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Editorial: Dropping the GAD – just a fad?

It is not without irony that, at the very moment that the UK’s National Institute for Health and Care Excellence (NICE) is poised to ratify the recommendation that multiparametric MRI (mpMRI) be introduced into the prostate cancer diagnostic pathway, we are seeking to significantly modify the very intervention on which they are about to provide judgement on [1].

The modification proposed is both compelling and plausible, as it renders the process of imaging the prostate in order to detect and localise clinically significant prostate cancer; simpler, quicker, safer and cheaper. It entails dropping the most complex and time‐consuming component of the three multiparametric sequences, the dynamic (time‐dependent) T1‐weighted gadolinium‐enhanced (GAD) sequence. This was a sequence that was, in the early days of MRI, imbued to have biological significance because it was capable of exploiting the differences in the microvascular architecture and function that we have tended to associate with cancer and non‐cancer in order to discriminate between the two. Or so we thought [2].

The systematic review in this issue of the BJUI by Alabousi et al. [3] explores, via the process of systematic review, whether the omission of the T1‐GAD sequence results in any clinically important reduction in test performance when compared with the full sequence scan comprising traditionally of T2, diffusion and T1‐GAD sequences. It did not.

By any stretch this is a tough analysis to pull‐off, as T1‐GAD sequences are not standardised in terms of acquisition or reporting. Every group seems to manage the dynamic images in a different way. As such they tend to suffer from quality control issues, possibly to a greater extent than the T2 and diffusion sequences. The verification of the signal by biopsy strategy and sampling intensity will have varied across studies, as will the threshold of the definition of clinically significant prostate cancer. These inherent methodological problems are all familiar to readers and issues that are pertinent to any imaging study in the detection of prostate cancer. However, there are two issues that make any current assessment of GAD vs no GAD really problematic. The first is the almost exclusive reliance on single‐centre retrospective data. In the few studies that claim a prospective design no comparative data were available. Studies of this type are typical in the early phase of exploring a clinical question and will, in time, be corrected. The other, largely hidden, hardly discussed and truly problematic issue relates to the manner by which we synthesise an overall risk score from the MRI sequences that we derive. The near ubiquitous use of the Prostate Imaging‐Reporting and Data System (PI‐RADS) scoring system introduces a systematic bias by the manner in which a Boolean form of logic is used to decide on the degree of influence that each sequence has in relation to the overall score. According to the manner by which PI‐RADS is applied, it tends to render the T1‐GAD sequence subordinate (only relevant in a minority of cases), contingent (to T2/diffusion) and disparate (dependent on prostate zone) in the way it is invoked [4]. The result is, that within the PIRADS framework, the T1‐GAD sequence is destined to play a relatively small role in driving the overall summary score of risk. It might, therefore, not be too surprising if its removal made little difference to the overall detection of clinically significant prostate cancer.

So what are the next steps? Clearly this is a very important issue and a simpler, quicker, safer and cheaper MRI would be desirable from multiple perspectives. It would render what is currently a complex intervention that comprises an invasive component into a totally passive image acquisition in which no medically trained health professional need be present. It is almost certainly a pre‐requisite for adoption in resource-poor jurisdictions and for entertaining the role of MRI as a primary population‐based screening test.

It took a large number of randomised trials to get mpMRI accepted into the prostate cancer diagnostic pathway. What is the minimum amount of evidence required to disinvest in one of its key components? In other words how many clinically significant cancers would we tolerate missing in order to offer the less complex test?

A direct (head‐to‐head) non‐inferiority randomised comparative study would, following some of our own recent calculations, require >3000 men to participate, which might just prove a little too challenging. An alternative approach is a study in which men would have lesions declared using a Likert score, thereby making no prior assumptions on the role and utility of any single sequence, by traditional mpMRI (standard) but also by a T2‐diffusion MRI (experimental) with appropriate blinding. Some lesions would be private to either standard or experimental imaging but most, it is likely, would be shared. All would require sampling. The yield, the misses, the test accuracy for each approach, could be calculated with necessary adjustments for the inevitable incorporation and verification biases.

It is interesting to observe that in many parts of the world mpMRI was introduced by clinicians before a large body of evidence was accumulated because they felt it was the right thing to do [5]. It may well be the case that ‘dropping the GAD’ will be subject to the same decision‐making process and precede any definitive judgement based on reliable evidence. Recent activity on PubMed would suggest that this might already have happened [6].

References

  1. National Institute for Health and Care Excellence (NICE). Non‐invasive MRI scan for Prostate Cancer recommended by NICE. Available at: https://www.nice.org.uk/news/article/non-invasive-mri-scan-for-prostate-cancer-recommended-by-nice. Accessed May 2019.
  2. Little, RABarjat, HHare, JI et al. Evaluation of dynamic contrast‐enhanced MRI biomarkers for stratified cancer medicine: how do permeability and perfusion vary between human tumours? Magn Reson Imaging 20184698– 105
  3. Alabousi, MSalameh, JPGusenbauer, K et al. Biparametric vs multiparametric prostate magnetic resonance imaging for the detection of prostate cancer in treatment‐naïve patients: a diagnostic test accuracy systematic review and meta‐analysis. BJU Int 2019124209– 20
  4. Turkbey, BRosenkrantz, ABHaider, MA et al. Prostate Imaging reporting and Data System version 2.1: 2019 update of Prostate Imaging Reporting and Data System version 2. Eur Urol 2019 [Epub ahead of print]. https://doi.org/10.1016/j.eururo.2019.02.033
  5. Ahmed, HUKirkham, AArya, M et al. Is it time to consider a role for MRI before prostate biopsy? Nat Rev Clin Oncol 20096197– 20
  6. Xu, MFang, MZou, J et al. Using biparametric MRI radiomics signature to differentiate between benign and malignant prostate lesions. Eur J Radiol 201911438– 44

 

Article of the month: NICE Guidance – Prostate cancer: diagnosis and management

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 month, it should be this one.

NICE Guidance – Prostate cancer: diagnosis and management

Read the full article

Overview

This guideline covers the diagnosis and management of prostate cancer in secondary care, including information on the best way to diagnose and identify different stages of the disease, and how to manage adverse effects of treatment. It also includes recommendations on follow‐up in primary care for people diagnosed with prostate cancer.

Who is it for?

  • Healthcare professionals
  • Commissioners and providers of prostate cancer services
  • People with prostate cancer, their families and carers

Context

Prostate cancer is the most common cancer in men, and the second most common cancer in the UK. In 2014, there were over 46,000 new diagnoses of prostate cancer, which accounts for 13% of all new cancers diagnosed. About 1 in 8 men will get prostate cancer at some point in their life. Prostate cancer can also affect transgender women, as the prostate is usually conserved after gender-confirming surgery, but it is not clear how common it is in this population.

More than 50% of prostate cancer diagnoses in the UK each year are in men aged 70 years and over (2012), and the incidence rate is highest in men aged 90 years and over (2012 to 2014). Out of every 10 prostate cancer cases, 4 are only diagnosed at a late stage in England (2014) and Northern Ireland (2010 to 2014). Incidence rates are projected to rise by 12% between 2014 and 2035 in the UK to 233 cases per 100,000 in 2035.

A total of 84% of men aged 60 to 69 years at diagnosis in 2010/2011 are predicted to survive for 10 or more years after diagnosis. When diagnosed at the earliest stage, virtually all people with prostate cancer survive 5 years or more: this is compared with less than a third of people surviving 5 years or more when diagnosed at the latest stage.

There were approximately 11,000 deaths from prostate cancer in 2014. Mortality rates from prostate cancer are highest in men aged 90 years and over (2012 to 2014). Over the past decade, mortality rates have decreased by more than 13% in the UK. Mortality rates are projected to fall by 16% between 2014 and 2035 to 48 deaths per 100,000 men in 2035.

People of African family origin are at higher risk of prostate cancer (lifetime risk of approximately 1 in 4). Prostate cancer is inversely associated with deprivation, with a higher incidence of cases found in more affluent areas of the UK.

Costs for the inpatient treatment of prostate cancer are predicted to rise to £320.6 million per year in 2020 (from
£276.9 million per year in 2010).

This guidance was updated in 2014 to include several treatments that have been licensed for the management of
hormone-relapsed metastatic prostate cancer since the publication of the original NICE guideline in 2008.
Since the last update in 2014, there have been changes in the way that prostate cancer is diagnosed and treated. Advances in imaging technology, especially multiparametric MRI, have led to changes in practice, and new evidence about some prostate cancer treatments means that some recommendations needed to be updated.

 

Read more Articles of the week
Read more Urology guidelines

 

Editorial: NICE guidelines on prostate cancer 2019

The much‐anticipated National Institute for Health and Care Excellence (NICE) Guidelines are finally published [1] after a period of consultation when they were in the draft phase. These are updated from the previous 2008 and 2014 versions and reflect the changes in our knowledge and practice over the last 10 years. While there are many similarities, the astute reader will find distinct differences from the AUA Guidelines, which feature in a summary booklet released at the #AUA19 meeting in Chicago this spring.

NICE does not comment on screening for prostate cancer so many of us continue to rely on our Guideline of Guidelines [2], which make pragmatic recommendations such as smart screening in well‐informed men who are at higher risk because of their family history. For staging, bone scan has not been replaced by prostate‐specific membrane antigen (PSMA)‐positron‐emission tomography/CT, and Lu‐PSMA theranostics is yet to become an option in castrate‐resistant disease as the international trials are not mature.

Multiparametric MRI before prostate biopsy in men suitable for radical treatment is a new addition, based on the PROMIS [3] and PRECISION trials [1]. This approach is thought to be cost‐effective through reducing the number of biopsies and side effects despite the initial added cost of MRI scanning. In Grade Group 1 and some low‐volume Grade Group 2 cancers, protocol‐based active surveillance is recommended provided the patients are well counselled and it has been discussed by a multidisciplinary team.

To reduce variations in active surveillance, Prostate Cancer UK has carefully examined eight different guidelines and published a consensus statement for the benefit of our patients [4]. We have already promoted this widely on social media and hope that our readers will use this practical tool in their clinics. We often find that some patients just cannot live with a cancer inside their body and seek surgery as a result, however small their tumour. Careful discussion about management options and their risks vs benefits [1] can help patients arrive at a pragmatic decision. The effect of a cancer diagnosis on patients’ minds should therefore not be underestimated and a trained psychologist should be available for appropriate counselling.

NICE also recommends hypofractionated intensity‐modulated radiotherapy, if appropriate, in combination with androgen deprivation therapy (ADT) for localized disease, and methods of decreasing the side effects while increasing accuracy of radiation. As in 2014, robot‐assisted radical prostatectomy remains a surgical option in centres performing at least 150 of these procedures per year [1]. These numbers are similar to those published from other health services such as Canada. One such very high‐volume centre is the Martini Clinic which has reported its comparison of open and robot‐assisted radical prostatectomy in >10 000 patients. The oncological and functional outcomes are no different, open surgery is quicker and there is less blood loss and shorter time to catheter removal after robotic surgery. Just like the randomized trial of the two techniques, this large series highlights that surgeon experience rather than the technique is more important for clinical outcomes [5]. Finally, based on the STAMPEDE results, docetaxel is recommended for metastasis in addition to ADT and can be considered for high‐risk patients receiving ADT and radiotherapy [6]. NICE has also identified a number of important research questions which we hope will be answered by ongoing studies in coming years.

by Prokar Dasgpta, John Davis & Simon Hughes

 

References

  1. NICE GuidanceNICE guidelines prostate cancer. BJU Int 20191249– 26.
  2. Loeb, SReview of prostate cancer screening guidelines. BJU Int 2014114323– 5
  3. Ahmed, HUThe PROMIS of MRI. BJU Int 20161187
  4. Merriel, SWDHetherington, LSeggie, A et al. PCUK consensus statement. BJUI 201912447– 54
  5. Haese, AKnipper, SIsbarn, H et al. A comparative study of robot‐assisted and open radical prostatectomy in 10 790 men treated by highly trained surgeons for both procedures. BJU Int 20191231031– 40
  6. Sathianathen, NJPhilippou, YAKuntz, GM et al. Taxane‐based chemohormonal therapy for metastatic hormone‐sensitive prostate cancer: a Cochrane ReviewBJU Int 2019; [Epub ahead of print]. https://doi.org/10.1111/bju.14711

 

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