Category: Article of the Week

Editorial: Human development and its impact on genitourinary cancers

December 6, 2017/by Mieke Van Hemelrijck

Using the extensive data from the WHO International Agency for Research on Cancer and the United Nations Human Development Report, Greiman et al. [1] aimed to investigate how human development is associated with incidence and mortality of genitourinary cancers. Even though they generate some interesting descriptive findings, we have to remain critical of these descriptive statistics and carefully assess what needs to be investigated next.

Firstly, despite having highlighted the need for attention to indicators of longevity, education, and income per head when assessing human development, the human development index (HDI) is a rather crude measurement. As a geometric mean of normalised indices for each of these three domains, the HDI simplifies but only captures part of what human development entails. Important indicators of health care such as inequalities, poverty, human security, and empowerment are not reflected in the HDI (www.hdr.undp.org). In the context of cancer incidence and mortality this is an important limitation, as it has for instance been shown that socioeconomic status affects early phase cancer trial referrals, which can be considered as a proxy for access to health care [2]. This inequality has been hypothesised to be linked to more comorbidities and lower education in those who are most deprived – a complex interaction which may not be completely captured by the HDI.

Secondly, registration of incidence and mortality of cancers may vary substantially between countries based on both medical practice and governance. These differences are important when trying to generate hypotheses following the ecological study of Greiman et al. [1]. In the case of bladder cancer, for instance, mortality has been estimated to be 17% in the Netherlands, compared to 22% in the USA, and 50% in the UK. As cancer treatments are expected to be similar in these developed countries, it has been thought that a lower registration of non-muscle-invasive bladder cancer in the UK could explain this higher proportion [3]. Thus, discrepancies in cancer registration, even between developed countries, may limit our awareness of cancer burden.

Thirdly, the study design suffers from ‘ecological fallacy’. The latter refers to the inability to draw causal inference about the effect of the HDI on genitourinary cancer at the individual level, in conjunction with the underlying problem of heterogeneity of exposure levels [4]. This limitation was not mentioned by Greiman et al. [1], but affects their conclusions. The lack of information on, for instance, smoking data, comorbidities, and ethnicity make it difficult to understand how development is affecting cancer incidence or mortality. It would have been interesting to also investigate cancers other than genitourinary cancers because a comparison of different tumour types might have shed light on differences in medical practice or risk factors across countries and help tease out the ecological effect of human development.

Despite the aforementioned limitations, the descriptive analysis by Greiman et al. [1] can be helpful for generating hypotheses – as also outlined by the authors. This ecological effect of human development on incidence and mortality rates of genitourinary cancers is particularly relevant when evaluating the impacts of prevention and intervention programmes for these cancers. Their findings suggest that further investigation is required to examine the hypothesis regarding human development and incidence/mortality of genitourinary cancers. To further elucidate this association, methodological challenges will need to be overcome, as HDI assessment has been criticised for being too crude. Nevertheless, it should be possible to collect more detailed information to allow for an understanding of which components of a country’s collective resources affect cancer incidence and mortality the most, e.g. differences in resources used for cancer detection and treatment.

Mieke Van Hemelrijck

Division of Cancer Studies, Translational Oncology and Urology Research (TOUR), King’s College London, London, UK

References

1 Greiman AK, Rosoff JS, Prasad SM. Association of Human Development Index with global bladder, kidney, prostate and testis cancer incidence and mortality. BJU Int2017; 120: 799-807

2 Mohd Noor A , Sarker D, Vizor S et al. Effect of patient socioeconomic status on access to early-phase cancer trials. J Clin Oncol 2013; 31: 224– 30.

3 Boormans JL, Zwarthoff EC. Limited funds for bladder cancer research and what can we do about it. Bladder Cancer 2016; 2: 49–51

4 Morgenstern H . Ecologic studies in epidemiology: concepts, principles, and methods. Annu Rev Public Health 1995; 16: 61–8

Article of the Month: Bladder cancer: diagnosis and management of bladder cancer

November 29, 2017/by admin Z.9

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. There is also a podcast created by a Urology Resident.

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

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Introduction

Bladder cancer is the seventh most common cancer in the UK. It is 3–4 times more common in men than in women. In the UK in 2011, it was the fourth most common cancer in men and the thirteenth most common in women. There were 10,399 people diagnosed with bladder cancer and 5081 deaths from bladder cancer in 2011. The majority of cases occur in people aged over 60. The main risk factor for bladder cancer is increasing age, but smoking and exposure to some industrial chemicals also increase risk.

Bladder cancer is usually identified on the basis of visible blood in the urine or blood found on urine testing, but emergency admission is a common way for bladder cancer to present, and is often associated with a poor prognosis.

Most bladder cancers (75–80%) do not involve the muscle wall of the bladder and are usually treated by telescopic removal of the cancer (transurethral resection of bladder tumour [TURBT]). This is often followed by instillation of chemotherapy or vaccine-based therapy into the bladder, with prolonged telescopic checking of the bladder (cystoscopy) as follow-up. Some people in this group who are at higher risk are treated with major surgery to remove the bladder (cystectomy). People with cancer in or through the bladder muscle wall may be treated with intent to cure using chemotherapy, cystectomy or radiotherapy, and those who have cancer too advanced to cure may have radiotherapy and chemotherapy.

The involvement of the urogenital tract and the nature of the treatments give this cancer a strong psychological impact, in addition to the physical impact of the disease and its treatments, which is often profound. The prevalence of the condition and the nature of its management make bladder cancer one of the most expensive cancers for the NHS.

There is thought to be considerable variation across the NHS in the diagnosis and management of bladder cancer and the provision of care to people who have it. There is evidence that the patient experience for people with bladder cancer is worse than that for people with other cancers.

This guideline covers adults (18 years and older) referred from primary care with suspected bladder cancer and those with newly diagnosed or recurrent bladder (urothelial carcinoma, adenocarcinoma, squamous-cell carcinoma or small-cell carcinoma) or urethral cancer. There was insufficient high-quality evidence on which to make specific recommendations for non-urothelial bladder cancer (adenocarcinoma, squamous-cell carcinoma or small-cell carcinoma).

It does not cover people aged under 18 or adults with bladder sarcoma, urothelial cancer of the upper urinary tract, or secondary bladder or urethral cancer (for example, bowel or cervix cancer spreading into the bladder).

Medicines

The guideline assumes that prescribers will use a medicine’s summary of product characteristics to inform decisions made with individual patients.

This guideline recommends some medicines for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information. Where recommendations have been made for the use of medicines outside their licensed indications (‘off-label use’), these medicines are marked with a footnote in the recommendations.

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Editorial: NICE guidance and the BJUI

November 29, 2017/1 Comment/by Prokar Dasgupta

As the year comes to an end, one cannot help but reflect on the successes of 2017. The impact factor of the BJUI has gone up to 4.439. Our infographics have introduced an entirely different level of interaction with our readers, some of whom are hard pressed for time. We have simply relied on the age old idiom – ‘a picture is worth a thousand words’. And we have credited our reviewers for giving up their valuable time, through Publons and the entirely new Four Seasons, where we will recognise the best reviewers each quarter through BJUI blogs.

Figure 1. Tower Bridge, London. ©John W. Davis 2017.

But perhaps the greatest accomplishment this year has been the publication of National Institute of Health and Care Excellence (NICE) Guidance for the very first time in the BJUI. Guidelines in general are now regarded as perhaps the highest level of evidence, which is obvious from the many hundred citations attracted by guidelines from the EAU and AUA. An absolute classic is the American Cancer Society Breast Cancer Screening Guideline from 2003, which was updated in 2015. In keeping with modern times and shorter attention spans, JAMAenhanced the guideline with an amazing infographic of a digital hand and pen drawing across a white paper! Whilst admiring such stunning quality, the team at the BJUI became acutely aware of our major weakness of being an international journal – we do not have society guidelines to publish. Until now…

NICE guidelines are based not just on the highest level of evidence; every effort is made to eliminate bias as far as possible. Every committee has at least two lay members. The processes and methods are based on internationally accepted criteria of quality, as detailed in the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrumen ns are clear and unambiguous, making them easier to implement and understand.

A unique feature of NICE Guidance is not just ‘clinical effectiveness’ but engagement with economists to make clear statements on ‘cost effectiveness’. It is no wonder that although NICE is based mainly in London, these guidelines are now popular worldwide and not just for the NHS.

We have earlier published NICE Guidance on the GreenLight XPS laser for BPH avoiding high risk patients such as those with risk of bleeding, prostate volume >100 mL, and urinary retention [1]. This technology would be cost effective if used on a day case basis.

NICE have also weighed the evidence for enzalutamide in hormone-relapsed prostate cancer before chemotherapy [2], in patients with mild symptoms, provided it is made available by the manufacturer on the agreed discounted price. Although expensive, it is regarded as an effective treatment amongst the new emerging therapies to prolong the lives of patients with prostate cancer.

In this issue of the BJUI, we feature the NICE Guidance on diagnosis and management of bladder cancer [3]. Not only is smoking cessation important in these patients, but perhaps somewhat controversially, NICE recommend discharge to primary care of patients with low-risk non-muscle-invasive bladder cancer with no recurrence within 12 months. They make a number of research recommendations on biomarkers that are increasingly becoming important with next generation sequencing but also patient satisfaction, which is what ultimately matters in this cancer that can adversely affect quality of life of those who suffer with it.

Wishing you all Greetings of the season!

Prokar Dasgupta

Editor in Chief, BJUI

References

1 National Institute of Health and Care Excellence (NICE). GreenLight XPS for treating benign prostatic hyperplasia: ©NICE (2016) GreenLight XPS for treating benign prostatic hyperplasia. BJU Int2017; 119: 823–30

2 National Institute of Health and Care Excellence (NICE). Enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated: ©NICE (2016) Enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated. BJU Int 2017; 120: 168–84

3 National Institute of Health and Care Excellence (NICE). Bladder cancer: diagnosis and management of bladder cancer: ©NICE (2015) Bladder cancer: diagnosis and management of bladder cancer. BJU Int2017; 120: 755–6

Video: Stereotactic ablative body radiotherapy for inoperable primary kidney cancer

November 22, 2017/by admin Z.9

Stereotactic ablative body radiotherapy for inoperable primary kidney cancer

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Abstract

Objective

To assess the feasibility and safety of stereotactic ablative body radiotherapy (SABR) for renal cell carcinoma (RCC) in patients unsuitable for surgery. Secondary objectives were to assess oncological and functional outcomes.

Materials and Methods

This was a prospective interventional clinical trial with institutional ethics board approval. Inoperable patients were enrolled, after multidisciplinary consensus, for intervention with informed consent. Tumour response was defined using Response Evaluation Criteria In Solid Tumors v1.1. Toxicities were recorded using Common Terminology Criteria for Adverse Events v4.0. Time-to-event outcomes were described using the Kaplan–Meier method, and associations of baseline variables with tumour shrinkage was assessed using linear regression. Patients received either single fraction of 26 Gy or three fractions of 14 Gy, dependent on tumour size.

Results

Of 37 patients (median age 78 years), 62% had T1b, 35% had T1a and 3% had T2a disease. One patient presented with bilateral primaries. Histology was confirmed in 92%. In total, 33 patients and 34 kidneys received all prescribed SABR fractions (89% feasibility). The median follow-up was 24 months. Treatment-related grade 1–2 toxicities occurred in 26 patients (78%) and grade 3 toxicity in one patient (3%). No grade 4–5 toxicities were recorded and six patients (18%) reported no toxicity. Freedom from local progression, distant progression and overall survival rates at 2 years were 100%, 89% and 92%, respectively. The mean baseline glomerular filtration rate was 55 mL/min, which decreased to 44 mL/min at 1 and 2 years (P < 0.001). Neutrophil:lymphocyte ratio correlated to % change in tumour size at 1 year, r² = 0.45 (P < 0.001).

Conclusion

The study results show that SABR for primary RCC was feasible and well tolerated. We observed encouraging cancer control, functional preservation and early survival outcomes in an inoperable cohort. Baseline neutrophil:lymphocyte ratio may be predictive of immune-mediated response and warrants further investigation.

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Editorial: Stereotactic radiotherapy for primary renal cell carcinoma: time for larger-scale prospective studies

November 22, 2017/by admin Z.9

A number of important trends in kidney cancer diagnosis have emerged in recent decades, including the increasing detection of renal tumours in older patients with more comorbidities. In the UK in 2012–2014, 50% of new cases were diagnosed in people aged 70 years and over. Whilst many of these lesions are incidental small renal masses suitable for active surveillance, the dilemma of how to manage the higher-risk lesion (rapid growth kinetics, larger size, symptomatic lesion) is increasingly encountered. Surgical management may pose an unacceptable risk of morbidity, mortality or dialysis, yet these patients may live long enough to experience the consequences of disease progression. Thermal ablation is an option for small cortical tumours (≤3 cm), but there are limitations for larger or centrally located tumours.

In this issue of BJUI, Siva and colleagues [1] report promising early efficacy and toxicity data using stereotactic ablative body radiotherapy (SABR) for the treatment of primary RCC in this difficult cohort. SABR is a non-invasive treatment that delivers very high doses of radiation over one to five outpatient sessions. It uses advanced motion management, radiation planning and image guidance techniques to ensure delivery of an ablative dose with millimetre precision. Survival benefits with stereotactic radiosurgery have been demonstrated in patients with solitary brain metastases [2], and SABR is now an accepted standard of care for patients with medically inoperable early-stage lung cancer [3]. Randomized phase III trials are currently under way, testing SABR against standard of care in primary prostate (clinicaltrials.gov ID NCT01584258) and liver cancer (NCT01730937) and in the oligometastatic setting (NCT02759783). Historically considered radio-resistant, both pre-clinical and clinical data now support the sensitivity of RCC to high-dose per fraction radiotherapy, as used in SABR [4].

The study by Siva and colleagues is one of the largest, early-phase, prospective studies of SABR for primary RCC to date, accruing 37 patients with cT1a–cT2a RCC not suitable for other therapies. Importantly, this was not a cohort of incidentally detected small renal masses. The majority (65%) of tumours were >4 cm (median 4.8 cm), were growing on surveillance or symptomatic, and were biopsy-proven. The inclusion of enlarging T1a tumours is not unreasonable. A recent analysis of patients with localized T1a kidney cancer from the Surveillance, Epidemiology and End Results (SEER) Medicare data reported an excess of kidney cancer deaths for non-surgically managed patients aged >75 years, highlighting how difficult it can be to find the right balance between active and expectant management in this group [5]. Indeed 11% of patients in the present study by Siva et al. developed distant metastases by 2 years.

In the present study, tumours <5 cm received a single 26-Gy fraction of SABR, whilst tumours >5 cm received 42 Gy over three fractions. Whilst acknowledging a number of uncertainties in modelling, this should equate to an equivalent biological dose in excess of 100 Gy. The authors found that delivering this SABR regimen was feasible and well tolerated with one grade 3 toxicity (transient fatigue) and no grade 4–5 toxicities. Most patients sustained only transient minor side effects (78%) or no treatment-related side effects (18%). The mean baseline estimated GFR was 55 mL/min, which decreased to 44 mL/min at 1 year, and was maintained for those with 2 years follow-up.

Similarly, short-term efficacy appears promising. With a median follow-up of 24 months, freedom from local progression at 2 years was 100%, with one patient subsequently progressing locally with concurrent distant metastases 28 months after treatment. Local progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. This is a pragmatic definition and takes into account the challenges in interpreting standard imaging after SABR and the difficulties in obtaining and interpreting repeat biopsies in this cohort. Similarly to the study by Sun et al. [6] it appears that stable or partial radiological responses will predominate in the early years after SABR and, unlike thermal ablation, changes in enhancement patterns can be very slow to evolve.

Longer-term follow-up is required to confirm these promising tumour control and nephron preservation rates, in addition to evaluating longer-term late effects. To that end, the present study has provided a platform for the authors to launch an international phase II clinical trial under the auspices of the TransTasman Radiation Oncology Group (TROG 15.03 FASTRACK, clinicaltrials.gov ID NCT02613819). Larger-scale prospective studies are essential to confirm the efficacy and safety of this non-invasive, nephron-sparing, ablative technique and provide further information to help refine patient selection and develop better biomarkers of response.

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David I. Pryor *† and Simon Wood†‡

*Department of Radiation Oncology, Princess Alexandra Hospital, Wooloongabba, †School of Medicine, University of Queensland, Brisbane, and ‡Department of Urology, Princess Alexandra Hospital, Wooloongabba, Qld, Australia

References

1 Siva S. Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial. BJU Int 2017; 120: 623–30

2 Andrews DW, Scott CB , Sperduto PW et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet (London, England) 2004; 363: 1665–72

3 Chang JY, Senan S, Paul MA et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol 2015; 16: 630–7

4 De Meerleer G, Khoo V, Escudier B et al. Radiotherapy for renal-cell carcinoma. Lancet Oncol 2014; 15: e170–7

5 Patel HD, Kates M, Pierorazio PM et al. Survival after diagnosis of localized T1a kidney cancer: current population-based practice of surgery and nonsurgical management. Urology 2014; 83: 126–32

6 Sun MR, Brook A, Powell MF et al. Effect of stereotactic body radiotherapy on the growth kinetics and enhancement pattern of primary renal tumors. AJR Am J Roentgenol 2016; 206: 544–53

Article of the Week: Evaluation of targeted and systematic biopsies using MRI and US image-fusion guided transperineal prostate biopsy

November 15, 2017/by admin Z.9

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.

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

Multicentre evaluation of targeted and systematic biopsies using magnetic resonance and ultrasound image-fusion guided transperineal prostate biopsy in patients with a previous negative biopsy

Nienke L. Hansen*†‡, Claudia Kesch§, Tristan Barrett‡¶, Brendan Koo‡¶, Jan P. Radtke§**, David Bonekamp** , Heinz-Peter Schlemmer**, Anne Y. Warren‡††, Kathrin Wieczorek‡‡, Markus Hohenfellner§, Christof Kastner‡§§ and Boris Hadaschik§

*Department of Diagnostic and Interventional Radiology, University Hospital RWTH Aachen, Aachen, Germany, †CamPARI Clinic, Addenbrooke’s Hospital and University of Cambridge, Cambridge, UK, ‡Department of Diagnostic and Interventional Radiology, University Hospital Cologne, Cologne, §Department of Urology, University Hospital Heidelberg, Heidelberg, Germany, ¶Department of Radiology, Addenbrooke’s Hospital and University of Cambridge, Cambridge, UK, **Department of Radiology, DKFZ, Heidelberg, Germany, ††Department of Pathology, Addenbrooke’s Hospital and University of Cambridge, Cambridge, UK, ‡‡Institute of Pathology, University of Heidelberg, Heidelberg, Germany, and §§Department of Urology, Addenbrooke’s Hospital and University of Cambridge, Cambridge, UK

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Abstract

Objectives

To evaluate the detection rates of targeted and systematic biopsies in magnetic resonance imaging (MRI) and ultrasound (US) image-fusion transperineal prostate biopsy for patients with previous benign transrectal biopsies in two high-volume centres.

Patients and Methods

A two centre prospective outcome study of 487 patients with previous benign biopsies that underwent transperineal MRI/US fusion-guided targeted and systematic saturation biopsy from 2012 to 2015. Multiparametric MRI (mpMRI) was reported according to Prostate Imaging Reporting and Data System (PI-RADS) Version 1. Detection of Gleason score 7–10 prostate cancer on biopsy was the primary outcome. Positive (PPV) and negative (NPV) predictive values including 95% confidence intervals (95% CIs) were calculated. Detection rates of targeted and systematic biopsies were compared using McNemar’s test.

Results

The median (interquartile range) PSA level was 9.0 (6.7–13.4) ng/mL. PI-RADS 3–5 mpMRI lesions were reported in 343 (70%) patients and Gleason score 7–10 prostate cancer was detected in 149 (31%). The PPV (95% CI) for detecting Gleason score 7–10 prostate cancer was 0.20 (±0.07) for PI-RADS 3, 0.32 (±0.09) for PI-RADS 4, and 0.70 (±0.08) for PI-RADS 5. The NPV (95% CI) of PI-RADS 1–2 was 0.92 (±0.04) for Gleason score 7–10 and 0.99 (±0.02) for Gleason score ≥4 + 3 cancer. Systematic biopsies alone found 125/138 (91%) Gleason score 7–10 cancers. In patients with suspicious lesions (PI-RADS 4–5) on mpMRI, systematic biopsies would not have detected 12/113 significant prostate cancers (11%), while targeted biopsies alone would have failed to diagnose 10/113 (9%). In equivocal lesions (PI-RADS 3), targeted biopsy alone would not have diagnosed 14/25 (56%) of Gleason score 7–10 cancers, whereas systematic biopsies alone would have missed 1/25 (4%). Combination with PSA density improved the area under the curve of PI-RADS from 0.822 to 0.846.

Conclusion

In patients with high probability mpMRI lesions, the highest detection rates of Gleason score 7–10 cancer still required combined targeted and systematic MRI/US image-fusion; however, systematic biopsy alone may be sufficient in patients with equivocal lesions. Repeated prostate biopsies may not be needed at all for patients with a low PSA density and a negative mpMRI read by experienced radiologists.

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Article of the Week: Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial

November 22, 2017/by admin Z.9

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.

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

Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial

Shankar Siva*,†, Daniel Pham*, Tomas Kron*,†, Mathias Bressel*, Jacqueline Lam*, Teng Han Tan*, Brent Chesson*, Mark Shaw*, Sarat Chander*, Suki Gill*,‡, Nicholas R. Brook§, Nathan Lawrentschuk*,¶, Declan G. Murphy*,† and Farshad Foroudi*,¶

*Peter MacCallum Cancer Centre, Melbourne, Vic., Australia, † Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic. Australia, ‡Sir Charles Gairdner Hospital, Nedlands Perth, WA, Australia, §Royal Adelaide Hospital, Adelaide, SA, Australia, and ¶Olivia Newton John Cancer Centre, Heidelberg, Vic., Australia

Read the full article

Abstract

Objective

Materials and Methods

Results

Conclusion

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Editorial: Getting to the right biopsy in the right patient at the right time

November 15, 2017/by admin Z.9

Guidelines now recommend performing multiparametric MRI (mpMRI) and targeted prostate biopsies in men with a history of prior negative biopsy and continued concern for significant cancer. This new approach to prostate re-biopsy is aimed at improving prostate cancer detection. However, several important clinical factors may help clinicians’ fine-tune the process of repeated prostate biopsy. In this month’s issue of the BJUI, Hansen et al. [1] present a multicentre study of patients with prior negative TRUS biopsy undergoing MRI/TRUS-fusion transperineal biopsy.

In the study, 487 men undergo mpMRI and transperineal biopsy with detection of clinically significant (Gleason score 7–10) cancer as the primary outcome. Several factors are evaluated to compare cancer detection rates, including systematic biopsies, targeted biopsies, PSA density (PSAD), and Prostate Imaging Reporting and Data System (PI-RADS) version 1 score. From their cohort, a suspicious lesion (PIRADS 3–5) was identified in 343 (70%) patients. Prostate cancer was detected in 249 (51%), with 149 (31%) having Gleason score 7–10 cancer. Potentially missed significant cancers from the anterior prostate were found in 27% (40/149). Cancer was detected in 28% (40/144) of patients with PI-RADS 1–2 lesions, with 8% (11/144) being Gleason score 7–10. For patients with PI-RADS 3–5 lesions, cancer was identified in 61% (209/343) with 40% (138/343) being Gleason score 7–10. For patients with PI-RADS 3–5 lesions, systematic biopsies alone failed to detect 13/138 significant cancers, while targeted biopsies missed 24/138 cancers. The combination of systematic and targeted biopsies was significantly better for Gleason score 7–10 prostate cancer detection than either alone. The addition of a PSAD threshold of 0.15 ng/mL/mL for the detection of Gleason score 7–10 resulted in a significant improvement in the area under the curve (0.846) of the receiver operating characteristic curve for PSAD groups and PI-RADS score.

Getting the right biopsy: In this study [1], patients with a prior negative TRUS biopsy underwent TRUS-fusion transperineal biopsy. Having two approaches to prostate biopsy can be advantageous when evaluating men with prior negative biopsies. Historical studies have found comparable prostate cancer detection between transrectal and transperineal biopsies for men undergoing both initial biopsy [2] and saturation re-biopsy [3]. However, the detection of anterior lesions has remained a persistent challenge from the transrectal approach. As in the current study [1], use of transperineal biopsy can detect cancer in up to 30% of tumours that would otherwise be missed on extended template TRUS biopsy [4]. Although attempts to reach anterior lesions from the transrectal approach may be feasible [5], the transperineal approach is felt to provide better sampling in comparison [6].

Getting the right patient: Patient-specific factors such as PI-RADS lesions 3–5 and PSAD have become increasing utilised for stratifying patients who may benefit from additional biopsies using image guidance. As the authors suggest, patients with negative imaging may consider deferring repeat biopsy, particularly those with reassuring PSADs (<0.15 ng/mL/mL). In their study [1], only 4% (6/144) of men with negative mpMRI and a PSAD of <0.15 ng/mL/mL harboured clinically significant cancer (five Gleason score 3 + 4 and one Gleason score 8). Patients with concerning PSAD, but negative mpMRI and those with lesions identified in the peripheral zone could have the option to undergo repeated, fusion-directed TRUS or transperineal biopsy. For patients with lesions identified in the anterior prostate, a transperineal prostate biopsy may provide the highest detection rate.

At the right time: Now that high quality prostate MRI is becoming more widely available; men with a prior negative biopsy should strongly consider the benefit of repeated biopsy after prostate imaging. In addition to identifying suspicious lesions, calculating PSAD has been found to improve the likelihood of detecting clinically significant prostate cancer. Without additional testing, a personalised biopsy plan can be created.

A thorough discussion of the prescribed biopsy approach and the likelihood of detecting a significant cancer is the final step to the right biopsy in the right patient at the right time.

Kelly Stratton

Department of Urology, University of Oklahoma College of Medicine, Oklahoma City, OK, USA

Read the full article

1 Hansen NL, Kesch C, Barrett T et al. Multicentre evaluation of target and systematic biopsies using magnetic resonance and ultrasound image-fusion guided transperineal prostate biopsy in patients with a previous negative biopsy. BJU Int 2016; 120: 631–8

2 Hara R, Jo Y, Fujii T et al. Optimal approach for prostate cancer detection as initial biopsy: prospective randomized study comparing transperineal versus transrectal systematic 12-core biopsy. Urology 2008; 71: 191–5

3 Abdollah F, Novara G, Briganti A et al. Trans-rectal versus trans- perineal saturation rebiopsy of the prostate: is there a difference in cancer detection rate? Urology 2011; 77: 921–5

4 KomaiY, Numao N, Yoshida S et al. High diagnostic ability of multiparametric magnetic re onance imaging to detect anterior prostate cancer miss ed by transrectal 1 2-core biopsy. JUrol2013; 190: 867– 7

5 Volkin D, Turkbey B, Hoang AN et al. Multiparametric magnetic resonance imaging (MRI) and subsequent MRI/ultrasonography fusion-guided biopsy increase the detection of anteriorly located prostate cancers. BJU Int 2014; 114: E43–9

6 Borkowetz A, Platzek I, Toma M et al. Direct comparison of multiparametric magnetic resonance imaging (MRI) results with ﬁnal histopathology in patients with proven prostate cancer in MRI/ ultrasonography-fusion biopsy. BJU Int 2016; 118: 213–20

Article of the Week: Clinical and patient-reported outcomes of SPARE

November 8, 2017/by admin Z.9

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

Clinical and patient-reported outcomes of SPARE – a randomised feasibility study of selective bladder preservation versus radical cystectomy

Robert A. Huddart*†, Alison Birtle‡, Lauren Maynard*, Mark Beresford§, Jane Blazeby¶, Jenny Donovan¶, John D. Kelly**, Tony Kirkbank††, Duncan B. McLaren‡‡, Graham Mead§§, Clare Moynihan*, Raj Persad¶¶, Christopher Scrase***, Rebecca Lewis* and Emma Hall*

*The Institute of Cancer Research, London, UK, †Royal Marsden NHS Foundation Trust, London, UK, ‡Royal Preston Hospital, Preston and University of Manchester, Manchester, UK, §Royal United Hospital Bath, Bath, UK, ¶University of Bristol, Bristol, UK, **University College London Hospital, London, UK, ††Patient Representative, Edinburgh, UK, ‡‡Western General Hospital, Edinburgh, UK, §§Southampton General Hospital, Southampton, UK, ¶¶North Bristol NHS Trust, Bristol, UK, and ***The Ipswich Hospital NHS Trust, Ipswich, UK

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Abstract

Objectives

To test the feasibility of a randomised trial in muscle-invasive bladder cancer (MIBC) and compare outcomes in patients who receive neoadjuvant chemotherapy followed by radical cystectomy (RC) or selective bladder preservation (SBP), where definitive treatment [RC or radiotherapy (RT)] is determined by response to chemotherapy.

Patients and Methods

SPARE is a multicentre randomised controlled trial comparing RC and SBP in patients with MIBC staged T2–3 N0 M0, fit for both treatment strategies and receiving three cycles of neoadjuvant chemotherapy. Patients were randomised between RC and SBP before a cystoscopy after cycle three of neoadjuvant chemotherapy. Patients with ≤T1 residual tumour received a fourth cycle of neoadjuvant chemotherapy in both groups, followed by radical RT in the SBP group and RC in in the RC group; non-responders in both groups proceeded immediately to RC following cycle three. Feasibility study primary endpoints were accrual rate and compliance with assigned treatment strategy. The phase III trial was designed to demonstrate non-inferiority of SBP in terms of overall survival (OS) in patients whose tumours responded to neoadjuvant chemotherapy. Secondary endpoints included patient-reported quality of life, clinician assessed toxicity, loco-regional recurrence-free survival, and rate of salvage RC after SBP.

Results

Trial recruitment was challenging and below the predefined target with 45 patients recruited in 30 months (25 RC; 20 SBP). Non-compliance with assigned treatment strategy was frequent, six of the 25 patients (24%) randomised to RC received RT. Long-term bladder preservation rate was 11/15 (73%) in those who received RT per protocol. OS survival was not significantly different between groups.

Conclusions

Randomising patients with MIBC between RC and SBP based on response to neoadjuvant chemotherapy was not feasible in the UK health system. Strong clinician and patient preferences for treatments impacted willingness to undergo randomisation and acceptance of treatment allocation. Due to the few participants, firm conclusions about disease and toxicity outcomes cannot be drawn.

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Editorial: Should we care more about SPARE?

November 8, 2017/by admin Z.9

Huddart et al. [1] report the results of a phase III clinical trial (SPARE) evaluating the feasibility of randomising participants with cT2/T3 muscle-invasive bladder cancer (MIBC) to either radiation or radical cystectomy (RC) following neoadjuvant chemotherapy. Whilst attempting to address an important, in fact crucial ongoing point of debate, due to poor patient accrual (45 participants recruited in 30 months) the study was terminated early. Additionally, compliance with study assignment was low, with as many as 24% of participants electing to proceed with a treatment arm that was the opposite of what they were randomised to. This underscores the problems with obtaining randomised data in an era where patient and clinician preference drive clinical decision-making.

Whilst well-performed prospective studies show acceptable results with bladder-sparing approaches (69% complete response and 71% 5-year disease-specific survival [2]), no randomised clinical trials comparing bladder sparing with RC have demonstrated equivocal results. As non-randomised studies are subject to selection bias [many patients with large bulky T3 tumours or those with carcinoma in situ (CIS) or hydronephrosis have not met inclusion criteria for trials of bladder sparing], it is often debated as to whether bladder sparing is appropriate for the entire population of patients with MIBC or a selected subset. This is especially important in a deadly disease such as bladder cancer, where we often have only one chance to get it right and hence recent guidelines state that bladder sparing and radical options should be discussed with the patient.

Whilst we acknowledge the limitations based on the number of participants analysed, these data show some interesting trends [1]. There appears to be more local recurrence with radiation therapy (69%) compared to RC (15%), this despite confirmation of ≤cT1 disease after neoadjuvant chemotherapy. And while most of the local failures are attributed to non-muscle-invasive recurrences; additional treatments, patient anxiety, and potential salvage RC, as well as the cost of surveillance, must be considered in reflecting on these results. It is unclear whether these factors are outweighed by the perceived lower toxicity in these patients.

It is our opinion that until randomised studies show equivalency, radiation-based approaches should definitely be discussed with all patients but patients should also be guided as to who are ideal candidates. Ideal candidates are those who have non-variant histology (pure urothelial carcinoma), non-bulky (minimal) invasive T2 cancer, absence of CIS, absence of a three-dimensional mass on imaging or examination, absence of hydronephrosis, and have an adequate bladder capacity [3]. The role of multidisciplinary care is paramount, maximal transurethral resection is a critical initial step, as incomplete resections can potentially double the odds of eventual RC in bladder-sparing protocols [4]. Additionally, concomitant chemotherapy has shown improved survival and should be considered standard of care based on a randomised control trial [5]. The addition of neoadjuvant chemotherapy is unknown and needs to be further evaluated. In addition to the treatment itself, it is clear that vigilant surveillance is critical in identifying patients at highest risk of failure and requires a combination of both cystoscopy and imaging, with expedient salvage RC.

Beyond the challenges of treating patients with MIBC, this report from Huddart et al. [1] reflects the larger issue of clinical trial accrual. As mentioned, patients and clinicians often have predetermined notions about the ‘best’ course of action, even in the context of a randomised clinical trial. These limitations have plagued early closure of other trials in bladder cancer as well. Similarly in prostate cancer, comparative treatment trials of radiation and surgery are limited as patients are reluctant to relinquish decisions about their treatment. Clearly, an intensive effort is necessary to create clinical trials that are palatable to a multi-disciplinary treatment team committed to answering tough therapy questions. MIBC is no different, where we often offer differing treatment modalities without having quality comparative data, which is a disservice to our patients who look to us to guide their treatment approaches based on best available hard evidence. We again commend the authors for their well-designed clinical trial and presenting their results and challenges from the SPARE trial.

Eugene K. Lee* and Ashish M. Kamat†

*University of Kansas Medical Center, Kansas City, KS and † Department of Urology, MD Anderson Cancer Center, Houston, TX, USA

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References

1 Huddart RA, Birtle A, Maynard L et al. Clinical and patient-reported outcomes of SPARE – a randomised feasibility study of selective bladder preservation versus radical cystectomy. BJU Int 2017; 120: 639–50

2 Mak RH, Hunt D, Shipley WU et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol 2014; 32: 3801–9

3 Smelser WW, Austenfeld MA, Holzbeierlein JM, Lee EK. Where are we with bladder preservation for muscle-invasive bladder cancer in 2017? Indian J Urol 2017; 33: 111–17

4 Efstathiou JA, Spiegel DY, Shipley WU et al. Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol 2012; 61: 705–11

5 James ND, Hussain SA, Hall E et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012; 366: 1477–88