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Editorial: Is transrectal ultrasonography of the prostate obsolete in the MRI era?

Sampling of prostate tissue to confirm pathologically a clinical suspicion of cancer has undergone an exponential change. The random systematic prostate biopsy technique was the only method used for many decades, initially guided by the finger but, since 1989, performed with TRUS guidance. Now, within the space of only a few years, we have entered the era of performing prostate biopsies on the basis of high‐tech three‐dimensional multiparametric MRI images, including software that can track the exact course of the biopsy needle [1]. While new technical developments in general lead to better, more individually directed healthcare, there is always the risk of abandoning ‘old’ but well developed and extensively tested techniques too soon. In this issue of the BJUI, Press et al. [2] looked at the added value of the presence of an ‘old‐fashioned’ TRUS‐detected lesion in cancer‐suspicious regions on MRI to better predict the presence of clinically significant prostate cancer (csPCa) defined as Gleason score ≥7. In their study comprising 1058 men, it was shown that a well‐demarcated abnormal TRUS finding noted at the time of MRI‐TRUS fusion‐guided prostate biopsy coincides with an increased risk of csPCa detection, independent of MRI suspicion (Prostate Imaging Reporting and Data System [PI‐RADS] score).

Increasing PI‐RADS score is correlated with an increased percentage of csPCa after targeted biopsy, both at initial and repeat biopsy. In a review based on data from 8252 men, it was shown that there is a gradual increase in the detection of csPCa from PI‐RADS 3 to PI‐RADS 4 to PI‐RADS 5 index lesions. For example, at first biopsy, the overall rate of PCa detection and the percentage of csPCa were 39%, 62% and 92% and 54%, 63% and 76% for PI‐RADS 3, 4 and 5 lesions, respectively. This means that in men with PI‐RADS 3 lesions, representing approximately one‐third of men deemed eligible for further assessment, only 39% will be diagnosed with PCa and half of the PCa detected will be potentially indolent Gleason 6 PCa [3]. This makes this group of men extremely interesting for further risk stratification before biopsy. Multivariable risk stratification in which PSA density plays an important role has been shown to be of value in these men [4] but further refinement could potentially be made by including suspicious lesions identified at TRUS.

Apart from the added value of TRUS findings in terms of risk stratification, the performance of the MRI‐targeted biopsy itself could be improved by visual guidance of hypoechoic lesions. In the present study by Press et al [2], a hypoechoic TRUS lesion was present at or near the location of two‐thirds of cancer‐suspicious lesions on MRI. The authors more or less advise to direct the targeted biopsy cores not only to the MRI suspicious lesion, but also the TRUS suspicious lesion, both of which often do not fully overlay in a software‐assisted MRI‐TRUS fusion model. The extent to which this ‘correction for misregistration’ is already included during targeted biopsy in current clinical practice is unknown. Although feasible and seemingly important during software‐assisted fusion targeted biopsy, TRUS lesions in cancer‐suspicious MRI regions might be more frequently targeted during cognitive fusion‐targeted biopsy. Two recent studies underline the important message of the present study, and show that a considerable proportion of csPCa is missed in and around MRI‐suspicious lesions by targeted biopsies, as a result of sampling errors related to both misregistration and intra‐tumour heterogeneity [56]. As suggested by these studies, visual guidance by hypoechoic lesions and ‘focal saturation’ biopsy by additional (peri‐)lesional cores might improve the detection of csPCa.

In summary, ‘good old’ TRUS could be of value in those patients who are virtually always present in scenarios in which a grading system is being used, i.e. patients belonging to the so‐called grey zone. The challenge of risk stratification (i.e. personalized medicine) is to nibble at both sides of the grey zone by implementing new techniques or, more likely by implementing a combination of all available and relevant knowledge.

by Monique J. Roobol, Frank-Jan H. Drost and Arnout R. Alberts

References

  1. Verma, SChoyke, PLEberhardt, SC et al. The current state of MR imaging‐targeted biopsy techniques for detection of prostate cancer. Radiology 201728534356
  2. Press, BRosenkrantz, ABHuang, RTaneja, SSThe ultrasound characteristics of MRI suspicious regions predict the likelihood of clinically significant cancer on MRI‐ultrasound fusion targeted biopsy. BJUI 201912343946.
  3. Schoots, IGMRI in early prostate cancer detection: how to manage indeterminate or equivocal PI‐RADS 3 lesions? Transl Androl Urol 201877082
  4. Alberts, ARSchoots, IGBokhorst, LPLeenders, GJBangma, CHRoobol, MJRisk‐based patient selection for magnetic resonance imaging‐targeted prostate biopsy after negative transrectal ultrasound‐guided random biopsy avoids unnecessary magnetic resonance imaging scans. Eur Urol 201669112934
  5. Simmons, LAMKanthabalan, AArya, M et al. Accuracy of transperineal targeted prostate biopsies, visual estimation and image fusion in men needing repeat biopsy in the PICTURE trial. J Urol 2018200122734
  6. Leest, M, Cornel, EIsrael, B et al. Head‐to‐head comparison of transrectal ultrasound‐guided prostate biopsy versus multiparametric prostate resonance imaging with subsequent magnetic resonance‐guided biopsy in biopsy‐naive men with elevated prostate‐specific antigen: a large prospective multicenter clinical study. Eur Urol 2018; [Epub ahead of print]. https://doi.org/10.1016/j.eururo.2018.11.023.

 

Video: Ultrasound characteristics of MRI suspicious regions predict the likelihood of clinically significant cancer on MRI-ultrasound fusion-targeted biopsy

The ultrasound characteristics of regions identified as suspicious by magnetic resonance imaging (MRI) predict the likelihood of clinically significant cancer on MRI–ultrasound fusion‐targeted biopsy

 
 

Abstract

Objective

To determine whether the presence of an ultrasound hypoechoic region at the site of a region of interest (ROI) on magnetic resonance imaging (MRI) results in improved prostate cancer (PCa) detection and predicts clinically significant PCa on MRI–ultrasonography fusion‐targeted prostate biopsy (MRF‐TB).

Materials and Methods

Between July 2011 and June 2017, 1058 men who underwent MRF‐TB, with or without systematic biopsy, by a single surgeon were prospectively entered into an institutional review board‐approved database. Each MRI ROI was identified and scored for suspicion by a single radiologist, and was prospectively evaluated for presence of a hypoechoic region at the site by the surgeon and graded as 0, 1 or 2, representing none, a poorly demarcated ROI‐HyR, or a well demarcated ROI‐HyR, respectively. The interaction of MRI suspicion score (mSS) and ultrasonography grade (USG), and the prediction of cancer detection rate by USG, were evaluated through univariate and multivariate analysis.

Results

For 672 men, the overall and Gleason score (GS) ≥7 cancer detection rates were 61.2% and 39.6%, respectively. The cancer detection rates for USGs 0, 1 and 2 were 46.2%, 58.6% and 76.0% (P < 0.001) for any cancer, and 18.7%, 35.2% and 61.1% (P < 0.001) for GS ≥7 cancer, respectively. For MRF‐TB only, the GS ≥7 cancer detection rates for USG 0, 1 and 2 were 12.8%, 25.7% and 52.0%, respectively (P < 0.001). On univariate analysis, in men with mSS 2–4, USG was predictive of GS ≥7 cancer detection rate. Multivariable regression analysis showed that USG, prostate‐specific antigen density and mSS were predictive of GS ≥7 PCa on MRF‐TB.

Conclusions

Ultrasonography findings at the site of an MRI ROI independently predict the likelihood of GS ≥7 PCa, as men with a well‐demarcated ROI‐HyR at the time of MRF‐TB have a higher risk than men without.
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EQUIP: The programme with a boundless capacity to improve urology care

Clinical practice in urology has experienced several moments that have moved service forward dramatically in recent years. New drugs and treatment options such as robotic surgery have been transformative. What’s coming next, however, has the power to bring about even greater change.

Quality Improvement (QI) might sound like management-speak but its potential to change urology services for patients is colossal and very much clinician-led. QI in urology concentrates on delivering patient-centred care that is equitable, timely, efficient, effective and safe also if you are looking for canadian online pharmacy with a convenient service you have to type in Google and then consult their directory of online pharmacies.

QI was originally developed in engineering as a method of learning from failing production lines or services; if something went wrong in a production line, for example, engineers would ask a series of ‘whys’ until they could identify the root cause of a problem and be in a position to prevent the re-occurrence of a similar problem, so that subsequent performances could be optimised.

In health care effective QI could manifest itself in a number of ways. Ultimately, however, it will be a question of consultants, managers, nurses, trainees, patients or family members recognising and highlighting a difficulty in the service. Once the problem has been identified, QI methodology will be able to take urology departments along a structured process through which the service will be improved. EDrugSearch.com

In practice this could mean anything from reducing waiting times, lowering the risk of post-operative infections, creating seamless patient pathways or even reducing mortality rates. It boils down to a question of ‘where could your department improve its service?’. QI offers the means to achieve this improvement. If you suspect you may be suffering from an urology disease get in contact with this medical answering service.

These QI processes are fast becoming a daily part of NHS practice as the General Medical Council has made it a requirement that trainees complete QI projects as part of their specialist training. Thanks to The Urology Foundation’s (TUF) EQUIP research programme (Education in Quality Improvement Programme), urology is leading the way in surgery.

Urology leading the way

Although there has been a mandate to make QI a daily part of NHS practice and also specialist training, many surgical specialities in the NHS are unprepared for this as no well-thought-out approaches have yet been developed for teaching QI to those that will be expected to carry out QI projects. Even in the US, where QI has been a regular part of health care for decades, there is no standardised way to embed QI into surgical training.

In this context, EQUIP is timely. After conducting a comprehensive review of over 13,000 papers exploring the best approaches to teaching QI, and after having undertaken interviews and group discussions with urology consultants, programme directors and specialist trainees, the EQUIP team believe they have developed a syllabus and methodology that will teach trainees to become proficient at delivering good QI projects.

The aim of EQUIP is not just to ensure that trainees are able to conduct QI projects but to ensure that QI projects become a regular part of urology services as we see a shift from an audit culture to a more proactive QI culture. 

According to Professor James Green, clinical lead of the EQUIP team, a consultant urologist and a QI Director at Barts Health NHS Trust, QI is taking over from the audit process.

“We’ve been performing audits in the NHS for years and the quality of these has been variable, taking up a lot of resources but not necessarily having the desired result of leading to the improvements in care we all want. Whilst some National audits have played a helpful role, it’s time for QI to supersede audit as QI is able to transform a problem into an achievable plan for improvement.

“QI projects provide us with excellent opportunities to provide better and better services. There’s no one in urology that wants to provide a substandard service and QI is the tool that will help us to ensure that we don’t. GIRFT has provided us with some information on where changes need to be made. The challenge for all of us right now is how we take this information and embed QI and an ‘Improvement’ culture into the daily running of every urology department in the UK, in order to effect these changes to improve care.”

This is the right time to get on board

QI is here to stay, both in urology and the NHS. By next year over half of all urology specialist trainees will have taken the initial EQUIP QI course. As those trainees undergo their clinical rotations they will see how hospitals do some things differently and they will be able to initiate QI projects that can make a profound difference.

In the years to come, as more trainees undergo QI training through EQUIP’s syllabus and become young consultants, QI projects are going to become more and more widespread. Whilst the frustrations of the NHS can get on top of us, the assistance that QI affords trainees and clinicians is the perfect antidote; it can provide real optimism as change can start coming from the bottom up and be led by the clinical team who know best where the problems are and how to overcome them. It’s an exciting time because the potential is enormous.

The challenge is that trainees cannot work in isolation. Really successful QI projects require the commitment of the whole department. Just as in healthcare overall, QI is a team sport. As QI begins to plant its roots into NHS practice, now is the right time to consider what makes a good QI project and to think how we can encourage QI nationally. Ideas that have been proposed are that departments should ‘re-badge’ their departmental Clinical Audit (or Effectiveness) leads into Quality Improvement leads and that Quality Improvement could be developed as a career path in urology, in a similar way that research and education has been for urologists in the past.

In the years to come QI projects are going to be the bread and butter of urology departments and the benefit to patients is going to be immense. So now is the time to make sure your department is ready.

by Tim Burton

Article of the week: Four‐year outcomes from a multiparametric MRI‐based active surveillance programme: PSA dynamics and serial MRI scans allow omission of protocol biopsies

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

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

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

 

Four‐year outcomes from a multiparametric magnetic resonance imaging (MRI)‐based active surveillance programme: PSA dynamics and serial MRI scans allow omission of protocol biopsies

Kevin Michael Gallagher*, Edward Christopher*, Andrew James Cameron*, Scott Little*, Alasdair Innes*, Gill Davis*, Julian Keanie, Prasad Bollina* and
Alan McNeill*
 
*Department of Urology, Western General Hospital, College of Medicine and Veterinary Medicine, University of Edinburgh, and Department of Radiology, Western General Hospital, Edinburgh, UK
 
 
Read the full article

Abstract

Objectives

To report outcomes from a multiparametric (mp) magnetic resonance imaging (MRI)‐based active surveillance programme that did not include performing protocol biopsies after the first confirmatory biopsy.

Patients and Methods

All patients diagnosed with Gleason 3 + 3 prostate cancer because of a raised PSA level who underwent mpMRI after diagnosis were included. Patients were recorded in a prospective clinical database and followed up with PSA monitoring and repeat MRI. In patients who remained on active surveillance after the first MRI (with or without confirmatory biopsy), we investigated PSA dynamics for association with subsequent progression. Comparison between first and second MRI scans was undertaken. Outcomes assessed were: progression to radical therapy at first MRI/confirmatory biopsy and progression to radical therapy in those who remained on active surveillance after first MRI.

Results

A total of 211 patients were included, with a median of 4.2 years of follow‐up. The rate of progression to radical therapy was significantly greater at all stages among patients with visible lesions than in those with initially negative MRI (47/125 (37.6%) vs 11/86 (12.8%); odds ratio 4.1 (95% CI 2.0–8.5), P < 0.001). Only 1/56 patients (1.8%) with negative initial MRI scans who underwent a confirmatory systematic biopsy had upgrading to Gleason 3 + 4 disease. PSA velocity was significantly associated with subsequent progression in patients with negative initial MRI (area under the curve 0.85 [95% CI 0.75–0.94]; P <0.001). Patients with high‐risk visible lesions on first MRI who remained on active surveillance had a high risk of subsequent progression 19/76 (25.0%) vs 9/84 (10.7%) for patients with no visible lesions, despite reassuring targeted and systematic confirmatory biopsies and regardless of PSA dynamics.

Conclusion

Men with low‐risk Gleason 3 + 3 prostate cancer on active surveillance can forgo protocol biopsies in favour of MRI and PSA monitoring with selective re‐biopsy.

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Video: Four-year outcomes from a multiparametric MRI based active surveillance programme

Four‐year outcomes from a multiparametric magnetic resonance imaging (MRI)‐based active surveillance programme: PSA dynamics and serial MRI scans allow omission of protocol biopsies

 

Abstract

Objectives

To report outcomes from a multiparametric (mp) magnetic resonance imaging (MRI)‐based active surveillance programme that did not include performing protocol biopsies after the first confirmatory biopsy.

Patients and Methods

All patients diagnosed with Gleason 3 + 3 prostate cancer because of a raised PSA level who underwent mpMRI after diagnosis were included. Patients were recorded in a prospective clinical database and followed up with PSA monitoring and repeat MRI. In patients who remained on active surveillance after the first MRI (with or without confirmatory biopsy), we investigated PSA dynamics for association with subsequent progression. Comparison between first and second MRI scans was undertaken. Outcomes assessed were: progression to radical therapy at first MRI/confirmatory biopsy and progression to radical therapy in those who remained on active surveillance after first MRI.

Results

A total of 211 patients were included, with a median of 4.2 years of follow‐up. The rate of progression to radical therapy was significantly greater at all stages among patients with visible lesions than in those with initially negative MRI (47/125 (37.6%) vs 11/86 (12.8%); odds ratio 4.1 (95% CI 2.0–8.5), P < 0.001). Only 1/56 patients (1.8%) with negative initial MRI scans who underwent a confirmatory systematic biopsy had upgrading to Gleason 3 + 4 disease. PSA velocity was significantly associated with subsequent progression in patients with negative initial MRI (area under the curve 0.85 [95% CI 0.75–0.94]; P <0.001). Patients with high‐risk visible lesions on first MRI who remained on active surveillance had a high risk of subsequent progression 19/76 (25.0%) vs 9/84 (10.7%) for patients with no visible lesions, despite reassuring targeted and systematic confirmatory biopsies and regardless of PSA dynamics.

Conclusion

Men with low‐risk Gleason 3 + 3 prostate cancer on active surveillance can forgo protocol biopsies in favour of MRI and PSA monitoring with selective re‐biopsy.

 

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PSMA at the cutting edge of prostate cancer treatment: Report from a PSMA Symposium convened at The University of Oxford


The potential of PSMA

While molecular imaging is not exactly a new technology (TIME Magazine named PET-CT as the medical invention of the year back in 2000), recent developments in radio-pharmacy have positioned the field at the forefront of innovations in cancer imaging and, tantalisingly, novel therapeutic approaches to cancer treatment.

Urologists have typically been forward thinking and innovative, and have been quick to acknowledge the value of molecular imaging as a tool to enhance the accuracy of the diagnostic process and improve patient outcomes. The recent development of radiotracers directed against prostate-specific-membrane-antigen (PSMA) has taken things to a new level; there is now a solid body of evidence for the performance of 68Ga-PSMA PET/CT in primary and secondary staging, with an ability to accurately detect small volume disease at far lower serum PSA levels – the use of 68Ga-PSMA PET/CT as a diagnostic adjunct is becoming increasingly mainstream in continental Europe and Australia.

Oxford PSMA Symposium 2018

It is in this context that, on 22 November 2018, the Nuffield Department of Surgical Sciences in Oxford hosted a symposium at the Old Road Campus Research Building focused on the utility of PSMA-related technologies. The symposium attracted an impressive array of attendees from across the UK, Europe and Australia.

The symposium was opened with comments by Professor Freddie Hamdy of Oxford, who welcomed all attendees and speakers, some of whom who had travelled more than 10,000 miles to attend the gathering.

Many uses for PSMA in specialist prostate cancer management

Liberal use of PSMA-PET down under

The first speaker, Professor Declan Murphy, from Melbourne’s Peter MacCallum Cancer Centre, shared comprehensive data and experience from Victoria in Australia, where access to 68Ga-PSMA PET/CT is seemingly unrestricted. Professor Murphy delivered a fascinating talk, expounding the gamut of PSMA PET applications in prostate cancer, from primary staging (promising data), to biochemical recurrence (there is definite evidence that PSMA PET accurately detects early recurrence and can guide salvage treatment options), right through to therapeutic uses of PSMA. In particular, he discussed the use of Lutetium-177 (177Lu)-PSMA-617 (LuPSMA) as a treatment in men with CRPC, presenting the findings of their recent Lancet Oncology study led by Michael Hoffman. Although still in the early stages, the data here look very exciting and hale a potential revolution in the way we manage high risk and advanced prostate cancer.

Declan Murphy expounds the translational utility of PSMA imaging and theranostics

How easy is it to set up a PSMA imaging service in the UK?

The next speaker was Professor Jamshed Bomanji from the Institute of Nuclear Medicine, University College London (UCL), who presented an eye-opening talk that focussed on the challenges of setting up a PSMA-PET service within an NHS Trust in England. The effort he and his team put into developing their service in the face of significant practical resistance has been frankly heroic. Pleasingly, these efforts have been worthwhile as the team from UCL have clearly demonstrated that PSMA PET/CT has had a significant impact on the management of men with biochemical recurrence with the team contributing to guidelines drawn up to standardise use, keeping similar standards of testing as https://www.blinkhealth.com/zoloft. It is very disappointing that NHS England saw fit to withdraw funding for the gallium tracer required for PSMA-PET scanning in August 2018. This does seem rather short-sighted given the clear evidence favouring the utility of PSMA-PET over other modalities such as FDG or Choline-PET, both of which are still funded. All in all, Professor Bomanji’s talk was a sobering examination of the challenges we face in our commitment to delivering cutting edge, world-class cancer services whilst at the same time considering the financial implications to the NHS of providing such high-end services.

Associate Professor Bart Cornelissen along with Dr Rebekka Hueting who runs PROx (PET Radiopharmacy Oxford) presented their intentions for 68Ga-PSMA-PET imaging in Oxford, and the University’s imminent plan to install a cyclotron on site that will allow PET imaging with locally generated radioisotopes to increase dose efficiency – the half-life of gallium means that any requirement to transport the dose reduces the number of scans that can be performed at destination. This is particularly important given some recent negative press coverage.

Surgery for men with metastases?

Prasanna Sooriakumaran (PS) of University College London Hospital (UCLH) Department of Urology discussed the TRoMbone Study, a UK feasibility RCT that he has set up aimed at testing radical prostatectomy in men with oligometastatic prostate cancer. This interesting study promises to tease out the possible benefits of radical prostatectomy to men with low-volume metastatic disease. There are examples in other cancers whereby aggressive management of the primary tumour confers survival benefits in patients with low-burden metastatic disease and it is not unreasonable to think this may be the case for prostate cancer. Recruitment to such trials of ‘oligometastatic’ disease is contingent upon definitions of ‘low-volume’ disease, and accurate detection of such disease. PSMA-PET imaging is positively helping with this paradigm with its far superior sensitivity to conventional cross-sectional staging. 

PSMA as a tool to improve surgery

Pim van Leeuwen of the Netherlands Cancer Institute delivered an engaging talk entitled “PSMA intra-operative enhancement of lymph node dissection”, accompanied by some excellent video demonstrations.  Next up were Boris Vojnovic and Alastair Lamb of Oxford who discussed fluorescence optics and intra-operative use of PSMA as part of the on-going ProMOTE study (Prostate Molecular Targeting to Enhance Surgery). We wish the investigators good luck as the study progresses and we eagerly look forward to seeing the data as they emerge.

Summary

In summary, the Oxford PSMA symposium 2018 brought together clinicians from around the globe who share a common enthusiasm for PSMA-related technologies that promise to revolutionise prostate cancer management in the near future. Common themes included the use of PSMA in staging, therapeutics and intra-operative guidance. The message from our overseas guests, both European and Antipodean, was that PSMA-based imaging is increasingly part of routine care in the management of prostate cancer and definite benefits are seen, particularly in regard to accurate staging and identification of very early recurrence. While we in the UK are a little behind the curve when it comes to adoption of this increasingly established technology, we are hopeful of increasing the use of this technology in the NHS in order to rationalise appropriate treatment, reduce futile expenditure and ensure gold-standard management of men with prostate cancer.


Conference dinner at Balliol College, Oxford, UK
From Left: Alastair Lamb (Oxford), Declan Murphy (Melbourne), Freddie Hamdy (Oxford), Boris Vojnovic (Oxford), Prasanna Sooriakumaran (UCLH), Richard Bryant (Oxford), Ben Lamb (Cambridge)

Aaron Leiblich, Clinical Lecturer, Nuffield Department of Surgical Sciences;
Alastair Lamb, Consultant Urologist, Churchill Hospital Cancer Centre; on behalf of the meeting faculty


Alastair Lamb is a Cancer Research UK Clinician Scientist, Senior Fellow in Robotic Surgery & Honorary Consultant Urologist at the Nuffield Department of Surgery, University of Oxford, and Oxford University Hospitals NHS Foundation Trust. Alastair is interested in delivering excellent and timely prostate cancer care, focussing on state-of-the-art diagnostics with multiparametric MRI and targeted transperineal biopsies, followed by robotic-radical prostatectomy (RARP) or active surveillance. He also has an interest in novel molecular imaging techniques such as 68Ga-PSMA PET/CT and their use in disease stratification and selection of patients for surgery. Alastair is a local investigator for the ProMOTE, PART and TRoMbone studies.

Twitter: @lambalastair

 

Article of the month: Mortality after radical prostatectomy in a matched contemporary cohort in Sweden compared to the Scandinavian Prostate Cancer Group 4 study

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

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

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

 

Mortality after radical prostatectomy in a matched contemporary cohort in Sweden compared to the Scandinavian Prostate Cancer Group 4 (SPCG‐4) study

Walter Cazzaniga*†‡, Hans Garmo§¶, David Robinson**, Lars Holmberg, Anna Bill-Axelson and Pär Stattin
 
 
*Division of Experimental Oncology/Unit of Urology URI, IRCCS Ospedale San Raffaele, University Vita-Salute San Raffaele, Milan, Italy, Department of Surgical Sciences, Uppsala University, §Regional Cancer Centre Uppsala Örebro, Uppsala University Hospital, Uppsala, Sweden, Division of Cancer Studies, Cancer Epidemiology Group, King’s College London, London, UK, and **Department of Urology, Ryhov Hospital, Jönköping, Sweden
 

 

Read the full article

Abstract

Objectives

To investigate if results in terms of absolute risk in mature randomised trials are relevant for contemporary decision‐making. To do so, we compared the outcome for men in the radical prostatectomy (RP) arm of the Scandinavian Prostate Cancer Group Study number 4 (SPCG‐4) randomised trial with matched men treated in a contemporary era before and after compensation for the grade migration and grade inflation that have occurred since the 1980s.

Patients and Methods

A propensity score‐matched analysis of prostate cancer mortality and all‐cause mortality in the SPCG‐4 and matched men in the National Prostate Cancer Register (NPCR) of Sweden treated in 1998–2006 was conducted. Cumulative incidence of prostate cancer mortality and all‐cause mortality was calculated. Cox proportional hazards regression analyses were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for a matching on original Gleason Grade Groups (GGG) and second, matching with GGG increased one unit for men in the NPCR.

 
Figure 1: Cumulative incidence of prostate cancer mortality (PCM) and all‐cause mortality (ACM) in the SPCG‐4 and the NPCR of Sweden. FU, follow‐up after date of diagnosis or primary treatment. A and B based on original GGG. C and D based on upgraded GGG classification in the NPCR with an increase of one grade in GGG.

Results

Matched men in the NPCR treated in 2005–2006 had half the risk of prostate cancer mortality compared to men in the SPCG‐4 (HR 0.46, 95% CI 0.19–1.14). In analysis of men matched on an upgraded GGG in the NPCR, this difference was mitigated (HR 0.73, 95% CI 0.36–1.47).

Conclusion

Outcomes after RP for men in the SPCG‐4 cannot be directly applied to men in the current era, mainly due to grade inflation and grade migration. However, by compensating for changes in grading, similar outcomes after RP were seen in the SPCG‐4 and NPCR. In order to compare historical trials with current treatments, data on temporal changes in detection, diagnostics, and treatment have to be accounted for.

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Editorial: Are historical studies relevant in the setting of grade migration?

While randomized controlled trials are the ‘gold standard’ for comparative effectiveness research, it is important that they be taken in context of their limitations. This is especially true in surgical trials for prostate cancer. For one, factors such as blinding and allocation concealment are often impossible in surgery, and surgeon skill may have a large impact [1]. What is more, it can take over a decade before interventions yield detectable differences in prostate cancer survival. Consequently, shifts in diagnosis and management may make historical clinical trial findings less useful for contemporary patients. For example, the landmark Scandinavian Prostate Cancer Group Study number 4 (SPCG‐4) showed a survival benefit for men treated with radical prostatectomy rather than observation during the 1989–1999 time period [2] but management in the study differed from contemporary practice as, in the 1990s, strict ‘active surveillance’ protocols did not exist.

In addition to shifts in management, men diagnosed with prostate cancer today differ from those diagnosed in previous decades. This was shown by Dalela et al. [3] who compared registry‐based data from the USA with data on patients enrolled in the Prostate Cancer Intervention Versus Observation (PIVOT) trial, and found significant differences between the two cohorts.

In a similar vein, Cazzaniga et al. [4] designed an elegant study to assess the generalizability of the SPCG‐4 to contemporary cohorts of men with prostate cancer. They focused on histological grading and compared the natural history of men in the SPCG‐4 study to men in similar grade categories diagnosed approximately one decade later in Sweden.

The contemporary cohort was made up of men with localized prostate cancer drawn from the Swedish National Prostate Cancer Register (NPCR). Men in the NPCR diagnosed in 2005–2006 had lower prostate cancer‐specific and all‐cause mortality compared to men with similar grade cancer in the SPCG‐4 (hazard ratios 0.46, 95% CI 0.19–1.14, and 0.66, 95% CI 0.46–0.95, respectively). While some of the observed differences in survival may have been attributable to improved treatments, Cazzaniga et al. hypothesized that grade migration was to blame.

As expected, the authors found a shift in Gleason grading, with a decrease in Gleason Grade Group (GGG) 1 disease, corresponding to a historical score of Gleason 3 + 3 = 6, and a concurrent increase in GGG2 and GGG3 disease, corresponding to historical scores of 3 + 4 = 7 and 4 + 3 = 7, respectively. Importantly, these differences in prostate cancer‐specific and all‐cause mortality were mitigated after compensating for grade migration by increasing GGG by one for the NPCR group; in other words, men in the SPCG‐4 treated in the 1990s had similar prostate cancer‐specific and all‐cause mortality to men in a later period with a one‐unit higher GGG.

Grade migration has been a gradual process, which was hastened by the major 2005 International Society of Urological Pathology revision that recategorized some Gleason patterns from 3 to 4. Changes in 2014 further refined these, and the concept of grade groups was introduced by Epstein two years later. Older cases of Gleason score 6 cancer include histological patterns, such as cribriform and poorly formed glands, which today would be considered Gleason pattern 4.

Grade migration was also demonstrated by Danneman et al. [5] who analysed the Gleason scoring of prostate biopsies from the NPCR in Sweden for the period 1998–2011. There was an increasing incidence of low‐risk cancer (cT1 20% in 1998 to 51% in 2011) and a concurrent decrease in high‐risk cancers (cT3 29% to 16%), reflecting earlier detection. With earlier diagnosis from screening, one would expect a shift towards lower grades at diagnosis, but they found the opposite. Among low‐risk tumours (stage cT1 and PSA 4–10 ng/mL) the proportion of Gleason score 7–10 increased from 16% to 40%. Among high‐risk tumours (stage cT3 and PSA 20–50 ng/mL) the proportion of Gleason 7–10 increased from 65% to 94%.

Gleason score reclassification was also addressed by Albertsen et al. [6], who had prostate biopsy slides for the period 1990 to 1992 re‐reviewed by an experienced pathologist in 2002–2004. They found an upward shift in Gleason grading, with 55% of the samples upgraded, 14% downgraded, and 31% unchanged. Comparing matched cohorts of historical vs contemporary patients with prostate cancer, one might erroneously infer better survival. This illusory change in prognosis is known as the ‘Will Rogers phenomenon’.

While randomized trials such as the SPCG‐4 represent one of the highest levels of clinical evidence, it is important to keep in mind that these trials have limitations. Given the interval changes in grading criteria for prostatic adenocarcinoma, predicting clinical outcomes based on historical cohorts is rarely as simple as it may seem. While the fundamental conclusions of the SPGC‐4 remain valid, the finding that Gleason grade did not modify the effect of prostatectomy on survival is now less certain. Physicians should therefore use caution when inferring prognosis based on those results.

Cazzaniga et al. should be congratulated for this important work which will help physicians better counsel patients making decisions based on trials like the SPCG‐4.

References

  1. Trinh QD, Cole AP, Dasgupta P. Weighing the evidence from surgical trials. BJU Int 2017; 119: 659–60
  2. Bill‐Axelson A, Holmberg L, Ruutu M et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011; 364: 1708–17
  3. Dalela D, Karabon P, Sammon J et al. Generalizability of the Prostate Cancer Intervention Versus Observation Trial (PIVOT) results to contemporary North American men with prostate cancer. Eur Urol 2017; 71: 511–4
  4. Cazzaniga W, Garmo H, Robinson D, Holmberg L, Bill‐Axelson A, Stattin P. Mortality after radical prostatectomy in a matched contemporary cohort in Sweden compared to the Scandinavian Prostate Cancer Group 4 (SPCG‐4) study. BJU Int 2019; 123: 421–8
  5. Danneman D, Drevin L, Robinson D, Stattin P, Egevad LJ. Gleason inflation 1998–2011: a registry study of 97,168 men. BJU Int 2015; 115: 248–55
  6. Albertsen PC, Hanley JA, Barrows GH et al. Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst 2005; 97: 1248–53C

 

March 2019 – About the cover

 

The Article of the Month for March (Mortality after radical prostatectomy in a matched contemporary cohort in Sweden compared to the Scandinavian Prostate Cancer Group 4 (SPCG-4) study) is from work carried out at Uppsala University in Sweden.

Uppsala University was founded in the 15th century in Sweden’s fourth biggest city, Uppsala. It was the first university in the nordic region and today has over 40 000 students.

March’s cover picture shows Uppsala Cathedral, which was built in 1270. It is open daily and offers tours in English.

 

Article of the week: Does the robot have a role in radical cystectomy?

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

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

If you only have time to read one article this week, we recommend this one.

Does the robot have a role in radical cystectomy?

Read the full article

Abstract

Between 2014 and 2015, 3742 radical cystectomies (RCs) were performed in the UK. The majority of these were open RCs (ORCs), and only 25% were performed with robot assistance. These data contrast starkly with the picture in radical prostatectomy (RP), for which most operations are robot assisted (79.4% of the 7673 in 2016). Given that most pelvic surgeons have access to robotic facilities (as shown by the RP trends) and urologists are typically early adopters, one must question why many surgeons have yet to be convinced by robot‐assisted RC (RARC). This question is particularly perplexing given that RC is a more morbid operation than RP and most patients with bladder cancer are considerably less fit than the average man with prostate cancer, and therefore, reductions in morbidity are especially rewarding in this cohort.

Read more Articles of the week
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