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 editorialwritten 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.
Pim J. van Leeuwen*, Maarten Donswijk†, Rohan Nandurkar‡, Phillip Stricker§¶, Bao Ho**, Stijn Heijmink††, Esther M.K. Wit*, Corinne Tillier*, Erik van Muilenkom*, Quoc Nguyen§, Henk G. van der Poel* and Louise Emmett‡§**
*Department of Urology, †Department of Nuclear Medicine, The Netherlands Cancer Institute, Amsterdam, The Netherlands, ‡Faculty of Medicine, University of New South Wales Sydney, §The Australian Prostate Cancer Research Centre-NSW, The Garvan Institute of Medical Research, ¶St Vincent’s Clinic, **Department of Theranostics and Nuclear Medicine, St Vincent’s Hospital Sydney, Sydney, New South Wales, Australia and ††Department of Radiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
To determine the value of gallium‐68‐prostate‐specific membrane antigen (68Ga‐PSMA)‐11 positron emission tomography (PET) /computed tomography (CT) in men with newly diagnosed prostate cancer.
Patients and methods
We analysed results of 140 men with intermediate‐ and high‐risk prostate cancer. All men underwent 68Ga‐PSMA‐11 PET/CT and multiparametric magnetic resonance imaging (mpMRI) before radical prostatectomy (RP) with extended pelvic lymph node (LN) dissection. For each patient, the clinical and pathological features were recorded. Prostate‐specific antigen (PSA) was documented at staging scan, and after RP, at a median (interquartile range) of 110 (49–132) days. A PSA level of ≥0.03 ng/mL was classified as biochemical persistence (BCP). Logistic regression was performed for association of clinical variables and BCP.
Results
In these 140 patients with intermediate‐ and high‐risk prostate cancer, 27.1% had PSMA PET/CT‐positive findings in the pelvic LNs. Sensitivity and specificity for detection of LN metastases were 53% and 88% (PSMA PET/CT) and 14% and 99% (mpMRI), respectively. The overall BCP rate was 25.7%. The BCP rate was 16.7% in men who were PSMA PET/CT LN‐negative compared to 50% in men who were PSMA PET/CT LN‐positive (P < 0.05). The presence of PSMA‐positive pelvic LNs was more predictive of BCP after RP than cT‐stage, PSA level, and the Gleason score, adjusted for surgical margins status.
Conclusions
68Ga‐PSMA‐11 PET/CT is highly predictive of BCP after RP, and should play an important role informing men with intermediate‐ or high‐risk prostate cancer.
The presence of lymph node metastases at the time of prostate cancer diagnosis has significant implications for treatment. According to current guidelines from the National Comprehensive Cancer Network, men with positive lymph nodes on initial staging imaging should be offered treatment with androgen deprivation (± abiraterone) along with consideration for external beam radiation therapy [1]. In contrast, men with clinically localised high‐ or very‐high‐risk prostate cancer have the option of undergoing radical prostatectomy. Unfortunately, currently available diagnostic imaging modalities (i.e. contrast‐enhanced CT and MRI) fall short in their ability to accurately identify lymph node metastases, which are often small and difficult to discern from other structures within the pelvis. Thus, there exists a conundrum: if we cannot accurately detect lymph node involvement, how can we appropriately manage it?
In this edition of the BJUI, Leeuwen et al. [2] report on the utility of molecular imaging with 68Ga‐PSMA‐11 positron emission tomography (PET)/CT in the preoperative staging of men with prostate cancer. To date, the greatest clinical utility of PSMA‐targeted PET has been in the management of men with biochemically recurrent prostate cancer [3]. In the present study by Leeuwen et al. [2], 140 patients with newly diagnosed intermediate‐ or high‐ risk prostate cancer underwent 68Ga‐PSMA‐11 PET/CT before radical prostatectomy with extended pelvic lymph node dissection. Surgical pathology served as the reference standard to which findings on 68Ga‐PSMA‐11 PET/CT were compared. In total, 27.1% of men were found to have radiotracer uptake in their pelvic lymph nodes, resulting in a sensitivity of 53% and a specificity of 88%. In contrast, multiparametric MRI had a sensitivity of only 14%, albeit with a higher specificity of 99%. These findings are in line with prior studies evaluating the diagnostic performance of PSMA‐targeted PET imaging for preoperative prostate cancer staging [4]. Of greater interest, however, is the authors’ observation that positivity on 68Ga‐PSMA‐11 PET/CT was strongly associated with postoperative PSA persistence (i.e. failure to cure). More specifically, after controlling for Gleason score, surgical margin status, and preoperative PSA level, positivity on PET/CT had an odds ratio of 5.87 (95% CI 1.30–26.59) for biochemical persistence. Furthermore, men with pN1 disease and a positive preoperative PET/CT (i.e. true positives) were over three times more likely to experience biochemical persistence than patients with pN1 disease and negative imaging (71.4% vs 21.4%). Thus, PSMA‐targeted PET not only stands to inform clinical staging, but also has the potential to offer independent prognostic information.
A future line of investigation is to explore the biological basis of the authors’ observation regarding PSMA as a prognostic marker. One explanation is that PET/CT identified men with higher volume lymph node metastases (a known prognostic factor), whilst patients with smaller more curable nodes were negative on imaging. After all, the authors state that the imaging test did not detect any pathologically positive lymph nodes <2 mm. Furthermore, only 27% of positive lymph nodes between 2 and 4 mm showed radiotracer uptake. Unfortunately, the authors did not account for differences in the volume of nodal metastases in their analysis. A second possible explanation for the authors’ observation is that PSMA is upregulated through the same signaling pathways that drive an aggressive prostate cancer phenotype, allowing for PSMA expression to provide prognostic information independent of tumour volume. Indeed, others have previously shown that PSMA expression, as measured by immunohistochemistry, corresponds with increasing tumour grade, stage and risk of biochemical failure [5]. Of course, these concepts are not mutually exclusive and further investigation is needed in order for PSMA‐targeted imaging to be rationally applied as a prognostic test.
While molecular imaging is not exactly a new technology (TIME Magazine named PET-CT as the medical invention of the year back in 2000), recent developments in radio-pharmacy have positioned the field at the forefront of innovations in cancer imaging and, tantalisingly, novel therapeutic approaches to cancer treatment.
Urologists have typically been forward thinking and innovative, and have been quick to acknowledge the value of molecular imaging as a tool to enhance the accuracy of the diagnostic process and improve patient outcomes. The recent development of radiotracers directed against prostate-specific-membrane-antigen (PSMA) has taken things to a new level; there is now a solid body of evidence for the performance of 68Ga-PSMA PET/CT in primary and secondary staging, with an ability to accurately detect small volume disease at far lower serum PSA levels – the use of 68Ga-PSMA PET/CT as a diagnostic adjunct is becoming increasingly mainstream in continental Europe and Australia.
Oxford PSMA Symposium 2018
It is in this context that, on 22 November 2018, the Nuffield Department of Surgical Sciences in Oxford hosted a symposium at the Old Road Campus Research Building focused on the utility of PSMA-related technologies. The symposium attracted an impressive array of attendees from across the UK, Europe and Australia.
The symposium was opened with comments by Professor Freddie Hamdy of Oxford, who welcomed all attendees and speakers, some of whom who had travelled more than 10,000 miles to attend the gathering.
Many uses for PSMA in specialist prostate cancer management
Liberal use of PSMA-PET down under
The first speaker, Professor Declan Murphy, from Melbourne’s Peter MacCallum Cancer Centre, shared comprehensive data and experience from Victoria in Australia, where access to 68Ga-PSMA PET/CT is seemingly unrestricted. Professor Murphy delivered a fascinating talk, expounding the gamut of PSMA PET applications in prostate cancer, from primary staging (promising data), to biochemical recurrence (there is definite evidence that PSMA PET accurately detects early recurrence and can guide salvage treatment options), right through to therapeutic uses of PSMA. In particular, he discussed the use of Lutetium-177 (177Lu)-PSMA-617 (LuPSMA) as a treatment in men with CRPC, presenting the findings of their recent Lancet Oncology study led by Michael Hoffman. Although still in the early stages, the data here look very exciting and hale a potential revolution in the way we manage high risk and advanced prostate cancer.
Declan Murphy expounds the translational utility of PSMA imaging and theranostics
How easy is it to set up a PSMA imaging service in the UK?
The next speaker was Professor Jamshed Bomanji from the Institute of Nuclear Medicine, University College London (UCL), who presented an eye-opening talk that focussed on the challenges of setting up a PSMA-PET service within an NHS Trust in England. The effort he and his team put into developing their service in the face of significant practical resistance has been frankly heroic. Pleasingly, these efforts have been worthwhile as the team from UCL have clearly demonstrated that PSMA PET/CT has had a significant impact on the management of men with biochemical recurrence with the team contributing to guidelines drawn up to standardise use, keeping similar standards of testing as https://www.blinkhealth.com/zoloft. It is very disappointing that NHS England saw fit to withdraw funding for the gallium tracer required for PSMA-PET scanning in August 2018. This does seem rather short-sighted given the clear evidence favouring the utility of PSMA-PET over other modalities such as FDG or Choline-PET, both of which are still funded. All in all, Professor Bomanji’s talk was a sobering examination of the challenges we face in our commitment to delivering cutting edge, world-class cancer services whilst at the same time considering the financial implications to the NHS of providing such high-end services.
Associate Professor Bart Cornelissen along with Dr Rebekka Hueting who runs PROx (PET Radiopharmacy Oxford) presented their intentions for 68Ga-PSMA-PET imaging in Oxford, and the University’s imminent plan to install a cyclotron on site that will allow PET imaging with locally generated radioisotopes to increase dose efficiency – the half-life of gallium means that any requirement to transport the dose reduces the number of scans that can be performed at destination. This is particularly important given some recent negative press coverage.
Surgery for men with metastases?
Prasanna Sooriakumaran (PS) of University College London Hospital (UCLH) Department of Urology discussed the TRoMbone Study, a UK feasibility RCT that he has set up aimed at testing radical prostatectomy in men with oligometastatic prostate cancer. This interesting study promises to tease out the possible benefits of radical prostatectomy to men with low-volume metastatic disease. There are examples in other cancers whereby aggressive management of the primary tumour confers survival benefits in patients with low-burden metastatic disease and it is not unreasonable to think this may be the case for prostate cancer. Recruitment to such trials of ‘oligometastatic’ disease is contingent upon definitions of ‘low-volume’ disease, and accurate detection of such disease. PSMA-PET imaging is positively helping with this paradigm with its far superior sensitivity to conventional cross-sectional staging.
PSMA as a tool to improve surgery
Pim van Leeuwen of the Netherlands Cancer Institute delivered an engaging talk entitled “PSMA intra-operative enhancement of lymph node dissection”, accompanied by some excellent video demonstrations. Next up were Boris Vojnovic and Alastair Lamb of Oxford who discussed fluorescence optics and intra-operative use of PSMA as part of the on-going ProMOTE study (Prostate Molecular Targeting to Enhance Surgery). We wish the investigators good luck as the study progresses and we eagerly look forward to seeing the data as they emerge.
Summary
In summary, the Oxford PSMA symposium 2018 brought together clinicians from around the globe who share a common enthusiasm for PSMA-related technologies that promise to revolutionise prostate cancer management in the near future. Common themes included the use of PSMA in staging, therapeutics and intra-operative guidance. The message from our overseas guests, both European and Antipodean, was that PSMA-based imaging is increasingly part of routine care in the management of prostate cancer and definite benefits are seen, particularly in regard to accurate staging and identification of very early recurrence. While we in the UK are a little behind the curve when it comes to adoption of this increasingly established technology, we are hopeful of increasing the use of this technology in the NHS in order to rationalise appropriate treatment, reduce futile expenditure and ensure gold-standard management of men with prostate cancer.
Conference dinner at Balliol College, Oxford, UK From Left: Alastair Lamb (Oxford), Declan Murphy (Melbourne), Freddie Hamdy (Oxford), Boris Vojnovic (Oxford), Prasanna Sooriakumaran (UCLH), Richard Bryant (Oxford), Ben Lamb (Cambridge)
Aaron Leiblich, Clinical Lecturer, Nuffield Department of Surgical Sciences; Alastair Lamb, Consultant Urologist, Churchill Hospital Cancer Centre; on behalf of the meeting faculty
Alastair Lamb is a Cancer Research UK Clinician Scientist, Senior Fellow in Robotic Surgery & Honorary Consultant Urologist at the Nuffield Department of Surgery, University of Oxford, and Oxford University Hospitals NHS Foundation Trust. Alastair is interested in delivering excellent and timely prostate cancer care, focussing on state-of-the-art diagnostics with multiparametric MRI and targeted transperineal biopsies, followed by robotic-radical prostatectomy (RARP) or active surveillance. He also has an interest in novel molecular imaging techniques such as 68Ga-PSMA PET/CT and their use in disease stratification and selection of patients for surgery. Alastair is a local investigator for the ProMOTE, PART and TRoMbone studies.
