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PROSTATE diSEASE 1 A tale of four prostates ROGER KIRBY, DAMIAN HANBURY, JOHN ANDERSON AND SEAN G. VESEY Four urologists relate their personal experiences of prostate cancer and highlight some important learning points. uring the past two years, rather ironically, all four authors of this article, each a busy urologist in practice with an interest in prostate cancer, have themselves been diagnosed and treated for prostate cancer. Rather than hush it up, as if it were a dark secret, we decided that there would be some merit in terms of education, debate and awareness, if we were to make public the presentation and treatment of each of our four individual cases. D CASE 1: ROGER KIRBY Roger Kirby, aged 61, an otherwise fit, asymptomatic individual who had measured his prostatespecific antigen (PSA) for more than a decade, noticed a gradual rise in PSA to 4.4ng/ml. 3-Tesla magnetic resonance imaging (MRI; Figure 1) revealed a suspicious focus in the right peripheral zone adjacent to but not penetrating the capsule. Figure 1. 3-Tesla magnetic resonance image Transrectal ultrasound (TRUS)of the prostate showing a suspicious focus in guided biopsy confirmed Gleason the right peripheral zone adjacent to but not 3+4=7 adenocarcinoma in three penetrating the capsule out of 12 cores. A bone scan was negative. A robotically assisted radical prostatectomy was performed, by Professor Dasgupta, without complications. Pathology confirmed complete excision of a Gleason 4+3=7 1.3cc tumour with invasion of the capsule but negative surgical margins. Recovery has been uneventful. LEARNING POINTS There are more than 1000 urologists presently practising in the UK. As there is a one in nine lifetime chance of being diagnosed with prostate cancer, the fact that there are at least four working urologists currently afflicted by the disease is probably not surprising. The four cases summarised here illustrate several important aspects of the management of prostate cancer, an area of medicine that is currently changing very rapidly.1 fact, thanks to the work of Parker3 and Klotz,4 and the publication of the NICE guidelines5 on prostate cancer, the majority of patients with low-risk, Gleason pattern 3+3=6 prostate cancer are now managed by active surveillance rather than by surgery or radiotherapy.6 The first case (RK) illustrates the value of early detection using serial PSA testing in terms of diagnosing prostate cancer, while it is still confined within the capsule of the gland, and therefore potentially still curable. The results of the European Randomized Study of Screening for Prostate Cancer (ERSPC)2 confirm that mortality from prostate cancer can be reduced by early detection, but the authors worry that the lives saved will be counterbalanced by those low-risk cases identified who are at risk of ‘overtreatment’. In A second learning point from this case is the value of high-resolution 3-Tesla MRI scanning, with gadolinium enhancement, in identifying suspect areas within the gland that can be targeted by either transrectal or transperineal ultrasound-guided biopsy (see Figure 1). Comparison of the preoperative MRI scan with the prostate itself after robotic surgery confirms the accuracy of this technology in localising the tumour. This in turn aids the surgeon in achieving negative surgical margins. TRENDS IN UROLOGY & MEN’S HEALTH MARCH/APRIL 2013 Go to the Trends website to view a video debate on this subject with Roger Kirby, Damian Hanbury and John Anderson: [URL to be added when available] Roger Kirby, MA, MD, FRCS(Urol), FEBU, Director, The Prostate Centre, London; Damian Hanbury, MS, FRCS(Urol), Consultant Urologist, The Lister Hospital, Stevenage, Herts; John Anderson, MB ChB, ChM, FRCS, Consultant Urologist, Royal Hallamshire Hospital, Sheffield; Sean G. Vesey, FRCS, FEBU, Retired Consultant Urologist, Southport and Ormskirk Hospital NHS Trust, Merseyside www.trendsinurology.com PROSTATE diSEASE 2 CASE 2: DAMIAN HANBURY Damian Hanbury, aged 55, a busy urologist in Hertfordshire, presented in 2010 with worsening lower urinary tract symptoms of frequency and poor flow. A PSA measurement came back at 29ng/ml. Biopsy confirmed Gleason 4+4=8 adenocarcinoma and an MRI suggested locally advanced disease. There was a single suspicious focus in the pelvic bone on both MRI and bone scanning. A decision was made to proceed with androgen ablation followed by external beam radiotherapy to include the presumed metastatic focus in the pelvis. Two years on, his PSA remains undetectable at 0.06ng/ml. The second case (DH) illustrates the not uncommon dilemma of whether to use external beam radiotherapy in addition to androgen ablation when there are equivocal skeletal or soft tissue lesions, which may or may not represent metastatic disease. In this case there was a biopsy-proven locally advanced disease involving the prostate, which was responsible for the lower urinary tract symptoms, and a lesion within the CASE 3: JOHN ANDERSON John Anderson, aged 58, a urologist from Sheffield and President Elect of the British Association of Urological Surgeons, was perfectly well and without symptoms in early October 2011, and had a routine PSA test, which came back at 1.7ng/ml. On 27 January 2012 (only four months later) he felt a mass in the upper abdomen and a computed tomography (CT) scan confirmed multiple liver metastases with no other detectable abnormality. With a normal PSA four months earlier, no urinary symptoms and no extrahepatic disease visible on the scan, the possibility of this being related to the prostate never really crossed anyone’s mind. A couple of weeks later, a liver biopsy confirmed a poorly differentiated adenocarcinoma. Subsequent immunohistochemistry of the liver biopsies stained positive for PSA, which confirmed the diagnosis of metastatic prostate cancer. It was only then that the serum PSA was measured, which had risen from normal 1.7 to 92.7ng/ml in four months. Androgen deprivation therapy resulted in a PSA nadir of 0.2ng/ml after four months of treatment, but the PSA then started to climb. In November, he developed sudden-onset severe right-sided abdominal pain requiring opiates to control symptoms. A further CT still showed no evidence of disease outside of the liver, although the liver metastases had increased considerably in size and were considered the likely explanation for the pain. The PSA at this time was 483ng/ml. In view of the symptoms and progressive disease, docetaxel-based chemotherapy was commenced. After two cycles the pain has improved significantly, the PSA has fallen somewhat and he is back playing golf. The side-effects from the chemotherapy are not too bad, other than he has lost his taste for white wine! Abiraterone/enzalutamide are further treatment options if there is further disease progression. www.trendsinurology.com pelvic bones, which may or may not have represented a metastasis. Fortunately, this area could be encompassed in the external beam radiotherapy field, which was used to treat the primary lesion. Case 3 (JA) is most unusual in presenting with liver metastases, in spite of a normal PSA only a few months before and no other evidence of disease elsewhere. It does illustrate how the PSA level can be misleading, in spite of quite large-volume metastases, especially in very poorly differentiated tumours. Hormonal therapy produced a useful but relatively short-lived response, and fortunately taxane-based chemotherapy seems to be producing a second remission. The final case (SV) illustrates the not uncommon presentation of locally advanced disease with lymph node metastases and the subsequent development of symptomatic bone metastases requiring local radiotherapy to resolve. A combination of androgen ablation with taxane-based chemotherapy and additional abiraterone7 has produced a prolonged response. The new oral agent enzalutamide,8 which has produced impressive results in clinical trials, and the encouraging clinical profile of the alpha-pharmaceutical Alpharadin,9 are likely to be the next therapeutic options. DISCUSSION Anxieties about overtreatment of low-risk, low-volume Gleason 3+3=6 prostate cancers have fostered the myth that prostate cancer is somehow a toothless tiger. Consideration of the four clinical situations above, drawn from the ranks of actively practising urologists, clearly illustrates that this is not always the case. Progress with treatment is being made with kinder, minimally invasive, robotically assisted surgery and better targeted, more powerful radiotherapy. Androgen ablation therapy still provides the mainstay of therapy for metastatic disease, but abiraterone, enzalutamide, Alpharadin and chemotherapy TRENDS IN UROLOGY & MEN’S HEALTH MARCH/APRIL 2013 PROSTATE diSEASE 3 CASE 4: SEAN VESEY 4. Sean Vesey, aged 58, a laparoscopic radical prostatectomist from Merseyside, presented in early 2010 with left iliac fossa discomfort, which prompted investigations, including a PSA. This came back at 78ng/ml. His PSA had been just 1.4ng/ml some 18 months earlier. TRUS biopsy confirmed T3b Gleason 4+3=7 adenocarcinoma in all cores and an MRI revealed pelvic and para-aortic lymphadenopathy. Although the original bone scan was clear, a subsequent bone scan at one year confirmed the presence of bone metastases in the cervical and lumbar spine. Initial hormonal therapy reduced the PSA to a nadir value of 8.9ng/ml. Three cycles of chemotherapy followed by abiraterone further reduced the PSA to 0.27ng/ml. Although currently well, local radiotherapy has been administered to a new pelvic metastasis. The new agents, radium-223 chloride (Alpharadin) and enzalutamide are being considered, but currently held in reserve. with taxotere or cabazitaxel are all now useful, evidence-based, second-line options when hormone relapse occurs.10 One key question is whether or not we should all carefully monitor our own, and our patients’, PSA levels over time, and respond to a rise by organising a 3-Tesla MRI and a targeted biopsy of the prostate to achieve early detection. In one of the four cases (JA), the PSA was negative only a few months before presentation; in another (SV), the PSA rose from 1.4 to 78ng/ml over an 18-month time frame. Clearly, annual PSA testing would not have been helpful in either of these situations. New, better ways are needed to identify poorly differentiated, aggressive prostate cancers as they often do not manufacture and secrete PSA in their early, potentially curative stages. The debate about screening for prostate cancer seems likely to run and run, especially since the ERSPC2 reported a positive result, while the US-based Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial11 produced a negative one. To compound the problem, while a Scandinavian study of radical prostatectomy versus watchful waiting revealed a survival advantage for patients treated surgically,12 the US-based Prostate Cancer Intervention versus Observation Trial (PIVOT) showed no benefit.13 TRENDS IN UROLOGY & MEN’S HEALTH MARCH/APRIL 2013 There is at last a realistic prospect for more targeted screening of those most susceptible to the disease.14 More than 30 prostate cancer susceptibility genes have been identified and it seems possible that men unlikely to develop prostate cancer could be excluded from screening protocols and instead attention focused on those most likely to develop the disease. Much remains to be done to improve awareness about the risks of prostate cancer, among not only urologists, but also family practitioners and the general public. Although screening is still controversial, better treatments for hormone-relapsed disease are now becoming available. We sincerely hope that the openness about our own diagnoses and management will help to dispel the taboo that still haunts this most common of cancers of men. 5. 6. 7. 8. 9. 10. 11. REFERENCES 1. 2. 3. Kirby RS, Challacombe B, Dasgupta P, Fitzpatrick JM. Prostate cancer treatment: the times they are a’ changin’. BJU Int 2012;110:1408–11. Schröder FH, Hugosson J, Roobol MJ, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012;366:981–90. Lees K, Durve M, Parker C. Active surveillance in prostate cancer: patient selection and 13. 14. triggers for intervention. Curr Opin Urol 2012;22:210–5. Klotz L. Active surveillance for favorable-risk prostate cancer: background, patient selection, triggers for intervention, and outcomes. Curr Urol Rep 2012;13:153–9. NICE. Prostate cancer: diagnosis and treatment. Clinical guideline 58. February 2008. http://guidance.nice.org.uk/CG58 Godtman RA, Holmberg E, Khatami A, et al. Outcome following active surveillance of men with screen-detected prostate cancer. Results from the Göteborg randomised population-based prostate cancer screening trial. Eur Urol 2013;63:101–7. Ryan CJ, Smith MR, de Bono JS, et al; the COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368:138. Berruti A, Generali D, Tampellini M. Enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367: 2448–9. Croke J, Leung E, Segal R, Malone S. Clinical benefits of alpharadin in castratechemotherapy-resistant prostate cancer: case report and literature review. BMJ Case Rep 2012; doi: 10.1136/bcr-2012-00654. Kirby R, Fitzpatrick JM. Improved survival prospects for patients with castrationresistant prostate cancer. BJU Int 2011; 107:697–700. Andriole GL, Crawford D, Grubb RL, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009;360:1310–19. 12. Bill-Axelson A, Holmberg L, Filén F, et al. for the Scandinavian Prostate Cancer Group Study Number 4. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian Prostate Cancer Group-4 Randomized Trial. J Natl Cancer Inst 2008;100:1144–54. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012;367:203–13. Kirby RS, Eeles RA, Kote-Jarai Z, et al. Screening for prostate cancer: the way ahead. BJU Int 2010;105:295–7. www.trendsinurology.com