surgery. BJU Int 2015; 478–86

3 Gavin AT, Drummond FJ, Donnelly C, O’Leary E, Sharp L, Kinnear HR. Patient-reported ‘ever had’ and ‘current’ long-term physical symptoms after prostate cancer treatments. BJU Int 2015; 397–406

John W. Davis, MD
Associate Editor, BJUI

#pass4prostate gears up for Rugby World Cup

August 17, 2015/by Declan Murphy

Here is a fun campaign which should appeal to anyone interested in rugby or prostate cancer for that matter. The 2015 Rugby World Cup kicks off in England and Wales next month and as part of their warm up schedule, Australia are playing USA Rugby in a friendly match at Soldier Field in Chicago on the 5th of September. As part of their sponsorship of this fixture, Astellas are supporting a social media campaign called #pass4prostate which will directly raise funds for prostate cancer research in both the USA and Australia.

As part of their support, Astellas will donate $5 to prostate cancer research and advocacy organizations for every qualifying #pass4prostate submission posted to Twitter, Facebook, or Instagram, up to a maximum contribution of $125,000 in the USA and a further $40,000 in Australia. At socialboost you will get the best review of the instagram traffic boosting tools. Therefore to make sure we maximize this commitment, we need to drive lots of traffic using the #pass4prostate hashtag! You can see examples of Australian and US rugby players supporting the campaign below by throwing around special blue rugby balls, but the campaign is encouraging people to make videos supporting the campaign and throwing anything blue around (in a rugby style of course!).

The campaign will run up to the match on 5^th September, and there be lots of activity at the 2^nd Prostate Cancer World Congress which takes place in sunny Far North Queensland, Australia, from 17-21^st August 2015. Follow #pcwc15 or #pass4prostate to get involved!

For full details, please visit the pass4prostate website.

Declan Murphy

Melbourne, Australia

@declangmurphy

Sailing into “UnCHAARTED” waters

August 5, 2015/4 Comments/by Simon Chowdhury

Chemotherapy comes alive for prostate cancer!

Systemic therapy for metastatic prostate cancer has radically changed in the last 10 years with the introduction of several novel agents that have shown significant improvements in progression free and overall survival. These have all been studied in metastatic castrate refractory prostate cancer (mCRPC) and have improved overall survival but in each case by less than 6 months. (The latest major breakthrough is the introduction of a relatively old drug, docetaxel chemotherapy, earlier in the disease for hormone sensitive patients).

In this week’s New England Journal of Medicine we see the eagerly awaited results from the CHAARTED study from Christopher Sweeney and colleagues. This novel study aimed to improve treatment for men with newly diagnosed hormone sensitive metastatic prostate cancer by adding docetaxel chemotherapy to androgen deprivation therapy (ADT).

790 men with newly diagnosed metastatic prostate cancer were randomised to ADT plus docetaxel (6 cycles at 75mg/m2) or ADT alone. The addition of docetaxel to ADT was shown to significantly improve overall survival by 13.6 months (57.6 months vs. 44.0 months; p<0.001). The clinical benefit was greatest in the subgroup with high volume disease where the improvement in overall survival was 17 months (49.2 months versus 32.2 months). High volume disease was defined as the presence of visceral metastases and/or 4 or more bone metastases with at least one beyond the vertebral bodies or pelvis. The combination was well tolerated with approximately 6% of patients having neutropenic fever and one death possibly related to docetaxel.

The results from this study are truly practice changing. Supporting evidence from the UK STAMPEDE study (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) was presented at this year’s American Society of Clinical Oncology (ASCO) meeting. STAMPEDE showed that for men with metastatic hormone sensitive prostate cancer 6 cycles of docetaxel in addition to ADT improved median overall survival by 22 months (43 versus 65 months).

Chemotherapy for metastatic prostate cancer has had a checkered past with a lack of enthusiasm and nihilism from clinicians and patients. The results from CHAARTED and STAMPEDE are already changing those views. The prostate cancer community needs to react to these results and look to make this treatment available to all suitable men. There are issues with regards to costs of chemotherapy (although docetaxel is now generic), workload, sequence, patient selection, toxicity management, etc. The CHAARTED and STAMPEDE investigators must also use this opportunity to interrogate the tumour samples from these studies to see if they can identify biomarkers that predict docetaxel activity. We will not get this opportunity again as docetaxel + ADT will be be standard of care for future studies.

The clinical benefit from the addition of docetaxel to ADT is one of the largest seen in any oncology study. All men presenting with newly diagnosed metastatic prostate cancer should be considered for 6 cycles of docetaxel in addition to ADT.

Simon Chowdhury is a Consultant Medical Oncologist at Guy’s, King’s and St Thomas’ Hospitals, London. He is actively involved in clinical trial research into urological cancers.

Further Randomised Controlled Trials are needed….No! say something original.

June 12, 2015/11 Comments/by Ben Challacombe

“As we all know, prostate/kidney/bladder cancer is a common disease…” aaargh!!! Of course it is, that’s why you are writing about it and trying to get this piece of work into this journal and why everyone who reads it might be interested; because it is so important and common! If we all know it anyway why are you bothering to tell us this whilst wasting time and your word count and not getting on with presenting the actual research? Anyone who doesn’t know that prostate cancer is pretty common isn’t a doctor let alone a urologist. This is found more often than I can stand and got me thinking about all the other scientific catchphrases and tactics that serve more to irritate than inform.

As the BJUI associate editor for Innovation and one of the triage editors, I read around 600 BJUI submissions each year as part of my role. This is not to mention the additional manuscripts I formally review for this journal and others and there are certain phrases and statements that really just make my blood boil. Time and time again the same statements come up that are put into medical papers seemingly without any thought and which add nothing other than serving to irritate the editor, reviewer and reader.

The throwaway statement that “further randomised trials are needed” is often added to the end of limited observational and cohort studies, presumably by young researchers and almost never adds anything. Anyone who has ever been involved with a surgical RCT will know how challenging it is to set one up and run one, let alone recruit to one which is why so few exist and why so many have failed. Just saying more RCTs are needed without thought to why they haven’t already been carried out just frustrates the reader and shows a lack of true comprehension of the subject. Suggesting an valid alternative to an RCT however might actually get people thinking.

So what else is in the wastebucket of things that cause journal irritation? Well conclusions that have no basis in the results that have been shown; such as XXX is a safe and generally acceptable procedure after 3 cases, of which one had a 2 litre blood loss; or we advise everyone to switch to our technique on the basis of this uncontrolled retrospective cohort. Another is YY is the “Gold Standard” even though this is just opinion that is usually very outdated and this way of doing things was really only the standard approach 20 years ago!

Failure to acknowledge the study limitations is another area that particularly winds me up especially when the authors did a procedure one way 500 times then subsequently did it 50 times in a subtly different way and state that the second is better without mentioning that they might have learnt a fair bit from the previous huge number of cases!

So please let me know what irritates you in a paper so I can watch out for it and makes sure never to use it myself

Ben Challacombe
Associate Editor, BJUI