Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

A multicentre assessment of prostate MRI quality and compliance with UK and international standards.

AIM: To assess prostate magnetic resonance imaging (MRI) image quality and compliance with technical standards between centres in the South West region of the UK. MATERIALS AND METHODS: Fifteen imaging sites in the region submitted seven consecutive anonymised MRI studies. These were assessed by two experienced radiologists in consensus. Overall, subjective image quality for T2-weighted imaging (T2W), diffusion weighted imaging (DWI), and dynamic contrast enhancement (DCE) was scored on a five-point Likert scale. Five additional quality parameters were also assessed visually, including image noise, motion, artefact, and distortion. The degree of compliance by each site with 21 published technical standards was also assessed. RESULTS: Ninety-four MRI examinations were reviewed from across all sites (mean 6.3 scans per site, range 5-7). Mean compliance with technical standards was 63% (range 38-86%). Forty-seven percent of sites did not perform DCE. One site used a 3 T scanner. The percentage of patients with overall quality scores of ≥3 (diagnostically acceptable) were 68% for T2W, 81% for DWI, and 60% for both T2W and DWI. Ninety-three percent of the 45 patients who underwent DCE had diagnostically acceptable studies. By scanner age, the percentage of patients with diagnostically acceptable T2W scores was 53% for scanners ≥7 years and 80% when <7 years (p=0.006). Comparing individual sites, the mean overall quality scores were 2.9 (range 2.2-4.2) for T2W, 3.2 (1.8-4.7) for DWI, and 3.4 (2.5-4.7) for DCE. CONCLUSION: There is wide variation in compliance with recognised technical standards and image quality across sites. If MRI is to replace biopsy in selected low-risk patients, improvements in image quality may be required.

Towards total voluntary non-remunerated blood donation in Trinidad and Tobago

Objective: Investigate the historical origins of voluntary nonremunerated blood donation (VNRD) and describe a UWI-led initiative. Design and Methodology: Historical review was performed using internet searches, documents, books, journals, interviews. Data from blood donor cards and Microsoft Excel spreadsheets was collected prospectively and analysed retrospectively. Donors were classified by age, gender, donation status (first-time or repeat) and donation outcome (accepted or deferred). The prevalence of transfusion transmissible infections and deferrals in donors was compared to the national donor pool using Chi square analysis to compare proportions and a p value < 0.05 to assign statistical significance. Results: Human to human blood transfusion and voluntary non-remunerated blood donation were first practised in metropolitan countries and amplified in large scale community blood donation programmes during World War II. Blood donation systems based on individual, transactional donations emerged in most developing countries, including Trinidad and Tobago, causing low donation rates, chronic blood shortage, unequal access, high donor infections and high donor deferrals. A voluntary non-remunerated blood donation programme started by the UWI Blood Donor Foundation and the North Central Health Authority has collected 660 units of blood in its first three years, the majority from persons aged 16 -25 age (52%), females (52%) and repeat donors (51%). Deferrals were < 10% and total transfusion transmissible infections in donors 0.9% compared with 43.6% and 2.4 % respectively (p < 0.05 for both) for the involuntary national donor pool. Conclusion: This model could be extended to all blood donation centres and the community to achieve 100% VNRD.

A systematic review of PFE pre-prostatectomy.

Male Stress Urinary Incontinence is a complication post robotic radical prostatectomy. This is a major problem that needs to be solved, since it has great impact on quality of life affecting the patient's physical activity and social well-being. A systematic review relating to literature on impact of preoperative PFE on continence outcomes for patients undergoing prostatectomy was conducted. The search strategy aimed to identify all references related to pelvic floor exercises and post-prostatectomy. Search terms used were as follows: (Pelvic floor exercises) AND (incontinence) AND (prostatectomy). The following databases were screened from 2000 to September 2017: CINAHL, MEDLINE (NHS Evidence), Cochrane, AMed, EMBASE, PsychINFO, SCOPUS, Web of Science. In addition, searches using Medical Subject Headings (MeSH) and keywords were conducted using Cochrane databases. Two UK-based experts in prostate cancer and robotic surgery were consulted to identify any additional studies. In the 6 months following surgery, the continence rates, as defined by the use of one pad or less per day, were 94% (44 of 47) and 96% (48 of 50) in the PFE and biofeedback groups and control groups (PFE alone), respectively (P = 0.596) (Bales et al. in Urology 56: 627-630, 2000). This demonstrates preoperative PFE may improve early continence after RP. Geraerts et al. (Eur Urol 64:766-772, 2013) demonstrated the "incontinence impact" was in favour of a group with PFE at 3 and 6 months after surgery. This demonstrates again the advantage of preoperative PFE. Cornel et al. [World J Urol 23:353-355, 2005] determined the benefit of starting pelvic floor muscle exercise (PFE) 30 days before RP and of continuing PFE postoperatively for early recovery of continence as part of a randomised, prospective study (Moher quality A). This demonstrated preoperative PFE may improve early continence and QoL outcomes after RP. Post-prostatectomy incontinence is a bothersome complication of radical prostatectomy [Chughtai et al. in Rev Urol 15:61-66, 2013]. Weak pelvic floor muscles compromised normal pelvic floor function and led to urinary incontinence and erectile dysfunction. Strengthening the pelvic floor muscles was shown to significantly improve post-prostatectomy urinary continence, post-micturition dribble and erectile function. It would be prudent for all men to exercise their pelvic floor muscles to maintain normal pelvic floor function and start prior to surgery.

Radical prostatectomy for locally advanced and metastatic prostate cancer.

The management of advanced prostate cancer remains challenging. Traditionally, radical prostatectomy was discouraged in patients with locally advanced or node positive disease owing to the increased complication rate and treatment related morbidity. However, technical advances and refinements in surgical techniques have enabled the outcomes for patients with high risk prostate cancer to be improved. More recently, the concept of cytoreductive prostatectomy has been described where surgery (often Combined with an extended lymph node dissection) is performed in the setting of metastatic disease. Indirect evidence suggests an advantage using the cytoreductive approach. Hypothetical explanations for this observed benefit include decreased tumour burden, immune modulation, improved response to secondary treatment and avoidance of secondary complications attributable to local tumour growth. Nevertheless, prospective trials are required to investigate this further.

Hyperglycaemia-induced resistance to Docetaxel is negated by metformin: a role for IGFBP-2.

The incidence of many common cancers varies between different populations and appears to be affected by a Western lifestyle. Highly proliferative malignant cells require sufficient levels of nutrients for their anabolic activity. Therefore, targeting genes and pathways involved in metabolic pathways could yield future therapeutics. A common pathway implicated in energetic and nutritional requirements of a cell is the LKB1/AMPK pathway. Metformin is a widely studied anti-diabetic drug, which improves glycaemia in patients with type 2 diabetes by targeting this pathway. We investigated the effect of metformin on prostate cancer cell lines and evaluated its mechanism of action using DU145, LNCaP, PC3 and VCaP prostate cancer cell lines. Trypan blue dye-exclusion assay was used to assess levels of cell death. Western immunoblotting was used to determine the abundance of proteins. Insulin-like growth factor-binding protein-2 (IGFBP-2) and AMPK genes were silenced using siRNA. Effects on cell morphology were visualised using microscopy. IGFBP-2 gene expression was assessed using real-time RT-PCR. With DU145 and LNCaP cells metformin alone induced cell death, but this was reduced in hyperglycaemic conditions. Hyperglycaemia also reduced the sensitivity to Docetaxel, but this was countered by co-treatment with metformin. LKB1 was required for the activation of AMPK but was not essential to mediate the induction of cell death. An alternative pathway by which metformin exerted its action was through downregulation of IGFBP-2 in DU145 and LNCaP cells, independently of AMPK. This finding could have important implications in relation to therapeutic strategies in prostate cancer patients presenting with diabetes.

Erectile function post robotic radical prostatectomy: technical tips to improve outcomes?

Robotic surgery is becoming more and more commonplace. At the same time, so are complications, especially related to erectile function. The population being diagnosed with cancer is younger, with more aggressive cancers and higher expectations for good erectile function postoperatively. We conduct a retrospective analysis of literature over 20 years for Embase and Medline. Search terms used include (Robotic) AND (prostatectomy) AND (erectile function). There are a variety of multifactorial causes, resulting in worsening ED post-robotic radical prostatectomy; however, there are a number of treatments that can support this. There is much we can do to help prevent patients getting postoperative erectile dysfunction post-radical surgery. However, part of this is management of realistic patient expectations.

Prostate cancer and supportive care: a systematic review and qualitative synthesis of men's experiences and unmet needs.

Prostate cancer is the second most common cancer in men worldwide, accounting for an estimated 1.1 million new cases diagnosed in 2012 (www.globocan.iarc.fr). Currently, there is a lack of specific guidance on supportive care for men with prostate cancer. This article describes a qualitative systematic review and synthesis examining men's experience of and need for supportive care. Seven databases were searched; 20 journal articles were identified and critically appraised. A thematic synthesis was conducted in which descriptive themes were drawn out of the data. These were peer support, support from partner, online support, cancer specialist nurse support, self-care, communication with health professionals, unmet needs (emotional support, information needs, support for treatment-induced side effects of incontinence and erectile dysfunction) and men's suggestions for improved delivery of supportive care. This was followed by the development of overarching analytic themes which were: uncertainty, reframing, and the timing of receiving treatment, information and support. Our results show that the most valued form of support men experienced following diagnosis was one-to-one peer support and support from partners. This review highlights the need for improved access to cancer specialist nurses throughout the care pathway, individually tailored supportive care and psychosexual support for treatment side effects.

Hyperglycaemia-induced chemoresistance of prostate cancer cells due to IGFBP2.

Clinically relevant prostate cancer (PCa) is more frequent in Westernised societies and increasingly men have co-morbidities associated with a Western lifestyle, primarily diabetes, characterised by hyperinsulinaemia and hyperglycaemia. IGFs and their binding proteins (IGFBPs) are important mediators of the effects of nutrition on growth and play a key role in the development of PCa. We used DU145, PC3 and LNCaP PCa cell lines to examine how hyperglycaemia altered their response to docetaxel. Trypan Blue dye-exclusion assay was used to determine the percentage of cell death. Protein abundance was determined using western immunoblotting. Levels of IGFBP2 were measured using an ELISA. IGFBP2 gene silencing was achieved using siRNA technology. DNA methylation was assessed using combined bisulphide restriction analysis. Acetylation status of histones H3 and H4 associated with IGFBP2 gene was assessed using chromatin immunoprecipitation assay. Hyperglycaemia reduced docetaxel-induced apoptosis by 40% for DU145 cells and by 88% for LNCaP cells. This reduced cell death was mediated by a glucose-induced up-regulation of IGFBP2, as silencing IGFBP2 negated the survival effect of high glucose. Glucose increased IGFBP2 via increasing the acetylation of histones associated with the IGFBP2 gene promoter. This finding could have important implications in relation to therapeutic strategies as epigenetic modulation could be reversible.

A multi-centre prospective development study evaluating focal therapy using high intensity focused ultrasound for localised prostate cancer: The INDEX study.

INTRODUCTION: Focal therapy offers the possibility of cancer control, without the side effect profile of radical therapies. Early single centre prospective development studies using high intensity focused ultrasound (HIFU) have demonstrated encouraging genitourinary functional preservation and short-term cancer control. Large multi-centre trials are required to evaluate medium-term cancer control and reproduce functional recovery. We describe the study design of an investigator-led UK multi-centre, single arm trial using HIFU to deliver focal therapy for men with localised prostate cancer. METHODS: One-hundred and forty men with histologically proven localised low or intermediate risk prostate cancer (PSA < 15, Gleason ≤ 7, ≤ T2cN0M0) will undergo precise characterisation of the prostate using a combination of multi-parametric (mp)MRI and transperineal template prostate mapping (TPM) biopsies. Unilateral dominant tumours, the so-called index lesion, will be eligible for treatment provided the contra-lateral side is free of 'clinically significant' disease (as defined by Gleason ≥ 7 or maximum cancer core length ≥4 mm). Patients will receive focal therapy using HIFU (Sonablate 500®). Treatment effect will be assessed by targeted biopsies of the treated area and TPM biopsies at 36-months. RESULTS: Primary outcome is the absence of clinically significant disease based on 36-month post-treatment TPM biopsies. Secondary outcomes address a) genitourinary function using validated patient questionnaires (IPSS, IPSS-QoL, IIEF-15, EPIC-Urinary, EPIC-Bowel, FACT-P, EQ-5D), b) the predictive validity of imaging, and c) risk factors for treatment failure. CONCLUSIONS: INDEX will be the first multi-centre, medium term follow-up trial to evaluate the outcomes of a tissue preserving strategy for men with localised prostate cancer using the TPM-ablate-TPM strategy.

Management of prostate cancer.

Prostate cancer is diagnosed in 37 000 new patients a year, and causes 10 000 deaths each year in the UK (Cancer Research UK, 2011). Diagnoses are increasingly the result of screening using measurement of prostate- specific antigen levels. The natural history of early disease is unclear. Autopsy studies before prostate-specific antigen screening showed an actual latent prevalence (not diagnosed during life) of around 30% at the age of 50 years and 75% at the age of 80 years, and many of these demonstrated local invasion (Franks, 1954). One of the main current challenges in urology is distinguishing indolent prostate cancers from potentially lethal ones. The specificity of the prostate-specific antigen test for clinically significant disease remains disappointingly low and population screening is not encouraged (Ilic et al, 2011). However, prostate-specific antigen testing is often done in good faith, but pre-test counselling is essential. Thus, prostate-specific antigen testing should only be undertaken by the patient's GP or on the advice of a urologist.