Comparative Analysis of Clinical Outcomes and Procedural Costs between the Conventional Two-stage Technique and 4D Brachytherapy for Early Prostate Cancer.

AIMS: To assess long-term outcomes and resource use of 4D Brachytherapy, a one-stage real-time implant for the treatment of prostate cancer that uses stranded and loose iodine-125 seeds, and to compare with the conventional two-stage (2S) technique. MATERIALS AND METHODS: Prospectively collected data of men who underwent 2S and 4D low dose rate brachytherapy in a single institution were analysed. Survival estimates were analysed using the Kaplan-Meier method and Log-rank test. Treatment failure rates were further compared by Cox proportional hazards (Coxph) regression or by a surrogate prostate-specific antigen value cut-off of 0.4 ng/ml 48 months post-implant. Treatment toxicity outcomes were also evaluated. Comparative costs were based on published English National Health Service data. RESULTS: We compared outcomes of 690 men treated with 2S and 1031 men with 4D brachytherapy. Median follow-up times were 10.4 and 5.2 years (P < 0.001) for 2S and 4D cases, respectively. Day 0 post-implant dosimetry was improved in 4D brachytherapy patients. Five years post-implant ≥98% of cases were alive and ≥95% were free from disease relapse irrespective of technique. Coxph regression showed the risk of relapse after 4D brachytherapy was similar to the 2S technique (hazard ratio 0.67, 95% confidence interval 0.44-1.03, P = 0.065). Forty-eight months post-implant there was a significantly greater proportion of 4D brachytherapy cases with a prostate-specific antigen below 0.4 ng/ml relative to the 2S technique. Urinary and bowel symptom scores showed reduced toxicity after 4D implants and potency conservation was similar to the 2S technique. The reduction in time and resource use decreased the cost of 4D brachytherapy by 40% compared with the 2S technique. CONCLUSION: Two-stage and 4D brachytherapy are both highly effective for the control of localised prostate cancer. However, relative to the 2S technique, the 4D technique was associated with improved dosimetry, reduced treatment-related toxicity and reduced cost. Further follow-up will assess disease control superiority of 4D brachytherapy beyond 5 years post-implant.

A gene expression profiling approach assessing celecoxib in a randomized controlled trial in prostate cancer.

BACKGROUND: We performed a pilot study, looking at the COX-2 inhibitor celecoxib, on newly diagnosed prostate cancer patients in the neo-adjuvant setting using DNA microarray analysis. PATIENTS AND METHODS: This was a single-blinded, randomized controlled phase II presurgical (radical prostatectomy) 28-day trial of celecoxib versus no drug in patients with localized T1-2 N0 M0 prostate cancer. cDNA microarray analysis was carried out on prostate cancer biopsies taken from freshly obtained radical prostatectomy samples. Results were confirmed by qPCR analysis of a selection of genes. RESULTS: Multiple genes were differentially expressed in response to celecoxib treatment. Statistical analysis of microarray data indicated 24 genes were up-regulated and 4 genes down-regulated as a consequence of celecoxib treatment. Gene changes e.g. survivin, SRP72kDa, were associated with promoting apoptotic cell death, enhancement of antioxidant processes and tumour suppressor function (p73 and cyclin B1 up-regulation). CONCLUSION: Celecoxib at 400 mg b.i.d. for 4 weeks perioperatively gave rise to changes in gene expression in prostate cancer tissue consistent with enhancement of apoptosis and tumour suppressor function. Given the short time interval for the duration of this study, the data are encouraging and provide a good rationale for conducting further trials of celecoxib in prostate cancer.

Metabolic syndrome and prostate cancer: a review.

Androgen deprivation therapy is widely used in a number of different settings in the treatment of prostate cancer. This overview will look at the current evidence for the potential development of metabolic syndrome and cardiovascular disease as a consequence of this therapy, and highlight strategies aimed at their prevention. The relationship between metabolic syndrome and prostate cancer development will also be examined.

Biochemical relapse-free survival in 400 patients treated with I-125 prostate brachytherapy: the Guildford experience.

A total of 1200 patients had undergone I-125 prostate brachytherapy (BXT) in our centre. We present prospective outcome data for the first 400 treated patients. Data were analysed from a prospective database of 400 consecutive patients treated with permanent prostate BXT between March 1999 and December 2003. Patients were stratified into low (49%), intermediate (36%) and high (15%) risk as defined by the Memorial Sloan-Kettering Prognostic Index. Patients received 145 Gy BXT alone (41%), BXT with 3 months neoadjuvant androgen deprivation (NAAD) (39%), 45 Gy external beam radiotherapy (EBRT) with 110 Gy BXT (3%) or a combination of NAAD, 45 Gy EBRT and 110 Gy BXT (17%). Biochemical relapse-free survival (bRFS) and prostate-specific antigen (PSA) nadirs were analysed for treatment received in each risk group. Median follow-up was 54 months (range, 38-96 months) with a mean patient age of 63 years. Prostate cancer-specific survival was 99.5%. Twenty-eight patients (7%) experienced biochemical failure according to the 2006 Radiation Therapy Oncology Group-American Society for Therapeutic Radiology and Oncology (RTOG-ASTRO) Phoenix Consensus definition (PSA nadir plus >or=2 ng ml(-1)): nine low-, fourteen intermediate- and five high-risk patients. When stratified by treatment group for low-, intermediate- and high-risk groups, the 5-year actuarial bRFS was 98, 89 and 100% for BXT; 91, 87 and 88% for NAAD and BXT; 100, 80 and 100% for EBRT and BXT; and 100, 92 and 88% for NAAD, EBRT and BXT, respectively. Overall 4- and 5-year PSA

State-of-the-art: prostate LDR brachytherapy.

This article on low dose rate (LDR) prostate brachytherapy reviews long-term results, patient selection and quality of life issues. Mature results from the United States and United Kingdom are reported and issues regarding definitions of biochemical failure are discussed. Latest data comparing brachytherapy with radical prostatectomy or no definitive treatment and also the risk of secondary malignancies after prostate brachytherapy are presented. Urological parameters of patient selection and quality of life issues concerning urinary, sexual and bowel function are reviewed. The position of prostate brachytherapy next to surgery as a first-line treatment modality is demonstrated.

COX-2 inhibition: a possible role in the management of prostate cancer?

There is mounting evidence to support a role for cyclooxygenase-2 (COX-2) inhibitors (coxibs) in the management of prostate cancer. This review considers the current evidence base for the use of coxibs in prostate cancer as well as their adverse event profile. A systematic literature review using the search terms 'cyclooxygenase', 'COX-2', 'coxibs', 'cardiovascular risk', and 'prostate cancer' was performed using Medline. Celecoxib appears safer in terms of cardiovascular toxicity than other coxibs, and this may relate to its lower selectivity for the COX-2 enzyme. This lower selectivity also provides rationale for its putative broader anti-cancer effects, via non-COX-2-dependent pathways that affect cell cycle regulation, angiogenesis, and hypoxic modulation. There are also interacting relationships between COX-2, chronic inflammation, and prostate cancer. There is much promise for the coxibs as anti-cancer agents. The future might be to pharmacologically adapt these agents to exert their COX-2 independent mechanisms of action while minimizing their COX-2-dependent adverse cardiovascular effects.

Interstitial low dose rate brachytherapy for prostate cancer--a focus on intermediate- and high-risk disease.

AIMS: To investigate the role of brachytherapy in intermediate- and high-risk prostate cancer. We report our results and a review of published studies. MATERIALS AND METHODS: Between March 1999 and April 2003, 300 patients were treated with low dose rate 1-125 interstitial prostate brachytherapy and followed prospectively. The patients were stratified into low-, intermediate- and high-risk groups and received brachytherapy alone or in combination with external beam radiotherapy (EBRT) and/or neoadjuvant androgen deprivation (NAAD). One hundred and forty-six patients were classified as low risk, 111 as intermediate risk and 43 as high risk. Biochemical freedom from disease and prostate-specific antigen (PSA) nadirs were analysed for risk groups and for treatment received in each risk group. RESULTS: The median follow-up was 45 months (range 33-82 months) with a mean age of 63 years. Actuarial 5-year biochemical relapse-free survival for the low-risk group was 96%, 89% for the intermediate-risk group and 93% for the high-risk group. When stratified by treatment group, low-risk patients had a 5-year actuarial biochemical relapse-free survival of 94% for brachytherapy alone (n=77), 92% for NAAD and brachytherapy (n=66) and 100% for NAAD, EBRT and brachytherapy (n=3). In the intermediate-risk patients, biochemical relapse-free survival was 93% for brachytherapy alone (n=15), 94% for NAAD and brachytherapy (n=67), 75% for EBRT and brachytherapy (n=4) and 92% for NAAD, EBRT and brachytherapy (n=25). In the high-risk group, biochemical relapse-free survival was 100% for brachytherapy alone (n=2), 88% for NAAD and brachytherapy (n=7), 80% for EBRT and brachytherapy (n=5) and 96% for NAAD, EBRT and brachytherapy (n=29). Overall 3- and 4-year PSA = 0.5 ng/ml were achieved by 71 and 86%, respectively, and a 4-year PSA = 0.2 ng/ml was achieved by 63%. CONCLUSION: Although the role of combination treatment with pelvic EBRT and androgen therapy is not clear, our early results show that many patients with intermediate- and high-risk disease have excellent results with brachytherapy.

Gleason scoring varies among pathologists and this affects clinical risk in patients with prostate cancer.

AIMS: To investigate whether our practice of specialist review of all diagnostic biopsies was necessary to prevent misgrading of referred prostate cancer patients, and whether this misclassification, if any, would have resulted in misclassification of clinical risk grouping (Seattle Risk Grouping [SRG]) and subsequent treatment strategy and prognosis. MATERIALS AND METHODS: Important prognostic indicators for prostate cancer include the presenting prostate-specific antigen (PSA), clinical stage and Gleason sum of the tumour. These three variables are incorporated into the SRG cohorts to establish treatment strategy. Patients with prostate cancer referred for brachytherapy had their prostate biopsies reviewed by a reference pathologist (PD) with a special interest in prostate cancer. We compared the agreement between the scoring of the referring pathologists with that of PD, and evaluated if any differences changed the SRG and therefore the clinical risk and treatment strategy for the patients. RESULTS: In only 52% (43/83) of cases, was there total agreement between the two sets of pathologists. The inter-rater agreement was statistically 'fair' (unweighted kappa statistic 0.27). In 90% (36/40) of cases with disagreement, PD assigned higher Gleason sums. In 40% (16/40) of cases with disagreement, the change in Gleason sum altered the SRG; in one out of 16 cases, the SRG was downgraded from 'intermediate' to 'low' risk disease; in six out of 16 cases, it was upgraded from 'low' to 'intermediate' risk, and, in nine out of 16, from 'intermediate' to 'high' risk. CONCLUSION: Our findings confirm previous reports of only limited correlation between pathologists in reporting Gleason sums. In this study, 19% (16/83) of cases had their grading changed to a level that altered clinical risk, almost always (94%; 15/16) to one that worsened prognosis. This would have significantly affected treatment strategy for these patients, and thus we recommend that all centres ensure accurate Gleason grading by the use of pathologists with special interests in prostate cancer.

Iodine seed prostate brachytherapy: an alternative first-line choice for early prostate cancer.

This article on permanent iodine-125 seed prostate brachytherapy reviews the techniques, results, and patient selection issues for early prostate cancer. The long-term 10 y results of brachytherapy from Seattle, and their reproducibility in other centres both in the USA and UK are reported. The use of hormone therapy in brachytherapy and the value of combining external beam radiotherapy with a brachytherapy implant are discussed. Reviewed comparative data show the similarity of biochemical survival in patients treated with brachytherapy, radical prostatectomy, and external beam radiotherapy. The role of brachytherapy as a first-line treatment option for patients with prostate cancer is demonstrated.

Outcome analysis and patient satisfaction following octant transrectal ultrasound-guided prostate biopsy: a prospective study comparing consultant urologist, specialist registrar and nurse practitioner in urology.

PURPOSE: To determine whether transrectal ultrasound-guided biopsy of the prostate is equally reliable and acceptable if performed by urology nurse practitioner or urologist. SCOPE: Octant biopsies were taken by each operator (consultant urologist n=2, urology specialist registrar n=1 and urology nurse practitioner n=2) from 50 consecutive unselected patients and demographics and cancer detection rate were compared between the groups. A postal survey was performed following nurse practitioner biopsy to assess patient satisfaction and acceptance of nurse practitioner biopsy. CONCLUSION: Transrectal ultrasound-biopsy of prostate whether performed by nurse practitioner or urologist is equally reliable if adequate training is provided. Patients are happy to undergo prostate biopsy and receive information about the diagnosis from an appropriately trained prostate cancer nurse specialist.

Toxicity and early biochemical outcomes from 125iodine prostate brachytherapy in the UK. A prospective study.

AIMS: Transperineal interstitial prostate brachytherapy is increasingly available to patients with early prostate cancer in the U.K., but limited data are available about the toxicity and early results in the U.K. prostate cancer population. We describe our experience and results from prostate brachytherapy to date. MATERIALS AND METHODS: Two hundred and fifty-five patients were treated at St Luke's Cancer Centre, Guildford, U.K., between March 1999 and November 2002. Of these, over 3 months of follow-up data were available for 216 patients. Patients were assessed at 6 weeks and then at 3, 6, 9 and 12 months after implant, and at 6 monthly intervals thereafter. Prostate-specific antigen (PSA), International Prostate Symptom Score (IPSS) and toxicity, including catheter use, was recorded prospectively. RESULTS: Median PSA at 1, 2 and 3 years was 0.5, 0.4 and 0.1 ng/ml, respectively. Ninety-five per cent of patients experienced temporary deterioration in their urinary symptoms, which persisted at clinically significant levels (IPSS increase >3 points) for 9 months after implant. The severity of urinary symptoms (IPSS) after implant was most closely related to IPSS at presentation (P<0.001). Acute urinary retention (AUR) occurred in 20 (9.3%) patients, with a further 26 (12.1%) patients using clean intermittent self-catheterisation (CISC) to reduce voiding frequency associated with chronic retention. Median duration of catheter use was 4 weeks. Multivariate analysis revealed that urodynamic status, prostate volume and IPSS score were independently significant (P<0.05) predictors of post-implant catheter use. Twelve patients (5.6%) reported either rectal urgency or mild, self-limiting rectal bleeding. CONCLUSION: Brachytherapy was tolerated well, with self-limiting urinary, bowel and sexual toxicity in most patients. Postoperative catheter use in our population is closely linked to pre-implant IPSS score, baseline prostate volume and urodynamic obstruction status. This work confirms the prognostic value of urodynamic assessment, which adds useful prognostic information to assessment of known risk factors such as prostate volume and IPSS.

Is bicalutamide equivalent to goserelin for prostate volume reduction before radiation therapy? A prospective, observational study.

INTRODUCTION: We compare the cytoreductive efficacy of bicalutamide or goserelin with no hormonal manipulation in prostate cancer before brachytherapy. MATERIALS AND METHODS: Transrectal ultrasound volume estimations were performed in clinic and during the brachytherapy-planning scan. Between volume estimations, patients received no hormonal treatment, bicalutamide 150 mg once daily or goserelin 3.6 mg every 28 days. RESULTS: Patients receiving no hormonal manipulation had a volume increase of 8% compared with an 8% volume reduction in the bicalutamide group and a 26% reduction in the goserelin group. As initial prostate volume was not equivalent in the three groups, a subgroup analysis was performed on patients who received active treatment for more than 3 months who had initial prostate volume less than 55 cm3. In this subgroup, a mean fall in prostate volume of 7%, occurred in the bicalutamide group compared with 21% in the goserelin group. In both the original and subgroup analysis, the cytoreductive efficacy of goserelin was significantly greater than bicalutamide (P < 0.0001). CONCLUSION: In the absence of data from randomised trials, comparing the efficacy of these agents, luteinising hormone-releasing hormone (LHRH) analogues remain the gold standard for cytoreduction before prostate brachytherapy. If the neoadjuvant efficacy of hormonal manipulation in external beam radiotherapy is dependent on prostate volume reduction, then LHRH analogues may also prove more effective in this neoadjuvant role.

(125)Iodine prostate brachytherapy: outcome from the first 100 consecutive patients and selection strategies incorporating urodynamics.

OBJECTIVE: To report the results from the first 100 consecutive patients treated with 125I transperineal interstitial prostate brachytherapy between March 1999 and June 2001, and to determine if the International Prostate Symptom Score (IPSS), prostate volume or urodynamic variables correlate with acute morbidity. PATIENTS AND METHODS: Patients were assessed prospectively by uroflowmetry, the IPSS, a physical examination and transrectal ultrasonography. Of the 100 patients, 57 had a full urodynamic assessment, 61 presented with lower urinary tract symptoms (LUTS), 25 were screen-detected and 14 presented with other problems. The IPSS was recorded at 1, 6 and 12 weeks, and then at 3-monthly intervals after treatment; significant events, e.g. acute urinary retention (AUR) and rectal symptoms, were recorded prospectively; the mean follow-up was 16 months. RESULTS: No patients were incontinent after treatment. There was a temporary deterioration in IPSS in 89% of patients. Peak symptoms occurred at 6 weeks and a statistically significant deterioration in IPSS persisted until 9 months, but continued to improve throughout the follow-up. AUR affected seven patients, with a further 20 using clean intermittent self-catheterization (CISC) for symptoms. In most patients the symptoms resolved spontaneously to the levels before treatment, with only two patients requiring surgery for bladder outlet obstruction. The IPSS before treatment did not predict urodynamic obstruction. Urodynamically unobstructed patients did not require catheterization. By 2 years after implantation the mean IPSS was better than before treatment. Five patients had mild, transient proctitis. CONCLUSION: Selecting patients with a low prostate volume and IPSS is likely to optimize the outcome of brachytherapy. Urodynamic studies may be helpful in predicting the risk of AUR and symptoms requiring CISC. Despite many patients presenting with LUTS, acute morbidity was no worse than that reported in large American series of predominantly screening-detected cancers. Prostate brachytherapy is well tolerated and may be safely delivered to patients with prostate cancer in the UK.