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Editorial: The prognostic value of prostate biopsy grade – Forever a product of sampling

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The ability to project clinical outcomes based on limited data is crucial to the practice of medicine. This principle is particularly germane to the management of prostate cancer, where clinical outcomes vary widely. In the current issue of BJUI, Danneman et al. [1] assess pathological grade concordance between diagnostic needle biopsy and subsequent radical prostatectomy specimens from 2000 to 2012. The authors observed increased concordance of biopsy and prostatectomy Gleason scores over the time period (from 55% in 2000 to 68% in 2012) with the majority of improvement occurring before 2005. Interestingly, concordance decreased over time (from 68 to 57%) with use of the newly revised grading system. These and other findings led to the proposal that increased concordance was attributable more to the elimination of Gleason scores 2–5 than the systematic change in grading itself.

We commend the authors for exploring this important topic. Our ability to derive meaningful information on disease biology and behaviour from biopsy specimens is essential to counselling patients on the many available management options. At the same time, biopsy grading is inherently limited in its ability to predict overall prostate pathology because it is not only dependent on architecture and morphology, but also on the, admittedly minimal, sample of tissue obtained. As such, we should be cautious in using terms such as ‘undergrading’ in describing biopsy specimens, which may have been properly graded, but simply lacked the higher grade tumour observed at prostatectomy. In reality, such a phenomenon represents undersampling rather than undergrading, and there is hope that such undersampling will decrease with improved methods of detection, such as multiparametric MRI/TRUS fusion-guided biopsy.

Notably, the authors refer to the updated grading system, which was first described by Dr Epstein and validated in a multi-institutional study [2] before the 2014 International Society of Urological Pathology (ISUP) consensus conference, as ISUP grades 1–5. For clarity, it should be noted that the initial report and validation of the new system [2], the 2014 ISUP consensus conference proceedings [3] and the WHO 2016 edition of Pathology and Genetics: Tumours of the Urinary System and Male Genital Organs [4], have all described the new system based on grade groups 1–5. Consistent use of the adopted terminology will be helpful moving forward.

Nonetheless, there are several potential explanations for the patterns observed in the present study. As the authors note, lower concordance based on the grade group system can be largely explained by the more precise classification of Gleason score 7 cancers. Based on evidence of disparate outcomes in Gleason score 3+4 = 7 and 4+3 = 7 disease [5], the ISUP system distinctly classifies these cancers as prognostic grades 2 and 3, respectively. Certainly, when compared with a system in which Gleason score 7 represents a single classification, one would expect poorer concordance in the more widely distributed group. We believe the clinical utility of separating these classifications far outweighs a modest decrease in concordance, which may be explained by other factors in any case. Previous studies have shown the importance of subdividing the Gleason score 7 population when comparing grading systems [6]. Furthermore, details are not provided as to whether a global grade was assigned to biopsy, a common practice in Sweden, which is not the currently recommended practice. That 5–7% of specimens received a Gleason score < 6 calls into question whether contemporary recommendations were fully adopted during the study period.

Regardless, Danneman et al. elegantly highlight the frequency with which biopsy and prostatectomy grades are discordant, and the fact that, to date, pathological grading remains a subjective practice. As noted, there are widespread efforts to address both of these issues, including the use of targeted biopsies and tissue-based genomic markers. Until these practices are well-validated and widely implemented, there are several reasons to believe the most recent grade group system will improve contemporary practice, despite limited concordance. For one, use of a more intuitive scale ranging from 1 to 5 should prove easier for patients to understand, a significant consideration in light of the information overload patients absorb with a new diagnosis of cancer. Furthermore, available data to this point demonstrate excellent prognostic value. In one study from Johns Hopkins, the revised Grade Group system showed improved accuracy for predicting 5-year metastasis (C-index 0.80 vs 0.70) and 10-year prostate cancer-specific mortality (C-index 0.77 vs 0.64) as compared with the original Gleason score [7].

Until truly objective methods of pathological assessment emerge, additional validation of the new grade group system is likely to further support its use moving forward. As Danneman et al. point out, however, we must keep in mind that biopsy, although perhaps our most useful tool, captures only a small fraction of the overall picture.

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Jeffrey J. Tosoian* and Jonathan I. Epstein*,†,‡ *James Buchanan

 

Brady Urological Institute and Department of Urology, †Department of Pathology, Johns Hopkins University School of Medicine, and ‡Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

 

References

 

1 Danneman D, Drevin L, Delahunt B et al. Accuracy of prostate biopsies for predicting Gleason score in radical prostatectomy specimens: nationwide trends 2000–2012. BJU Int 2017; 119: 50–6

 

2 Pierorazio PM, Walsh PC, Partin AW, Epstein JI. Prognostic gleason grade grouping: data based on the modified gleason scoring system. BJU Int 2013; 111: 753–60

 

3 Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA. The 2014 international society of urological pathology (isup) consensus conference on gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol 2016; 40:244–52

 

4 Moch H, Humphrey P, Ulbright T, Reuter V. WHO classification of tumours: pathology and genetics.Tumours of the Urinary and Male Reproductive System. Lyon, France:IARC Press; 2016.

 

5 Eggener SE, Scardino PT, Walsh PC et al. Predicting 15-year prostate cancer specific mortality after radical prostatectomy. J Urol 2011; 185: 869–75

 

6 Lee MC, Dong F, Stephenson AJ, Jones JS, Magi-Galluzzi C, Klein EA. The Epstein criteria predict for organ-confined but not insignificant disease and a high likelihood of cure at radical prostatectomy. Eur. Urol 2010; 58: 90–5

 

7 Faraj SF, Bezerra SM, Yousefi K et al. Clinical validation of the 2005 ISUP gleason grading system in a cohort of intermediate and high risk men undergoing radical prostatectomy. PLoS One 2016; 11: e0146189

 

Article of the Week: Detecting PSMs – using LRS on ex vivo RP specimens

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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 accompanying editorial written by a prominent member of the urological community. This blog is 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.

Detecting positive surgical margins: utilisation of light-reflectance spectroscopy on ex vivo prostate specimens

Aaron H. Lay*, Xinlong Wang†, Monica S. C. Morgan*, Payal Kapur‡, Hanli Liu†,Claus G. Roehrborn* and Jeffrey A. Cadeddu*

 

*Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, †Department of Bioengineering, University of Texas at Arlington, Arlington, TX, and ‡Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

 

Read the full article

Abstract

Objective

To assess the efficacy of light-reflectance spectroscopy (LRS) to detect positive surgical margins (PSMs) on ex vivo radical prostatectomy (RP) specimens.

Materials and Methods

A prospective evaluation of ex vivo RP specimens using LRS was performed at a single institution from June 2013 to September 2014. LRS measurements were performed on selected sites on the prostate capsule, marked with ink, and correlated with pathological analysis. Significant features on LRS curves differentiating malignant tissue from benign tissue were determined using a forward sequential selection algorithm. A logistic regression model was built and randomised cross-validation was performed. The sensitivity, specificity, accuracy, negative predictive value (NPV), positive predictive value (PPV), and area under the receiver operating characteristic curve (AUC) for LRS predicting PSM were calculated.

aotwdec-4-results

Results

In all, 50 RP specimens were evaluated using LRS. The LRS sensitivity for Gleason score ≥7 PSMs was 91.3%, specificity 92.8%, accuracy 92.5%, PPV 73.2%, NPV 99.4%, and the AUC was 0.960. The LRS sensitivity for Gleason score ≥6 PSMs was 65.5%, specificity 88.1%, accuracy 83.3%, PPV 66.2%, NPV 90.7%, and the AUC was 0.858.

Conclusions

LRS can reliably detect PSMs for Gleason score ≥7 prostate cancer in ex vivo RP specimens

Read more articles of the week

Editorial: Light reflectance spectroscopy is one more emerging technique with the potential to adjust excision limits during radical prostatectomy

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In this issue of BJUI, Lay et al. [1] report that light reflectance spectroscopy (LRS) can detect Gleason ≥7 positive surgical margins (PSMs) with 92.5% accuracy. In this initial study, the authors have reported the use of LRS in an ex situ setting to analyse the prostate surface; however, this technology could ultimately be developed to identify PSMs before choosing the surgical plane of dissection, which could allow the surgeon to immediately perform a wider complementary excision.

As long as PSMs are detected ex situ, it is not clear why spectroscopy should be preferred to frozen sections. NeuroSAFE, for example, is a standardized and validated margin evaluation procedure in pathology [2]. It does not lengthen operating time, does not require any new equipment and provides a pathological assessment which is the best level of evidence for PSM status; however, as a conventional pathological procedure, it is not conceivable in situ, and real-time detection of PSMs that ensures the safest oncological resection during a nerve-sparing dissection is needed.

In this effort to examine in vivo/in situ prostate PSMs, several other technologies can be considered. During radical prostatectomy, optical coherence tomography (OCT) has been used in situ in humans, but only to identify the neurovascular bundles [3]. Field of view and depth of penetration were limited and OCT has never been evaluated in situ for prostate PSM detection. Confocal endomicroscopy has recently been reported during robot-assisted radical prostatectomy [4]. With this technique, optical biopsies were feasible in situ but the PSM detection rate and the overall efficiency of this confocal endomicroscopy in prostate specimens remain unknown. Similarly, illumination microscopy has been used to generate gigapixel images of the full prostate circumference in vivo for the detection of PSMs [5]. Illumination microscopy allows images to be interpreted readily by pathologists, but the feasibility series was too small to assess the accuracy of this technique for PSM detection. Ex situ multi-photon microscopy (MPM) is an optical technique that enables the imaging of prostatic and periprostatic tissue at sub-micron resolution to a depth of up to 0.5 mm [6]. On a fresh specimen, it generates three-dimensional images of periprostatic nerves, blood vessels and capsule, but also underlying acini and pathological changes such as prostate cancer. MPM technology has also been miniaturized and its accuracy in situ is currently under investigation.

In this context, the study by Lay et al. [1] shows that, for the time being, LRS is one more promising technique on the road to real-time PSM detection. More will undoubtedly be done to overcome the spectroscope’s light absorption in the presence of blood and, subsequently, to evaluate its reliability in situ; however, the recent developments of these protocols and technologies (endomicroscopy, illumination microscopy, OCT, MPM, LRS) show a progressive effort amongst clinicians to obtain intra-operative feedback on the PSM status. Fortunately, this is taking place while the urological community is increasingly considering surgical treatment even for the high-risk disease, where oncological adequacy is of paramount importance. While we are witnessing these promising evolutions in high-grade prostate cancer, the optimum technique which will safely end margin-blind radical prostatectomy in an actual surgical field (filled with blood and often distorted because of inflammation) still needs to go through clinical trials and validation; however, the future is bright as a result of these newer developments.

Read the full article
Thomas Bessede*†‡ and Ash Tewari*

 

*Department of Urology, Icahn School of Medicine at Mount Sinai, New York , NY, USA, †U1195, INSERM, Universite Paris-Saclay, and ‡Department of Urology, APHP, Hopitaux Universitaires Paris-Sud, Le Kremlin-Bicetre, France

 

References

 

1 Lay AH, Wang X, Morgan MSC et al. Detecting positive surgical margins: utilisation of light-reflectance spectroscopy on ex vivo prostate specimens. BJU Int 2016; 118: 885–9

 

2 Beyer B, Schlomm T, Tennstedt P et al. A feasible and time-efficient adaptation of NeuroSAFE for da Vinci robot-assisted radical prostatectomy. Eur Urol 2014; 66: 138–44

 

3 Aron M, Kaouk JH, Hegarty NJ et al. Second prize: preliminary experience with the Niris optical coherence tomography system during laparoscopic and robotic prostatectomy. J Endourol 2007; 21: 814–8

 

4 Lopez A, Zlatev DV, Mach KE et al. Intraoperative optical biopsy during robotic assisted radical prostatectomy using confocal endomicroscopy. J Urol 2016; 195: 1110–7

 

5 Wang M, Tulman DB, Sholl AB et al. Gigapixel surface imaging ofradical prostatectomy specimens for comprehensive detection of cancer-positive surgical margins using structured illumination microscopy. Sci Rep 2016; 6: 27419

 

6 Tewari AK, Shevchuk MM, Sterling J et al. Multiphoton microscopy for structure identification in human prostate and periprostatic tissue: implications in prostate cancer surgery. BJU Int 2011; 108: 1421–9

 

Article of the Week: Co-introduction of a steroid with docetaxel chemotherapy for metastatic castration-resistant PCa affects PSA flare

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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 accompanying editorial written by a prominent member of the urological community. This blog is 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.

Co-introduction of a steroid with docetaxel chemotherapy for metastatic castration-resistant prostate cancer affects PSA flare

Masaki Shiota*, Akira Yokomizo*, Ario Takeuchi*, Keijiro Kiyoshim a*,Junichi Inokuchi*, Katsunori Tatsugami*, Ken-ichiro Shiga†, Hirofumi Koga†, Akito Yamaguchi†, Seiji Naito† and Masatoshi Eto*
*Department of Urology, Graduate School of Medical Sciences, Kyushu University, and †Division of Urology, Harasanshin Hospital, Fukuoka, Japan
Read the full article

Abstract

Objective

To investigate the potential relationship of steroid usage with prostate-specific antigen (PSA) flare as well as the prognostic impact of PSA flare, which is known to occur in 10–20% of patients with metastatic castration-resistant prostate cancer during docetaxel chemotherapy. In the world of fat-burners, Clenbuterol has a place of importance among bodybuilders and others. Several athletes also utilize the drug for its long list of potential benefits. While great care should be taken with something like this, there are nonetheless some advantages that should be considered. For example, understand that Clenbuterol is not a steroid, Red Thai Kratom is one of the most widely used for beginners.

Patients and Methods

This study included 71 patients with metastatic castration-resistant prostate cancer treated by docetaxel chemotherapy with co-introduction of a steroid. PSA flare was defined as a transient PSA increase followed by a PSA decrease.

aotwdec2-results

Results

PSA flare was recognized in 7.0–23.9% of patients according to the definition used. Intriguingly, men with steroid intake before the initiation of docetaxel chemotherapy experienced significantly fewer PSA flares. The progression-free survival rate in men with PSA flare was equivalent to that of PSA responders, but significantly better than men with PSA failure.

Conclusions

Our results suggest that de novo steroid co-introduction with docetaxel chemotherapy induces the PSA flare phenomenon. This novel finding may account for the mechanism of PSA flare as well as being valuable for distinguishing PSA elevation attributable to PSA flare from that attributable to PSA failure.

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Editorial: What is behind the flare phenomenon?

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In the present issue of BJUI, Shiota et al. [1] propose a potential explanation for the PSA ‘flare’ observed in many patients as they initiate docetaxel chemotherapy. The PSA flare or ‘surge’ phenomenon has been noted for years, and may affect up to one-fifth of patients treated with docetaxel. Multiple reviews have concluded that the development of flare does not influence disease-specific outcomes [2, 3], which is further supported by the present paper [1]. However, there are no pragmatic analyses of how this flare is interpreted in real-world practice. As treatment of prostate cancer becomes more complex, and definitions of progression on treatment continue to evolve, practitioners must be aware of this laboratory pattern to avoid unnecessary discontinuation of therapy based on early PSA change alone.

The cause of such flare has only been postulated. Many suggest that it could be caused by PSA release from lysed cells or by aberrant androgen receptor (AR) activation, but other theories are also proposed. The present paper supports the hypothesis that transactivation of the AR by corticosteroids contributes to the flare. Further translational work may provide additional insight into this mechanism, but we have long discussed the influence of steroid administration on the AR. Similar flare phenomena have been observed with cabazitaxel [4] and abiraterone acetate, two regimens that are reliant on concomitant steroid use. Interestingly, patients in the present cohort treated with steroids before treatment initiation had less flare. This is a unique observation in that steroid activation may occur, but at an earlier time point, mitigating the coincidental rise when starting chemotherapy. Just as one must be aware of the existence of flare to avoid premature abandonment of a regimen, perhaps we now must take into account previous steroid use and interpret a PSA rise slightly differently. The present work is certainly hypothesis-generating and larger series may offer additional insight.

Recent data have shown significant survival gains using docetaxel in the hormone-sensitive metastatic setting, in which patients received chemotherapy without daily prednisone use [5]. Practitioners may find themselves managing patients on docetaxel chemotherapy who may or may not be taking corticosteroids. These recent data will probably also contribute to a ‘resurgence’ of sorts in the use of chemotherapy, and remembrance of the flare is important. We may find ourselves interpreting PSA flare in multiple steps: we will assess the agent (i.e. a taxane) and the use of prednisone (i.e. present prior to treatment or initiated at the start) and then interpret the results accordingly. The work of Shiota et al. in this observational study continues to highlight the flare phenomenon and the fact that the use of steroids before, or during, chemotherapy may further complicate our approach to the care of patients on chemotherapy. The field is moving forward and, as we work to understand the intricacies of PSA response, we also create more and more reliance on providers to really marry the art and science of medicine.

Read the full article

 

Elizabeth R. Kessler

 

Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

 

References

 

1 Shiota M, Yokomizo A, Takeuchi A et al. Co-introduction of a steroid with docetaxel chemotherapy for metastatic castration-resistant prostate cancer affects PSA flare. BJU Int 2016; 118: 880–4

 

2 Sella A, Sternberg CN, Skoneczna I, Kovel S. Prostate-specific antigen flare phenomenon with docetaxel-based chemotherapy in patients with androgen-independent prostate cancer. BJU Int 2008; 102: 1607–9

 

3 Nelius T, Klatte T, de Riese W, Filleur S. Impact of PSA flare-up in patients with hormone-refractory prostate cancer undergoing chemotherapy. Int Urol Nephrol 2008; 40: 97–104

 

4 Angelergues A, Maillet D, Flechon A et al. Prostate-specific antigen flare induced by cabazitaxel-based chemotherapy in patients with metastatic castration-resistant prostate cancer. Eur J Cancer 2014; 50: 1602–9

 

5 Sweeney CJ, Chen YH, Carducci M et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015; 373: 737–46

 

Article of the Month: PROMs in the ProtecT trial of PCa treatments

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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 accompanying editorial written by a prominent member of the urological community. This blog is 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.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video discussing the paper.

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

Patient-reported outcomes in the ProtecT randomized trial of clinically localized prostate cancer treatments: study design, and baseline urinary, bowel and sexual function and quality of life

Athene Lane*,†, Chris Metcalfe*,†, Grace J. Young*,†, Tim J. Peters‡,§, Jane Blazeby*, Kerry N. L. Avery*, Daniel Dedman, Liz Down*, Malcolm D. Mason**, David E. Neal††, Freddie C. Hamdy†† and Jenny L. Donovan*,§ for the ProtecT Study group

 

*School of Social and Community Medicine, University of Bristol, Bristol, †Bristol Randomised Trials Collaboration, University of Bristol, Bristol, ‡School of Clinical Sciences, University of Bristol, Bristol, §Collaboration for Leadership in Applied Health Research and Care West, United Hospitals Bristol, Bristol, Clinical Practice Research Datalink Group, Medicines and Healthcare Products Regulatory Agency, London, **School of Medicine, Cardiff University, Cardiff, and ††Nuffield Department of Surgery, University of Oxford, Oxford, UK
Read the full article

Objectives

To present the baseline patient-reported outcome measures (PROMs) in the Prostate Testing for Cancer and Treatment (ProtecT) randomized trial comparing active monitoring, radical prostatectomy and external-beam conformal radiotherapy for localized prostate cancer and to compare results with other populations.

Materials and Methods

A total of 1643 randomized men, aged 50–69 years and diagnosed with clinically localized disease identified by prostate-specific antigen (PSA) testing, in nine UK cities in the period 1999–2009 were included. Validated PROMs for disease-specific (urinary, bowel and sexual function) and condition-specific impact on quality of life (Expanded Prostate Index Composite [EPIC], 2005 onwards; International Consultation on Incontinence Questionnaire-Urinary Incontinence [ICIQ-UI], 2001 onwards; the International Continence Society short-form male survey [ICSmaleSF]; anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), generic mental and physical health (12-item short-form health survey [SF-12]; EuroQol quality-of-life survey, the EQ-5D-3L) were assessed at prostate biopsy clinics before randomization. Descriptive statistics are presented by treatment allocation and by men’s age at biopsy and PSA testing time points for selected measures.

aotmdec1

Results

A total of 1438 participants completed biopsy questionnaires (88%) and 77–88% of these were analysed for individual PROMs. Fewer than 1% of participants were using pads daily (5/754). Storage lower urinary tract symptoms were frequent (e.g. nocturia 22%, 312/1423). Bowel symptoms were rare, except for loose stools (16%, 118/754). One third of participants reported erectile dysfunction (241/735) and for 16% (118/731) this was a moderate or large problem. Depression was infrequent (80/1399, 6%) but 20% of participants (278/1403) reported anxiety. Sexual function and bother were markedly worse in older men (65–70 years), whilst urinary bother and physical health were somewhat worse than in younger men (49–54 years, all P < 0.001). Bowel health, urinary function and depression were unaltered by age, whilst mental health and anxiety were better in older men (P < 0.001). Only minor differences existed in mental or physical health, anxiety and depression between PSA testing and biopsy assessments.

Conclusion

The ProtecT trial baseline PROMs response rates were high. Symptom frequencies and generic quality of life were similar to those observed in populations screened for prostate cancer and control subjects without cancer.

Read more articles of the week

Editorial: ‘Killing Two Birds With One Stone’ – PROMS from the ProtecT Trial

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Very few areas of medicine generate more controversy than the management of clinically localised prostate cancer. This is in large part due to the somewhat conflicting nature of the scant level I evidence that exists on the subject. Whereas the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) demonstrated a clinically meaningful and durable survival advantage for surgery when compared to watchful waiting in a predominantly White Scandinavian population of patients with clinically palpable yet localised prostate cancer [1], the Radical Prostatectomy Versus Observation for Localized Prostate Cancer (PIVOT) trial reported a mostly null effect of surgery in a predominantly older, less healthy population of American patients with clinically indolent disease [2]. Neither trial addresses the effect of radiotherapy on prostate cancer survival and both may lack relevance in contemporary prostate cancer practice.

For these reasons and a myriad of others, the medical community eagerly awaits the results of the Prostate Testing for Cancer and Treatment (ProtecT) trial [3]. With a fastidiously designed protocol that involves 337 primary care centres across nine cities in the UK, the use of dedicated study nurses, the successful enrolment of pre-specified sample size targets, and the inclusion of patient-reported quality-of-life measures, the ProtecT trial is poised to make enormous inroads for men with prostate cancer and the providers who care for them.

In this issue of the BJUI, the investigators from the ProtecT trial publish baseline patient-reported outcome measures (PROMs) from the ProtecT trial [4]. While others have previously reported baseline PROMs in large comparative effectiveness studies [5], the findings from this study are notable for several reasons. First, this is the first randomised trial comparing the effect of surgery, radiation, and active monitoring on PROMs. While several high-quality prospective observational cohort studies have reported long-term quality-of-life outcomes after prostate cancer treatment [6, 7], ProtecT will offer randomised comparisons that minimise confounding and selection bias from the outset. Second, the ProtecT trial will not only measure disease-specific health-related quality of life through the use of psychometrically validated survey instruments, such as the Expanded Prostate Index Composite, but also general health-related quality of life through the use of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C-30 (as well as depression and anxiety through the use of the Hospital Anxiety and Depression Scale). Finally, and perhaps most importantly, the investigators collected baseline PROMs at the time of the first biopsy before cancer diagnosis, which will offer distinct advantages when modelling patient-reported function over time, as well as avoiding recall bias associated with retrospective collection of baseline patient-reported outcomes.

In the absence of the long-term survival data from randomised trials comparing surgery and radiation, previous studies have rightly focused on understanding how the effect of prostate cancer treatments differ with respect to PROMs. With the ProtecT trial, we will not only start to have answers to longstanding questions about how surgery, radiation and active surveillance compare with respect to clinical outcomes, such as survival and cancer control, but also with respect to PROMs. By addressing both of these domains, the ProtecT investigators are in position to ‘kill two birds with one stone’ and in so doing will undoubtedly make large strides in facilitating data-driven decision-making for patients with prostate cancer worldwide.

Read the full article
Mark D. Tyson* and David F. Penson*,†,‡

 

Departments of *Urologic Surgery and †Health Policy, Vanderbilt University Medical Center, and‡ Geriatric, Research, and Educational Center, Veterans Affairs Tennessee Valley Health Care System, Nashville, TN, USA

 

References

 

1 Bill-Axelson A, Holmberg L, Garmo H et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 2014; 370: 932–42

 

2 Wilt TJ, Brawer MK, Jones KM et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367: 203–13

 

3 Lane JA, Donovan JL, Davis M et al. Active monitoring, radical prostatectomy, or radiotherapy for localised prostate cancer: study design and diagnostic and baseline results of the ProtecT randomised phase 3 trial. Lancet Oncol 2014; 15: 1109–18

 

4 Lane A, Metcalfe C, Young GJ et al. Patient-reported outcomes in the ProtecT randomized trial of clinically localized prostate cancer treatments: study design, and baseline urinary, bowel and sexual function and quality of life. BJU Int 2016; 118: 869–79

 

5 Resnick MJ, Barocas DA, Morgans AK et al. Contemporary prevalence of pretreatment urinary, sexual, hormonal, and bowel dysfunction: defining the population at risk for harms of prostate cancer treatment. Cancer 2014; 120: 1263–71

 

6 Sanda MG, Dunn RL, Michalski J et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008; 358: 1250–61

 

7 Resnick MJ, Koyama T, Fan KH et al. Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med 2013; 368: 436–45

 

Video: PROMs in the ProtecT trial of PCa treatments

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Patient-reported outcomes in the ProtecT randomized trial of clinically localized prostate cancer treatments: study design, and baseline urinary, bowel and sexual function and quality of life

Athene Lane*,†, Chris Metcalfe*,†, Grace J. Young*,†, Tim J. Peters‡,§, Jane Blazeby*, Kerry N. L. Avery*, Daniel Dedman, Liz Down*, Malcolm D. Mason**, David E. Neal††, Freddie C. Hamdy†† and Jenny L. Donovan*,§ for the ProtecT Study group

 

*School of Social and Community Medicine, University of Bristol, Bristol, †Bristol Randomised Trials Collaboration, University of Bristol, Bristol, ‡School of Clinical Sciences, University of Bristol, Bristol, §Collaboration for Leadership in Applied Health Research and Care West, United Hospitals Bristol, Bristol, Clinical Practice Research Datalink Group, Medicines and Healthcare Products Regulatory Agency, London, **School of Medicine, Cardiff University, Cardiff, and ††Nuffield Department of Surgery, University of Oxford, Oxford, UK
Read the full article

Objectives

To present the baseline patient-reported outcome measures (PROMs) in the Prostate Testing for Cancer and Treatment (ProtecT) randomized trial comparing active monitoring, radical prostatectomy and external-beam conformal radiotherapy for localized prostate cancer and to compare results with other populations.

Materials and Methods

A total of 1643 randomized men, aged 50–69 years and diagnosed with clinically localized disease identified by prostate-specific antigen (PSA) testing, in nine UK cities in the period 1999–2009 were included. Validated PROMs for disease-specific (urinary, bowel and sexual function) and condition-specific impact on quality of life (Expanded Prostate Index Composite [EPIC], 2005 onwards; International Consultation on Incontinence Questionnaire-Urinary Incontinence [ICIQ-UI], 2001 onwards; the International Continence Society short-form male survey [ICSmaleSF]; anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), generic mental and physical health (12-item short-form health survey [SF-12]; EuroQol quality-of-life survey, the EQ-5D-3L) were assessed at prostate biopsy clinics before randomization. Descriptive statistics are presented by treatment allocation and by men’s age at biopsy and PSA testing time points for selected measures.

aotmdec1

Results

A total of 1438 participants completed biopsy questionnaires (88%) and 77–88% of these were analysed for individual PROMs. Fewer than 1% of participants were using pads daily (5/754). Storage lower urinary tract symptoms were frequent (e.g. nocturia 22%, 312/1423). Bowel symptoms were rare, except for loose stools (16%, 118/754). One third of participants reported erectile dysfunction (241/735) and for 16% (118/731) this was a moderate or large problem. Depression was infrequent (80/1399, 6%) but 20% of participants (278/1403) reported anxiety. Sexual function and bother were markedly worse in older men (65–70 years), whilst urinary bother and physical health were somewhat worse than in younger men (49–54 years, all P < 0.001). Bowel health, urinary function and depression were unaltered by age, whilst mental health and anxiety were better in older men (P < 0.001). Only minor differences existed in mental or physical health, anxiety and depression between PSA testing and biopsy assessments.

Conclusion

The ProtecT trial baseline PROMs response rates were high. Symptom frequencies and generic quality of life were similar to those observed in populations screened for prostate cancer and control subjects without cancer.

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Article of the Week: High PCA3 score, PI-RADS grade and Gleason score in patients with elevated PSA undergoing MRI/US fusion TBx

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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 accompanying editorial written by a prominent member of the urological community. This blog is 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.

High prostate cancer gene 3 (PCA3) scores are associated with elevated Prostate Imaging Reporting and Data System (PI-RADS) grade and biopsy Gleason score, at magnetic resonance imaging/ultrasonography fusion software-based targeted prostate biopsy after a previous negative standard biopsy

Stefano De Luca*, Roberto Passera†, Giovanni Cattaneo*, Matteo Manfredi*, Fabrizio Mele*, Cristian Fiori*, Enrico Bollito‡, Stefano Cirillo§ and Francesco Porpiglia*

 

*Departments of Urology, San Luigi Gonzaga Hospital, University of Torino, Orbassano, †Nuclear Medicine, San Giovanni Battista Hospital, University of Torino, Torino, ‡Pathology, San Luigi Gonzaga Hospital, University of Torino, Orbassano, and §Department of Radiology, Mauriziano Hospital, Torino, Italy

 

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Objective

To determine the association among prostate cancer gene 3 (PCA3) score, Prostate Imaging Reporting and Data System (PI-RADS) grade and Gleason score, in a cohort of patients with elevated prostate-specific antigen (PSA), undergoing magnetic resonance imaging/ultrasonography fusion software-based targeted prostate biopsy (TBx) after a previous negative randomised ‘standard’ biopsy (SBx).

Patients and Methods

In all, 282 patients who underwent TBx after previous negative SBx and a PCA3 urine assay, were enrolled. The associations between PCA3 score/PI-RADS and PCA3 score/Gleason score were investigated by K-means clustering, a receiver operating characteristic analysis and binary logistic regression.

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Results

The PCA3 score difference for the negative vs positive TBx cohorts was highly statistically significant. A 1-unit increase in the PCA3 score was associated to a 2.4% increased risk of having a positive TBx result. A PCA3 score of >80 and a PI-RADS grade of ≥4 were independent predictors of a positive TBx. The association between the PCA3 score and PI-RADS grade was statistically significant (the median PCA3 score for PI-RADS grade groups 3, 4, and 5 was 58, 104, and 146, respectively; P = 0.006). A similar pattern was detected for the relationship between the PCA3 score and Gleason score; an increasing PCA3 score was associated with a worsening Gleason score (median PCA3 score equal to 62, 105, 132, 153, 203, and 322 for Gleason Score 3+4, 4+3, 4+4, 4+5, 5+4, and 5+5, respectively; P < 0.001).

Conclusion

TBx improved PCA3 score diagnostic and prognostic performance for prostate cancer. The PCA3 score was directly associated both with biopsy Gleason score and PI-RADS grade: notably, in the ‘indeterminate’ PI-RADS grade 3 subgroup.

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Editorial: PCA3 assay in the MRI/US fusion TBx era: a future to believe in

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Men with persistently elevated serum PSA levels after a negative first TRUS-guided systematic prostate biopsy (SBx) represent a great diagnostic challenge. To meet this challenge, urologists need new imaging methods and biomarkers for use in daily clinical practice. The study by De Luca et al. [1] in the present issue of BJUI contributes further data to a growing body of literature addressing the role of prostate cancer gene 3 (PCA3) score and MRI/ultrasonography fusion-targeted prostate biopsy (TBx) in the detection of prostate cancer (PCa) in men who had undergone a previous negative SBx.

De Luca et al. retrospectively analysed data from 282 men undergoing a TBx after a previous negative SBx and PCA3 urine assay for an ongoing suspicion of PCa. They found that the PCA3 score was significantly higher in patients with a positive TBx as compared to those with a negative TBx (121 vs 56; P < 0.001). Futhermore, PCA3 was significantly associated with Prostate Imaging Reporting and Data System (PI-RADS) group (The median PCA3 scores for PI-RADS groups 3, 4 and 5 were 58, 104 and 146, respectively; P = 0.006). Similarly, an increasing PCA3 score was associated with a worse Gleason score (GS) after TBx. These findings are not necessarily novel, but rather are consistent with some of the previous literature [2, 3]. Conversely, Kaufmann et al. [4] did not find any association between PCA3 score and either PI-RADS group or GS. Importantly from a clinical perspective, the authors of the present study observed a statistically significant association between PCA3 score and the ‘indeterminate’ PI-RADS grade III subgroup, thus allowing for the possibility that the combined use of these two diagnostic tools could prevent unnecessary biopsies.

Prostate biopsies are associated with discomfort, anxiety and severe complications. Repeated SBx also results in a greater economic cost and has been associated with overall low PCa detection rates (being negative in almost 80% of examined men). The recent literature has therefore focused on additional tests with the goal of preventing unnecessary biopsies and increasing the probability of detecting PCa during a repeat biopsy. Since its introduction in clinical practice, the urinary PCA3 assay has shown promising results for PCa detection, staging and prognosis; however, recent studies have shown high variability in PCA3 sensitivity and specificity, which can be explained by the low diagnostic performance of SBx in detecting PCa. MRI-guided TBx has shown higher detection rates than SBx and thus could be of clinical utility in improving PCA3 prognostic accuracy in detecting PCa in men with previous negative SBx. De Luca et al. [1], using a univariate logistic regression model to estimate the effect of PCA3 score on TBx results, found that a 1-unit increase in PCA3 score was associated with a 2.4% increase in the odds of having a positive TBx result (odds ratio [OR] 1.024; P < 0.001). The accuracy of this model was 76.2%, with a sensitivity of 82.3% and specificity of 68.5%. A multivariate logistic regression model showed that PI-RADS group ≥4 (OR 10.85) and a PCA3 score >80 (OR 7.17) were independent risk factors for a positive TBx (all P < 0.001). The authors concluded that TBx improved the diagnostic and prognostic performance of the PCA3 score for PCa. Importantly, considering only the ‘indeterminate’ PI-RADS grade III subgroup, a 1-unit increase in PCA3 score was associated with a 2.2% increase in the odds of having a positive TBx (OR 1.022; P < 0.001). These findings are consistent with recent literature showing that the use of multiparametric (mp)MRI to direct biopsies can significantly improve PCA3 score sensitivity [5]. Similarly, Busetto et al. [2] estimated the sensitivity and specificity for PCA3 test and mpMRI to be 68 and 49%, and 74 and 90%, respectively, for cancer detection after an initial negative biopsy, and concluded that mpMRI increased PCA3 score test accuracy.

Repeated prostate biopsy strategies for the suspicion of PCa remain one of the most controversial dilemmas in urology. The results of the present trial help strengthen the evidence in favour of the diagnostic role of the PCA3 score, which could aid the selection of patients for mpMRI. Large prospective trials are needed to confirm the association between PCA3, PI-RADS group and GS in men with PCa. Interestingly, De Luca et al. believe that PCA3 score could be part of a ‘fusion-biopsy era’ in the not-so-distant future. Should the positive correlation between PCA3 and GS be confirmed, PCA3 could have a role in the selection of candidates for active surveillance, and in predicting disease progression during active surveillance follow-up.

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Bernardo Rocco*† and Luca Boeri*

 

*Department of Urology, University of Milan Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Milan, Italy and †Urology, Global Robotics Institute, Florida Hospital Celebration Health, Celebration, FL, USA

 

References

 

1 De Luca S, Passera R, Cattaneo G et al. High prostate cancer gene 3 (PCA3) scores are associated with elevated Prostate Imaging Reporting and Data System (PI-RADS) grade and biopsy Gleason Score, at magnetic resonance imaging/ultrasonography fusion software-based targeted prostate biopsy after a previous negative standard biopsy. BJU Int 2016; 118: 723–30

 

2 Busetto GM, De Berardinis E, Sciarra A et al. Prostate cancer gene 3 and multiparametric magnetic resonance can reduce unnecessary biopsies: decision curve analysis to evaluate predictive models. Urology 2013; 82: 1355–60

 

3 De Luca S, Passera R, Bollito E et al. Biopsy and radical prostatectomy pathological patterns influence Prostate cancer gene 3 (PCA3) score. Anticancer Res 2013; 33: 4657–62

 

4 Kaufmann S, Bedke J, Gatidis S et al. Prostate cancer gene 3 (PCA3) is of additional predictive value in patients with PI-RADS grade III (intermediate) lesions in the MR-guided re-biopsy setting for prostate cancer. World J Urol 2016; 34: 509–15

 

5 Sciarra A, Panebianco V, Cattarino S et al. Multiparametric magnetic resonance imaging of the prostate can improve the predictive value of the urinary prostate cancer antigen 3 test in patients with elevated prostate- specific antigen levels and a previous negative biopsy. BJU Int 2012; 110: 1661–5

 

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