Randomised Trial of No, Short-term, or Long-term Androgen Deprivation Therapy with Postoperative Radiotherapy After Radical Prostatectomy: Results from the Three-way Comparison of RADICALS-HD (NCT00541047).

BACKGROUND AND OBJECTIVE: The use and duration of androgen deprivation therapy (ADT) with postoperative radiotherapy (RT) have been uncertain. RADICALS-HD compared adding no ("None"), 6-months ("Short"), or 24-mo ("Long") ADT to study efficacy in the long term. METHODS: Participants with prostate cancer were indicated for postoperative RT and agreed randomisation between all durations. ADT was allocated for 0, 6, or 24 mo. The primary outcome measure (OM) was metastasis-free survival (MFS). The secondary OMs included freedom from distant metastasis, overall survival, and initiation of nonprotocol ADT. Sample size was determined by two-way comparisons. Analyses followed standard time-to-event approaches and intention-to-treat principles. KEY FINDINGS AND LIMITATIONS: Between 2007 and 2015, 492 participants were randomised one of three groups: 166 None, 164 Short, and 162 Long. The median age at randomisation was 66 yr; Gleason scores at surgery were as follows: <7 = 64 (13%), 3+4 = 229 (47%), 4+3 = 127 (26%), and 8+ = 72 (15%); T3b was 112 (23%); and T4 was 5 (1%). The median follow-up was 9.0 yr and, with MFS events reported for 89 participants (32 None, 31 Short, and 26 Long), there was no evidence of difference in MFS overall (logrank p = 0.98), and, for Long versus None, hazard ratio = 0.948 (95% confidence interval 0.54-1.68). After 10 yr, 80% None, 77% Short, and 81% Long patients were alive without metastatic disease. The three-way randomisation was not powered to conventional levels for assessment, yet provides a fair comparison. CONCLUSIONS AND CLINICAL IMPLICATIONS: Long-term outcomes after radical prostatectomy are usually favourable. In those indicated for postoperative RT and considered suitable for no, short-term, or long-term ADT, there was no evidence of improvement with addition of ADT. Future research should focus on patients at a higher risk of metastases in whom improvements are required more urgently.

Admissions to hospital due to fracture in England in patients with prostate cancer treated with androgen-deprivation therapy - do we have to worry about the hormones?

OBJECTIVE: To investigate the association between androgen-deprivation therapy (ADT) and fracture risk in men with prostate cancer in England. PATIENTS AND METHODS: Using the Hospital Episodes Statistics database, which contains all the information about National Health Service (NHS) and NHS-funded hospital admissions in England, for the years 2004-2008, 8 902 patients were found to have had prostate cancer and an admission to hospital with a fracture. Of these patients, 3 372 (37.8%) were identified as being treated with ADT, whilst 5 530 (62.2%) were not. There was a total of 228 852 admissions in the background population. RESULTS: The risk of a fracture requiring hospitalisation increased from 1.12 to 1.41 per 100 person-years in a man with prostate cancer treated with ADT compared with those without ADT, an absolute increase of only 0.29 per 100 person-years. When compared with the background population, there was an increase from 0.58 to 1.41 per 100 person-years, a relative rate ratio increase of 2.4 (P < 0.01) with an absolute increase of 0.83 per 100 person-years. CONCLUSION: In England there was a small but statistically significant increased risk of fracture in men who had been treated with ADT. Men with prostate cancer, with or without ADT, were at an increased risk of fracture compared with the background population. We therefore suggest that if bone health is to be taken seriously in men with prostate cancer that all these men should be risk assessed (FRAX(®) or Qfracture(®) tools, as National Institute for Health and Care Excellence advised), as all men with prostate cancer have an increased risk of fracture, with those on ADT having slightly higher risk.

Current Status of Hemostatic Agents and Sealants in Urologic Surgical Practice.

There has been a recent and near exponential increase in the use of hemostatic agents and sealants to supplement the rapidly evolving methods in the surgical management of urologic patients. This article reviews the use of hemostatic agents and sealants in current urologic practice.

The penile tourniquet.

Tourniquets are commonly used in penile surgery to achieve a bloodless operating field or produce artificial erections intraoperatively. Several techniques have been described, but there is a paucity of data and a lack of guidelines to direct their safe use. In penile surgery, it is the local rather than systemic effects of tourniquet use that are the main concern. Tourniquet time should be kept to a minimum, as the limited data available suggests that reperfusion injury can occur even after short periods of ischaemia. High risk groups such as diabetics and arteriopaths are at particular risk. Further studies are needed to determine safe tourniquet times and pressures.

Prognosis is deteriorating for upper tract urothelial cancer: data for England 1985-2010.

OBJECTIVE: To ascertain current trends in the incidence and mortality rates for upper tract urothelial cancer (UTUC) and identify any relationship with age, stage at presentation, social deprivation and treatment method. PATIENTS AND METHODS: We used national databases to collect the data: incidence, stage and survival data from the National Cancer Data Repository (NCDR) and British Association of Urological Surgeons (BAUS) audit database; mortality data from the Office for National Statistics (ONS); and treatment method data from the Hospital Episodes Statistics (HES). RESULTS: The incidence of UTUC is increasing (from 1985 to 2009 it increased by 38% in men and 77% in women). It affects mainly those aged >60 years, and diagnoses are increasingly made in those aged >80 years. Diagnoses at advanced stage have increased from 45 to 80%. Mortality has risen faster than incidence; the overall 5-year survival rate has dropped from 60 to 48%. Survival is worst in stage IV disease and in patients aged ≥80 years; when analysed by age or stage group, survival rates are unchanged. Nephroureterectomy has increased by 75%, but endoscopic treatment, which only became available part way through the study period, now accounts for 11% of surgical interventions for UTUC, mainly in stage I disease and in the elderly. CONCLUSIONS: Despite sharing its risk factors with bladder cancer, current incidence and mortality trends for UTUC contrast with those in bladder cancer. Increasing use of cross-sectional imaging may explain some of the identified increased incidence. Higher incidence specifically in people >80 years, together with stage migration to more advanced cancers, are likely to have caused at least some of the observed increased mortality. Further study is required to answer the questions of whether there are other hitherto unidentified aetiological or prognostic factors; whether less aggressive treatment of UTUCs in the elderly is always justified; and whether the rising frequency of minimally invasive treatment means suboptimum oncological management.

Competition amongst Eph receptors regulates contact inhibition of locomotion and invasiveness in prostate cancer cells.

Metastatic cancer cells typically fail to halt migration on contact with non-cancer cells. This invasiveness is in contrast to normal mesenchymal cells that retract on contact with another cell. Why cancer cells are defective in contact inhibition of locomotion is not understood. Here, we analyse the dynamics of prostate cancer cell lines co-cultured with fibroblasts, and demonstrate that a combinatorial code of Eph receptor activation dictates whether cell migration will be contact inhibited. The unimpeded migration of metastatic PC-3 cells towards fibroblasts is dependent on activation of EphB3 and EphB4 by ephrin-B2, which we show activates Cdc42 and cell migration. Knockdown of EphB3 and EphB4 restores contact inhibition of locomotion to PC-3 cells. Conversely, homotypic collisions between two cancer cells results in contact inhibition of locomotion, mediated by EphA-Rho-Rho kinase (ROCK) signalling. Thus, the migration of cancer cells can switch from restrained to invasive, depending on the Eph-receptor profile of the cancer cell and the reciprocal ephrin ligands expressed by neighbouring cells.

Genetic polymorphisms in the DNA repair genes XPD and XRCC1, p53 gene mutations and bladder cancer risk.

Previous studies have suggested that certain genetic polymorphisms, specifically the Xeroderma pigmentosum group D (XPD) gene codon 751 and the X-ray repair cross-complementing group 1 (XRCC1) gene codon 399 polymorphisms, were associated with an increased risk of lung cancer, and, in some studies, with a greater risk for mutations in the p53 tumor suppressor gene in lung tumors. To evaluate whether these gene polymorphisms may be associated with an increased risk for bladder cancer or in association with p53 mutation status in bladder tumors, we screened for polymorphisms at XPD codons 751 and XRCC1 codon 399 in DNA isolated from blood of 194 bladder cancer patients and 313 healthy controls and for mutations in exons 4 to 8 of the p53 gene in bladder tumor DNA from 174 bladder cancer patients. There was a significantly higher prevalence of the XPD 751 Gln allele among the bladder cancer group, compared with the control group. No association was found between bladder cancer risk and the XRCC1 399 polymorphism. p53 mutations were found in 20.1% (35/174) patients. There was no difference in p53 mutation status among individuals with different genotypes. These results suggest that individuals who have the XPD 751 Gln allele may be at an increased risk for bladder cancer, although this may not lead to an increased risk for mutations in the p53 gene.

Serum insulin-like growth factor-I is positively associated with serum prostate-specific antigen in middle-aged men without evidence of prostate cancer.

We have examined the relationship between serum insulin-like growth factor-I (IGF-I) and prostate-specific antigen in 367 healthy men without evidence of prostate cancer and found a positive association (P = 0.05). In men without prostate cancer, serum prostate-specific antigen is closely related to prostate size, and our findings, therefore, suggest that IGF-I may induce prostatic epithelial proliferation. Higher circulating levels of IGF-I have been associated with increased risk of both prostate cancer and possibly benign prostatic hyperplasia. Greater rates of cell proliferation induced by IGF-I may be a key biological pathway underlying these disorders.