Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

What is the optimal systemic treatment of men with metastatic, hormone-naive prostate cancer? A STOPCAP systematic review and network meta-analysis.

Background: Our prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies. Methods: Overall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed. Results: We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53-0.71], Doc (HR = 0.77, 95% CI 0.68-0.87), ZA + Cel (HR = 0.78, 95% CI 0.62-0.97), ZA + Doc (HR = 0.79, 95% CI 0.66-0.94), Cel (HR = 0.94 95% CI 0.75-1.17) and ZA (HR = 0.90 95% CI 0.79-1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability). Conclusions: Uniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

The volume of liver irradiated during modern free-breathing breast radiotherapy: Implications for theory and practice.

INTRODUCTION: Incidental liver irradiation during breast radiotherapy can increase the risk of second primary malignancy and induce adverse inflammatory states. This study establishes the volume of liver irradiated during free-breathing breast radiotherapy. Novel associations between liver dose-volume data and systemic interleukin-6 soluble receptor and blood counts are evaluated. METHODS: The volume of liver within the 10%, 50% and 90% isodose was determined for 100 women with stage 0 to II breast carcinoma undergoing 40Gy in 15 fractions over three weeks tangential irradiation. Blood counts and interleukin 6 soluble receptor concentration were recorded before, during and four weeks after radiotherapy. Dose-volume data for right-sided treatments was associated with longitudinal measures at bivariate and multivariable levels. RESULTS: A maximum of 226cm3 (19%), 92 cm3 (8%) and 62 cm3 (5%) of the liver was irradiated within the 10%, 50% and 90% isodose. Liver irradiation was almost exclusively a feature of the 52 right-sided treatments and was strongly correlated with breast volume (ρ = 0.7, p < 0.0001). Liver V10% was significantly associated with interleukin-6 soluble receptor concentration four weeks post-radiotherapy (beta = 0.38, p = 0.01) after controlling for theoretical confounding variables. CONCLUSION: Up to 8% of the liver is irradiated within the primary beam during local right-sided breast radiotherapy. Select use of a deep inspiration breath hold technique would reduce this volume, and minimise the risk of radiation-induced malignancy and acute systemic elevation of inflammatory interleukin 6 soluble receptor.

Radiotherapy after radical prostatectomy for adenocarcinoma of the prostate: a UK institutional experience and review of published studies.

AIMS: The role of radiotherapy to the prostate bed after radical prostatectomy is the subject of much debate. We carried out a retrospective analysis of all patients treated with either adjuvant radiotherapy (ART) or salvage radiotherapy (SRT) in a single UK cancer centre and compared outcomes with published studies. MATERIALS AND METHODS: All patients receiving radiotherapy at any time after a radical prostatectomy were identified and data collected. Patients were referred for ART because of positive surgical margins. SRT was carried out in patients with a detectable or rising prostate-specific antigen (PSA) postoperatively. Patients received either 55 Gy in 20 fractions or 60-64 Gy in 30-32 fractions. All but eight patients were treated using three-dimensional conformal radiotherapy. Both groups were combined for statistical analysis. Biochemical progression-free survival (BPFS) was calculated and displayed using Kaplan-Meier curves. Cox regression was used for univariate and multivariate analysis. RESULTS: In total, 40 patients received postoperative radiotherapy and had a 3-year overall BPFS of 64%. There was no significant difference in 3-year BPFS between ART and SRT (73% vs 61%, P=0.33). Univariate analysis showed that 3-year BPFS was significantly longer if the highest postoperative PSA was<0.5 ng/ml compared with> or =0.5 ng/ml (83% vs 47%, P=0.019), and if the Gleason grade was <7 compared with > or =7 (92% vs 49%, P=0.007). A PSA at diagnosis<10 ng/ml, positive surgical margins, absence of seminal vesicle involvement and neoadjuvant hormones were all associated with a trend towards improved BPFS. Patients with all of these factors had a 3-year BPFS of 91%. Multivariate analysis of the same parameters showed that only Gleason grade remained statistically significant (P=0.019). CONCLUSIONS: The results from this series are in line with published studies, and support the evidence that prostate bed radiotherapy may affect biochemical control in a proportion of patients at risk of relapse. It is not clear whether ART in patients at high risk of relapse or SRT on relapse is most effective.

Cryotherapy for localised prostate cancer.

BACKGROUND: Prostate cancer is a common cancer in elderly men and in some will prove fatal. Standard treatments for localised disease include surgery ( radical prostatectomy), radiotherapy and active monitoring. New emerging therapies are being evaluated with the aim of reducing the complication rate associated with standard therapies, as well as developing an effective treatment. One such modality is cryotherapy, a procedure that introduces probes directly into the prostate tumour and kills the malignant cells by a freezing process. OBJECTIVES: This review aims to evaluate the relative clinical and economic benefits of cryotherapy compared to standard therapies for the primary treatment of localised prostate cancer. SEARCH STRATEGY: Our search strategy included an electronic search of MEDLINE from 1996 to December 2006, plus EMBASE (Excerpta Medica Database), the Cochrane library, ISI Science Citation Index, Database of Abstracts and Reviews of Effectiveness (DARE), and LILACS to identify all relevant published randomised trials of cryotherapy for localised prostate cancer. Cancerlit and HealthSTAR databases were searched to their final date. Handsearching of relevant journals was undertaken. SELECTION CRITERIA: Only published randomised trials comparing the effectiveness of cryotherapy with radical prostatectomy, radiotherapy or active monitoring for the primary treatment of men with localised prostate cancer were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: Data were extracted from eligible studies, and included study design, participants, interventions and outcomes. Primary outcome measures were biochemical disease-free survival, disease-free survival and treatment-induced complications. Secondary outcomes included disease-specific survival, overall survival, quality-of-life outcome measures and economic impact measures. MAIN RESULTS: There were no randomised trials found comparing cryotherapy with other therapies for the primary treatment of localised prostate cancer. All studies identified were case series. To indicate the level of the available evidence, studies that evaluated cryotherapy as a primary therapy, using transrectal ultrasound guidance and urethral warming in at least 50 patients with localised prostate cancer, and a minimum of one year follow up, were reviewed. Eight case series were identified that complied with these criteria; two were retrospective. The patients recruited (n = 1483) had an age range from 41 to 84 years, stages T1 = 0 to 43%, T2 = 24 to 88%, T3 = 1 to 41%, and T4 = 0 to 14%. The mean preoperative PSA level ranged from 9.7 to 39 ng/mL, with Gleason scores < 7 and ranging from 6 to 37%. One additional study that compared cryotherapy (total cryotherapy and standard cryotherapy with urethral preservation) with radical prostatectomy was also identified and reviewed. In this study the success rates, defined as a post-treatment PSA of 0.2 ng/mL or less, were reported as 96% for total cryotherapy, 49% for standard cryotherapy and 73% for radical prostatectomy. Four studies did not monitor the temperature of the cyro-procedure and reported 17 to 28% of patients had a positive biopsy following cryotherapy with a mean PSA nadir of 0.55 to 1.75 ng/mL (median 0.4 to 1.85 ng/mL). The other four studies used thermocouples to monitor the temperature of the cryo-procedure and reported progression-free survival rates of 71 to 89% with 1.4 to 13% of patients having a positive biopsy post-cryotherapy. At 5 years, overall survival was reported as 89 to 92% in two studies, and disease-specific survival as 94% in one study. The major complications observed in all studies included impotence (47 to 100%), incontinence (1.3 to 19%), and urethral sloughing (3.9 to 85%), with less common complications of fistula (0 to 2%), bladder-neck obstruction (2 to 55%), stricture (2.2 to 17%) and pain (0.4 to 3.1%). Most patients were sent home the following day (range 1 to 4 days). AUTHORS' CONCLUSIONS: Cryotherapy offers a potential alternative to standard therapies for the primary treatment of localised prostate cancer. However, the poor quality of the available studies makes it difficult to determine the relative benefits of this modality. Randomised trials are needed to fully evaluate the full potential of cryotherapy in men with this disease. Patients selecting cryotherapy as their therapeutic option should be made fully aware of the reported efficacy, complications and the low-grade evidence from which these data are derived.

Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial.

BACKGROUND: Adjuvant radiotherapy is effective treatment for stage I seminoma, but is associated with a risk of late non-germ-cell cancer and cardiovascular events. After good results in initial studies with one injection of carboplatin, we undertook a large randomised trial to compare the approaches of radiotherapy with chemotherapy in seminoma treatment. METHODS: Between 1996 and 2001, 1477 patients from 70 hospitals in 14 countries were randomly assigned to receive radiotherapy (para-aortic strip or dog-leg field; n=904) or one injection of carboplatin (n=573; dose based on the formula 7x[glomerular filtration rate+25] mg), at two trial centres in the UK and Belgium. The primary outcome measure was the relapse-free rate, with the trial powered to exclude absolute differences in 2-year rates of more than 3%. Analysis was by intention to treat and per protocol. This trial has been assigned the International Standard Randomised Controlled Trial Number ISRCTN27163214. FINDINGS: 885 and 560 patients received radiotherapy and carboplatin, respectively. With a median follow-up of 4 years (IQR 3.0-4.9), relapse-free survival rates for radiotherapy and carboplatin were similar (96.7% [95% CI 95.3-97.7] vs 97.7% [96.0-98.6] at 2 years; 95.9% [94.4-97.1] vs 94.8% [92.5-96.4] at 3 years, respectively; hazard ratio 1.28 [90% CI 0.85-1.93], p=0.32). At 2 years' follow-up, the absolute differences in relapse-free rates (radiotherapy-chemotherapy) were -1.0% (90% CI -2.5 to 0.5) by direct comparison of proportions, and 0.9% (-0.5 to 3.0) by a hazard-ratio-based approach. Patients given carboplatin were less lethargic and less likely to take time off work than those given radiotherapy. New, second primary testicular germ-cell tumours were reported in ten patients allocated irradiation (all after para-aortic strip field) and two allocated carboplatin (5-year event rate 1.96% [95% CI 1.0-3.8] vs 0.54% [0.1-2.1], p=0.04). One seminoma-related death occurred after radiotherapy and none after carboplatin. INTERPRETATION: This trial has shown the non-inferiority of carboplatin to radiotherapy in the treatment of stage I seminoma. Although the absence of disease-related deaths and preliminary data indicating fewer second primary testicular germ-cell tumours favour carboplatin use, these findings need to be confirmed beyond 4 years' follow-up.

The influence of CD44v3-v10 on adhesion, invasion and MMP-14 expression in prostate cancer cells.

The expression of certain CD44 variants has been linked with metastasis and tumour progression. In particular, high molecular weight forms of CD44 show restricted expression in tumours and may correlate with tumour development and metastasis. In this study, we examined the expression of CD44 variants in prostate cancer cell lines: the invasive PC-3 and DU-145, low invasive LNCaP, and two non-invasive prostate epithelial cell lines. PC-3 prostate cancer cells were transfected with a high molecular weight CD44 variant isoform, CD44v3-v10, isolated from non-invasive prostate epithelial cell lines. These transfected cells (PC-NIVO) were assessed using in vitro invasion, tumour-endothelial, growth, and migration assays. The expression of MMP-14 was examined using SDS-PAGE and Western blot analysis. Transfected PC-3 cells (PC-NIVO) were found to be less adherent to endothelial cells and had significantly reduced invasiveness compared to wild-type PC-3 or control cells. In addition, tumour cell adhesion to endothelial cells and invasiveness was increased after exposure to HGF/SF, and can be blocked by the presence of anti-CD44 antibodies. Further investigation revealed a reduction in the expression of MMP-14 in PC-NIVO cells, but not in PC-3 or control cells. In conclusion, non-invasive prostate epithelial cells express a high molecular weight CD44 isoform, CD44v3-v10, which may counteract the standard isoform function of CD44 by reducing adhesion and invasion of endothelium by prostate tumour cells through negation of the MMP-14 function.

Neo-adjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer.

BACKGROUND: Hormone therapy for early prostate cancer has demonstrated an improvement in clinical and pathological variables, but not always an improvement in overall survival. We performed a systematic review of both adjuvant and neo-adjuvant hormone therapy combined with surgery or radiotherapy in localised or locally advanced prostate cancer. OBJECTIVES: The objective of this review was to undertake a systematic review and, if possible, a meta-analysis of neo-adjuvant and adjuvant hormone therapy in localised or locally advanced prostate cancer. SEARCH STRATEGY: We searched MEDLINE (1966-2006), EMBASE, The Cochrane Library, Science Citation Index, LILACS, and SIGLE for relevant randomised trials. Handsearching of appropriate publications was also undertaken. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of patients with localised or locally advanced prostate cancer, that is, stages T1-T4, any N, M0, comparing neo-adjuvant or adjuvant hormonal deprivation in combination with primary therapy (radical radiotherapy or radical prostatectomy) versus primary therapy alone were included in this review. DATA COLLECTION AND ANALYSIS: Data were extracted from eligible studies and assessed for quality, and included information on study design, participants, interventions, and outcomes. Comparable data were pooled together for meta-analysis with intention-to treat principle. MAIN RESULTS: Men with prostate cancer have different clinical outcomes based on their risk (T1-T2, T3-T4, PSA levels and Gleason score). However, the majority of studies included in this review did not report results by risk groups; therefore, it was not possible to perform sub-group analysis. Neo-adjuvant hormonal therapy prior to prostatectomy did not improve overall survival (OR 1.11, 95% CI 0.67 to 1.85, P = 0.69). However, there was a significant reduction in the positive surgical margin rate (OR 0.34, 95% CI 0.27 to 0.42, P < 0.00001) and a significant improvement in other pathological variables such as lymph node involvement, pathological staging and organ confined rates. There was a borderline significant reduction of disease recurrence rates (OR 0.74, 95% CI 0.55 to 1.0, P = 0.05), in favour of treatment. The use of longer duration of neo-adjuvant hormones, that is either 6 or 8 months prior to prostatectomy, was associated with a significant reduction in positive surgical margins (OR 0.56, 95% CI 0.39 to 0.80, P = 0.002). In one study, neo-adjuvant hormones prior to radiotherapy significantly improved overall survival for Gleason 2 to 6 patients; although, in two studies, there was no improvement in disease-specific survival (OR 0.99, 95% CI 0.75 to 1.32, P = 0.97). However, there was a significant improvement in both clinical disease-free survival (OR 1.86, 95% CI 1.93 to 2.40, P < 0.00001) and biochemical disease-free survival (OR 1.93, 95% CI 1.45 to 2.56, P < 0.00001). Adjuvant androgen deprivation following prostatectomy did not significantly improve overall survival at 5 years (OR 1.50, 95% CI 0.79 to 2.85, P = 0.2); although one study reported a significant disease-specific survival advantage with adjuvant therapy (P = 0.001). In addition, there was a significant improvement in disease-free survival at both 5 years (OR 3.73, 95%CI 2.30 to 6.03, P < 0.00001) and 10 years (OR 2.06, 95% CI 1.34 to 3.15, P = 0.0009). Adjuvant therapy following radiotherapy resulted in a significant overall survival gain apparent at 5 (OR 1.46, 95% CI 1.17 to 1.83, P = 0.0009) and 10 years (OR 1.44, 95% CI 1.13 to 1.84, P = 0.003); although there was significant heterogeneity (P = 0.09 and P = 0.07, respectively). There was also a significant improvement in disease-specific survival (OR 2.10, 95% CI 1.53 to 2.88, P = 0.00001) and disease-free survival (OR 2.53, 95% CI 2.05 to 3.12, P < 0.00001) at 5 years. AUTHORS' CONCLUSIONS: Hormone therapy combined with either prostatectomy or radiotherapy is associated with significant clinical benefits in patients with local or locally advanced prostate cancer. Significant local control may be achieved when given prior to prostatectomy or radiotherapy, which may improve patient's quality of life. When given adjuvant to these primary therapies, hormone therapy, not only provides a method for local control, but there is also evidence for a significant survival advantage. However, hormone therapy is associated with significant side effects, such as hot flushes and gynaecomastia, as well as cost implications. The decision to use hormone therapy should, therefore, be taken at a local level, between the patient, clinician and policy maker, taking into account the clinical benefits, toxicity and cost. More research is needed to guide the choice, the duration, and the schedule of hormonal deprivation therapy, and the impact of long-term hormone therapy with regard to toxicity and the patient's quality of life.

Bisphosphonates for advanced prostate cancer.

BACKGROUND: Prostate cancer is the most common cancer in men in many western countries. It is characterized by its propensity for bone metastases which occur in more than 80% of patients with advanced disease. Patients are at risk of complications including pain, hypercalcaemia, bone fracture and spinal cord compression. Hormonal treatment is the mainstay of treatment for these patients but most of them will then become hormone refractory. Bisphosphonates act by inhibiting osteoclast activities and are a potential therapeutic option for metastatic prostate cancer. In addition, they have been shown to reduce pain in patients with bone metastases as a consequence of multiple myeloma. Early uncontrolled studies of bisphosphonates in metastatic prostate cancer patients have shown encouraging results. OBJECTIVES: The objective of this review was to determine the effectiveness of bisphosphonates in relieving pain in patients with bone metastases from prostate cancer. SEARCH STRATEGY: Studies were identified by electronic search of bibliographic databases including MEDLINE, EMBASE, CancerLit and the Cochrane Controlled Trials Register. Handsearching included Proceedings of American Society of Clinical Oncology and reference lists of all eligible trials identified. SELECTION CRITERIA: Randomised controlled studies comparing the effectiveness of bisphosphonates with placebo or open control for pain relief in patients with bone metastases from prostate cancer. DATA COLLECTION AND ANALYSIS: Data were extracted from eligible studies and included study design, participants, interventions and outcomes. Comparable data were pooled together for meta-analysis with intention-to-treat principle. Outcomes included pain response, analgesic consumption, skeletal events (including pathological fractures, spinal cord compression, bone radiotherapy, bone surgery), prostate cancer death, disease progression, radiological response, PSA response, adverse events, performance status, quality of life and comparisons between different routes, doses and types of bisphosphonates. MAIN RESULTS: One thousand nine hundred and fifty-five patients from ten studies were included in this review. The pain response rates were 27.9% and 21.1% for the treatment group and the control group, respectively, with an absolute risk difference of 6.8%. The OR for pain response was 1.54 (95% CI 0.97 to 2.44, P = 0.07), showing a trend of improved pain relief in the bisphosphonate group, although this was not statistically significant. The rates for skeletal events were 37.8% and 43.0% for the treatment group and the control group, respectively, with an absolute risk difference of 5.2%. The OR for skeletal events was 0.79 (95% CI 0.62 to 1.00, P = 0.05). A significant increase in nausea was observed in patients who received bisphosphonates compared to placebo. No increase in other adverse events was observed. There was no statistically significant difference between the bisphosphonate group and the control group in terms of prostate cancer death, disease progression, radiological response and PSA response. There are insufficient data to guide the choice of bisphosphonates or the dose and the route of administration . AUTHORS' CONCLUSIONS: Bisphosphonates should be considered for patients with metastatic prostate cancer for the treatment of refractory bone pain and prevention of skeletal events. More research is needed to guide the choice of bisphosphonates, optimal treatment schedule as well as cost-benefit comparisons. Combining results from different studies is difficult because different tools were used to assess pain, and also, bisphosphonates vary considerably in potency. This review highlights the need for standardisation and co-ordination among researchers in cancer pain studies.

Radiotherapy for Prostate Cancer: is it 'what you do' or 'the way that you do it'? A UK Perspective on Technique and Quality Assurance.

AIMS: The treatment of prostate cancer has evolved markedly over the last 40 years, including radiotherapy, notably with escalated dose and targeting. However, the optimal treatment for localised disease has not been established in comparative randomised trials. The aim of this article is to describe the history of prostate radiotherapy trials, including their quality assurance processes, and to compare these with the ProtecT trial. MATERIALS AND METHODS: The UK ProtecT randomised trial compares external beam conformal radiotherapy, surgery and active monitoring for clinically localised prostate cancer and will report on the primary outcome (disease-specific mortality) in 2016 following recruitment between 1999 and 2009. The embedded quality assurance programme consists of on-site machine dosimetry at the nine trial centres, a retrospective review of outlining and adherence to dose constraints based on the trial protocol in 54 participants (randomly selected, around 10% of the total randomised to radiotherapy, n = 545). These quality assurance processes and results were compared with prostate radiotherapy trials of a comparable era. RESULTS: There has been an increasingly sophisticated quality assurance programme in UK prostate radiotherapy trials over the last 15 years, reflecting dose escalation and treatment complexity. In ProtecT, machine dosimetry results were comparable between trial centres and with the UK RT01 trial. The outlining review showed that most deviations were clinically acceptable, although three (1.4%) may have been of clinical significance and were related to outlining of the prostate. Seminal vesicle outlining varied, possibly due to several prostate trials running concurrently with different protocols. Adherence to dose constraints in ProtecT was considered acceptable, with 80% of randomised participants having two or less deviations and planning target volume coverage was excellent. CONCLUSION: The ProtecT trial quality assurance results were satisfactory and comparable with trials of its era. Future trials should aim to standardise treatment protocols and quality assurance programmes where possible to reduce complexities for centres involved in multiple trials.

Hepatocyte growth factor/scatter factor and prostate cancer: a review.

Men who die from prostate cancer do so from uncontrolled metastatic disease. A better understanding of the mechanisms involved in the progression and metastasis of prostate cancer may lead to novel therapeutic approaches to prevent its natural progression. Hepatocyte Growth Factor / Scatter factor (HGF/SF) has been demonstrated to elicit a number of key functions in numerous tissues that are important in the progression, invasion and metastasis of cancer. Studies have demonstrated that the activity of HGF/SF and its receptor c-Met are linked to disease progression in numerous cancers. However, research into these functions, which include activities as a mitogen, a motogen and an anti-apoptotic and angiogenic factor in prostate cancer are limited. This article reviews the published evidence of the roles HGF/SF plays in prostate cancer progression and highlights the clinical and therapeutic potential of research into this pleiomorphic cytokine.

Matrilysin mediates extracellular cleavage of E-cadherin from prostate cancer cells: a key mechanism in hepatocyte growth factor/scatter factor-induced cell-cell dissociation and in vitro invasion.

PURPOSE: The current study examined the effects of hepatocyte growth factor/scatter factor (HGF/SF) on cell-cell dissociation, invasion, and its association with the mediated release of matrix metalloproteinase-7 (Matrilysin) on the extracellular cleavage of E-cadherin in prostate cancer cells. EXPERIMENTAL DESIGN: The effects of HGF/SF on cell-cell dissociation, in vitro invasion, and on the expression of E-cadherin at both protein and mRNA levels were assessed in cells whose expression of Matrilysin was altered by treatment with antisense oligonucleotide. RESULTS: Incubation with HGF/SF mediated the release of active Matrilysin (M(r) 19,000), resulting in extracellular cleavage of E-cadherin from prostate cancer cells. This resultant soluble M(r) 80,000 fragment of E-cadherin was subsequently recognized upon immunoprobing with an anti-E-cadherin antibody. Both recombinant human Matrilysin (rh-Matrilysin) and/or HGF/SF increased the level of soluble E-cadherin and decreased the level of full-length (M(r) 120,000) E-cadherin as detected by Western blotting. The effects of rh-Matrilysin and HGF/SF were inhibited by an antisense oligonucleotide specifically directed toward human Matrilysin. In addition, stimulation with either rh-Matrilysin or HGF/SF resulted in disruption to the E-cadherin/beta-catenin complex, as shown by a significant increase (P < 0.05) in both cell scattering and invasion index. CONCLUSIONS: Treatment with HGF/SF induced Matrilysin-mediated cleavage to the extracellular domain of E-cadherin, resulting in its dissociation from the cadherin/catenin complex. This provides a new mechanism in HGF/SF-induced cell scattering, resulting in a switch to a more invasive phenotype in LNCapFGC cells, as demonstrated by in vitro invasion.

Naphthyl phosphoramidate derivatives of BVdU as potential anticancer agents: design, synthesis and biological evaluation.

The phosphoramidate technology we have developed has been recently applied to BVdU, leading to NB1011 (NewBiotics Inc., California), a novel potential anticancer compound recently entered into phase 2 of the clinical trials for colon cancer. We report in this work a new series of derivatives containing naphthol as aryl masking group on the phosphate moiety, which has shown a significant increase in anticancer activity in preliminary biological evaluations.

Interdisciplinary pain management is beneficial for refractory orchialgia in children.

INTRODUCTION: Idiopathic testicular/groin pain can be a difficult entity for children, their families, and caregivers. The role of interdisciplinary pain management has previously been demonstrated in treating chronic orchialgia at the present pediatric pain clinic. OBJECTIVE: To evaluate the role of interdisciplinary pain management in managing refractory orchialgia. It was hypothesized that children with refractory orchialgia might respond well. Interdisciplinary care was defined as that which crosses two medical disciplines such as a surgical specialty and specialist in analgesia. SUBJECTS AND METHODS: Pediatric patients were identified who were: ≥ 10 years old; evaluated in the pediatric urology clinic between 2002 and 2012; were diagnosed wtih ICD code 608.9 or had the diagnosis of male genital disorder NOS. Children were included if they presented with orchialgia without an identifiable cause and failed conservative management (rest, scrotal support, Sitz bath, timed voiding, constipation avoidance) including conventional anti-nociceptive analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids). Patient electronic medical records were reviewed retrospectively. RESULTS: Twenty-two children met inclusion criteria. Mean age was 13.7 years (range 10-17). Nearly half (45%) of the children had chronic medical conditions such as asthma, allergies, and obesity. Twenty-one of the 22 children were referred to the pediatric pain clinic; 15 were evaluated, and one refused treatment. All children evaluated in the pediatric pain clinic were initially offered an empiric anti-neuropathic anti-convulsant (i.e. gabapentin) and/or an anti-depressant (i.e. amitriptyline) before being offered a nerve block. Of the 14 children accepting treatment in the pediatric pain clinic, six were treated solely with an empiric anti-neuropathic anti-convulsant and/or anti-depressant; eight received medications followed by nerve block (seven ilioinguinal-iliohypogastric blocks, one spinal and ilioinguinal-iliohypogastric block) (see Fig. 1). A total of eight of the 14 children (57%) treated by the pain clinic had resolution of pain, with 50% of those treated with medications alone (three out of six children) responding (two responding to gabapentin and a tricyclic antidepressant, one to gabapentin alone); and five out of eight (63%) treated with medications and then nerve block (ilioinguinal-iliohypogastric block) responding. Of the eight children undergoing nerve block, five required more than one block. The time between each block ranged from 4 to 22.6 weeks. Response to nerve block required an average of 1.4 procedures (range 1-2); mean follow-up after nerve block was 2.4 months (range 0.1-4.8). DISCUSSION: Children with refractory orchialgia often have comorbidities that suggest a multidisciplinary approach would be useful for treating them. The present study found that the majority of children with refractory orchialgia treated in the pediatric pain clinic responded to management. Major limitations, however, included small cohort size and short follow-up, particularly in those children undergoing nerve block. There was also no objective assessment of pain improvement or improvement in quality of life, which could be rectified with a prospective study. CONCLUSION: Collaboration and early referral for interdisciplinary pain management as one of these multidisciplinary approaches may help to coordinate care and ease patient suffering.

Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes.

Activation of myofibroblast rich stroma is a rate-limiting step essential for cancer progression. The responsible factors are not fully understood, but TGFß1 is probably critical. A proportion of TGFß1 is associated with extracellular nano-vesicles termed exosomes, secreted by carcinoma cells, and the relative importance of soluble and vesicular TGFß in stromal activation is presented. Prostate cancer exosomes triggered TGFß1-dependent fibroblast differentiation, to a distinctive myofibroblast phenotype resembling stromal cells isolated from cancerous prostate tissue; supporting angiogenesis in vitro and accelerating tumour growth in vivo. Myofibroblasts generated using soluble TGFß1 were not pro-angiogenic or tumour-promoting. Cleaving heparan sulphate side chains from the exosome surface had no impact on TGFß levels yet attenuated SMAD-dependent signalling and myofibroblastic differentiation. Eliminating exosomes from the cancer cell secretome, targeting Rab27a, abolished differentiation and lead to failure in stroma-assisted tumour growth in vivo. Exosomal TGFß1 is therefore required for the formation of tumour-promoting stroma.

The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer.

Sex hormones appear to play a pivotal role in determining cardiovascular risk. Androgen deprivation therapy for males with prostate cancer results in a hypogonadal state that may have important, but as yet undetermined, effects on the vasculature. We studied the effects of androgen deprivation therapy on large artery stiffness in 22 prostate cancer patients (mean age, 67 +/- 8 yr) over a 6-month period. Arterial stiffness was assessed using pulse-wave analysis, a technique that measures peripheral arterial pressure waveforms and generates corresponding central aortic waveforms. This allows determination of the augmentation of central pressure resulting from wave reflection and the augmentation index, a measure of large artery stiffness. Body compositional changes were assessed using bioelectrical impedance analysis. Fasting lipids, glucose, insulin, testosterone, and estradiol were measured. After a 3-month treatment period, the augmentation index increased from 24 +/- 6% (mean +/- SD) at baseline to 29 +/- 9% (P = 0.003) despite no change in peripheral blood pressure. Timing of wave reflection was reduced from 137 +/- 7 to 129 +/- 10 msec (P = 0.003). Fat mass increased from 20.2 +/- 9.4 to 21.9 +/- 9.6 kg (P = 0.008), whereas lean body mass decreased from 63.2 +/- 6.8 to 61.5 +/- 6.0 kg (P = 0.016). There were no changes in lipids or glucose during treatment. Median serum insulin rose from 11.8 (range, 5.6-49.1) to 15.1 (range, 7.3-83.2) mU/liter at 1 month (P = 0.021) and to 19.3 (range, 0-85.0 mU/liter by 3 months (P = 0.020). There was a correlation between the changes in fat mass and insulin concentration over the 3-month period (r = 0.56; P = 0.013). In a subgroup of patients whose treatment was discontinued after 3 months, the augmentation index decreased from 31 +/- 7% at 3 months to 29 +/- 5% by 6 months, in contrast to patients receiving continuing treatment in whom the augmentation index remained elevated at 6 months compared with baseline (P = 0.043). These data indicate that induced hypogonadism in males with prostate cancer results in a rise in the augmentation of central arterial pressure, suggesting large artery stiffening. Adverse body compositional changes associated with rising insulin concentrations suggest reduced insulin sensitivity. These adverse hemodynamic and metabolic effects may increase cardiovascular risk in this patient group.

Treatment of testicular germ-cell cancer: a cochrane evidence-based systematic review.

Testicular germ-cell cancer is relatively rare, affecting less than 6 men per 100,000 in the UK, nevertheless, it is the most common cancer in men under 45 years. The two main types of tumours, seminomas and non-seminomas, respond to treatment differently. The standard treatment for stage I seminomas following orchidectomy is infradiaphragmatic lymph node irradiation with response rates approaching 100%, although surveillance is also a management option. The majority of early stage non-seminomas are cured by orchidedctomy alone. Bleomycin, etoposide and cisplatin, (BEP) is the most widely used chemotherapeutic regimen for metastatic germ cell tumours. In patients with 'good prognosis' the current focus is to reduce the drug-related toxicity but maintain the cure potential. Most attempts using dose reduction or alternative regimens have not proved superior to BEP. In patients with 'poor prognosis' the aim has been to increase the efficacy of treatment using high-dose chemotherapy and investigate new regimens. This article comprehensively reviews the treatment of testicular germ cell cancer with emphasis on high-grade evidence from randomised controlled trials.

Immunohistochemical and biochemical characterisation of the expression of a human embryonal carcinoma cell proteoglycan antigen in human germ cell tumours and other tissues.

In the embryonal carcinoma (EC) cell line GCT 27, monoclonal antibody GCTM-2 recognises an epitope on a 200 kD pericellular matrix keratan sulphate proteoglycan. Immunohistochemical analyses demonstrated staining of tissue sections from 21 out of 22 human non-seminomatous germ cell tumours, and from 22 out of 28 sections of seminomas. In normal human fetal tissues gut epithelium and muscle stained strongly, and certain other epithelia stained moderately. In adult tissues, the distribution of the epitope was similar, but staining intensity was weaker. Neoplastic tissues showed reactivity with embryonal rhabdomyosarcoma and colorectal carcinoma, but no other non-germ cell tumours. Immunofluorescence microscopy showed that GCTM-2 also stained cell lines from human colorectal carcinoma, embryonal rhabdomyosarcoma and choriocarcinoma. In contrast to EC cells the epitope in these other cell types required permeabilization of the cells to be visualised, and the protein bands in immunoblots lacked extensive modification with keratan sulphate and were smaller. Thus, GCTM-2 reacts with an epitope which has a previously unrecognised tissue distribution; its expression as a pericellular matrix proteoglycan is predominantly a characteristic of human EC cells.