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.

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.

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.

Discovery and refinement of muscle weight QTLs in B6 × D2 advanced intercross mice.

The genes underlying variation in skeletal muscle mass are poorly understood. Although many quantitative trait loci (QTLs) have been mapped in crosses of mouse strains, the limited resolution inherent in these conventional studies has made it difficult to reliably pinpoint the causal genetic variants. The accumulated recombination events in an advanced intercross line (AIL), in which mice from two inbred strains are mated at random for several generations, can improve mapping resolution. We demonstrate these advancements in mapping QTLs for hindlimb muscle weights in an AIL (n = 832) of the C57BL/6J (B6) and DBA/2J (D2) strains, generations F8-F13. We mapped muscle weight QTLs using the high-density MegaMUGA SNP panel. The QTLs highlight the shared genetic architecture of four hindlimb muscles and suggest that the genetic contributions to muscle variation are substantially different in males and females, at least in the B6D2 lineage. Out of the 15 muscle weight QTLs identified in the AIL, nine overlapped the genomic regions discovered in an earlier B6D2 F2 intercross. Mapping resolution, however, was substantially improved in our study to a median QTL interval of 12.5 Mb. Subsequent sequence analysis of the QTL regions revealed 20 genes with nonsense or potentially damaging missense mutations. Further refinement of the muscle weight QTLs using additional functional information, such as gene expression differences between alleles, will be important for discerning the causal genes.

Does magnetic resonance imaging of the spine have a role in the staging of prostate cancer?

AIMS: Magnetic resonance imaging (MRI) is an effective method for evaluating the spine in patients with a high risk of metastatic disease. The aim of this study was to compare MRI spine with radionuclide bone scan in detecting spinal metastases for staging prostate cancer patients. MATERIALS AND METHODS: A cohort of 99 patients with locally advanced prostate cancer at high risk of skeletal metastasis (prostate-specific antigen>10 ng/ml, composite Gleason score>or=8) or equivocal findings on bone scan were included in the retrospective study, and their MRI spine and bone scans were analysed. RESULTS: Ten patients were detected to have definite spinal metastasis by bone scan, whereas 12 patients had definite skeletal metastasis by MRI spine. Compared with the 'gold standard', derived from clinical and radiological follow-up, the sensitivities for radionuclide bone scan and that for MRI spine for detecting skeletal metastasis were 71.4 and 85.7%, respectively (P=0.023), whereas the specificities were 96.5 and 97.7%, respectively (P=0.95). Of the 34 individual metastatic lesions in the spine, 15 were concordantly positive on both scans, whereas five lesions were positive only by bone scan and 11 positive only by MRI. The addition of MRI spine in the staging for prostate cancer resulted in a change of stage and management plan in seven (7%) patients. CONCLUSION: MRI spine has comparable specificity and slightly better sensitivity than bone scan to detect spinal metastasis from prostate cancer.

Viable Eimeria oocysts in poultry house litter at the time of chick placement.

The purpose of this study was to determine if Eimeria oocysts recovered from litter at the time of chick placement in commercial broiler houses contained oocysts that were infectious for chickens. Over 100 litter samples were collected from 30 poultry farms representing a total of 60 different broiler houses with 9 houses sampled more than once over 1.5 yr. The samples were collected just before the placement of newly hatched chicks and after an anticoccidial drug (ACD) or Eimeria vaccine (VAC) program, and processed for counting oocysts followed by Eimeria species determination using ITS1 PCR. Broiler chicks were inoculated with recovered Eimeria oocysts to determine if the litter oocysts were viable and capable of causing patent infection. At placement, E. maxima (Emax) oocysts were detected in 70 of 75 houses after ACD program and 46 of 47 houses after VAC program. Eimeria acervulina, E. praecox, and/or E. tenella (Eapt) were detected in 75 of 75 houses after ACD program and 47 of 47 houses after VAC program. Viability testing revealed that 33.0% of broiler houses contained viable Emax oocysts, while 46.9% contained viable Eapt oocysts. During VAC programs, the concentration of Emax oocysts at placement and the total number of Emax oocysts shed by chickens in viability studies showed a very strong correlation (r = 0.83). Likewise, during ACD programs, the concentration of Eapt oocysts at placement and the total number of Eapt oocysts shed by chickens in the viability study showed a strong correlation (r = 0.62). In general, Eimeria oocyst levels at placement and number of viable oocysts shed by chickens in the viability study were similar among houses on the same farm. However, the number of Eimeria oocysts shed in the viability studies was considerably less than expected based on the number of oocysts given. These data suggest that nearly 100% of all poultry houses contain Emax and Eapt oocysts at placement with 30 to 50% of the houses containing viable Eimeria oocysts, thus possibly representing a source of the protozoa to newly hatched chicks.

Baseline urinary phytoestrogen levels and the natural history of untreated, localised prostate cancer in a British population.

AIM: To determine whether urinary concentrations of phytoestrogens are associated with the rate of disease progression in men with untreated, localised prostate cancer. PATIENTS AND METHODS: Patients with untreated, localised prostatic adenocarcinoma on a prospective clinical study of active surveillance had urine samples collected at baseline. Patients underwent monitoring with serial PSA levels and repeat octant prostate biopsies. Disease progression was defined as either adverse histology on repeat biopsy (primary Gleason grade >or= 4, or >50% positive cores) or radical treatment for PSA velocity >1 ng/mL/year. Time to disease progression was analysed with respect to baseline urinary levels of genistein, enterolactone, daidzein and equol, assayed using liquid chromatography/tandem mass spectrometry. RESULTS: 191 patients were evaluable, with a median follow-up of 2.5 years. 71 patients experienced disease progression. No significant association was seen between time to disease progression and baseline urinary levels of daidzein (p=0.85), genistein (p=0.81), enterolactone (p=0.085) or equol (p=0.33). No significant association was seen between adverse histology on repeat biopsy and urinary levels of either daidzein (p=0.85), genistein (p=0.58), enterolactone (p=0.88) or equol (p=0.71). There was no significant correlation between PSA velocity and urinary levels of daidzein (p=0.90), genistein (p=0.98), enterolactone (p=0.10) or equol (p=0.60). CONCLUSION: These data do not support the hypothesis that phytoestrogens prevent disease progression in men with localised prostate cancer.

Reproducibility of reference tissue quantification of dynamic contrast-enhanced data: comparison with a fixed vascular input function.

Reference tissues are currently used to analyse dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data. The assessment of tumour response to treatment with anti-cancer drugs is a particularly important application of this type of analysis and requires a measure of reproducibility to define a level above which a significant change due to therapy can be inferred. This study compares the reproducibility of such quantification strategies with that found using a published, group-averaged uptake curve. It is shown that reference tissue quantification gives poorer reproducibility for most parameters than that found using a group-averaged plasma curve (a change in K(trans) of greater than 41.8% and 16.4% would be considered significant in the two approaches, respectively), but successfully incorporates some of the variability observed in plasma kinetics between visits and provides vascular input functions that, across the group, are comparable with the group-averaged curve. This study therefore provides an indirect validation of the methodology.

Detection of occult spinal cord compression with magnetic resonance imaging of the spine.

AIMS: Spinal cord compression (SCC) is the most significant complication due to skeletal metastasis from prostate cancer. The early detection of SCC is essential as the neurological status before treatment is the major determinant influencing outcome. The aim of this investigation was to determine the role of magnetic resonance imaging of the spine in detecting SCC or occult SCC in patients with metastatic prostate cancer with no functional neurological deficit (FND). MATERIALS AND METHODS: A retrospective analysis of the clinical data of 150 consecutive patients with metastatic prostate cancer and no FND, who had MRI of the spine from January 2001 to May 2005, was carried out. 'Overt SCC' on MRI was defined as the involvement or compression of either the spinal cord or the cauda equina by an epidural or intramedullary mass lesion and 'occult SCC' as metastatic disease causing impingement, indentation or loss of definition of the thecal sac, which were considered together for statistical purposes as radiological spinal cord compromise (rSCC). RESULTS: Twenty-four (16%) patients had overt SCC, whereas 17 (11.3%) patients had occult SCC. Seven patients had rSCC at multiple non-contiguous sites. The significant clinical determinants of rSCC on univariate analysis were extensive bone metastasis (P=0.005) and back pain (P=0.002). On multivariate analysis, both back pain (P=0.012) and extensive bone metastasis (P=0.047) significantly predicted for rSCC. CONCLUSION: A significant proportion (27.3%) of patients with metastatic prostate cancer may harbour overt or occult SCC in the absence of FND. MRI of the spine for the early diagnosis of SCC may be considered useful in patients with extensive skeletal metastasis and back pain.

When no treatment is the best treatment: Active surveillance strategies for low risk prostate cancers.

Although the incidence of prostate cancer is rising due to PSA screening and increased life expectancy, the metastatic potential of low-grade, organ-confined disease remains low. An increasing number of studies suggest that radical treatment in such cases confers little or no survival benefit at a significant cost to morbidity. Active surveillance is a promising management approach of such low-risk cancers: eligible patients are selected based on clinical and pathological findings at diagnosis and are regularly monitored with digital rectal examinations, PSA testing and biopsies. Treatment, however, is deferred until and unless there is evidence of disease progression. This is a key difference from watchful waiting, where treatment is avoided until and unless there are symptoms. The purpose of this work is to review the rationale and evidence behind active surveillance and to offer an overview of current active surveillance strategies and outcomes.

Distribution of lymph nodes in men with prostatic adenocarcinoma and lymphadenopathy at presentation: a retrospective radiological review and implications for prostate and pelvis radiotherapy.

AIMS: To describe the distribution of enlarged lymph nodes by nodal group found radiologically in patients presenting with adenocarcinoma of the prostate. This will help to define which nodal groups should be treated during the pelvic radiotherapy of patients with less advanced disease. MATERIALS AND METHODS: The scans of 55 men presenting with prostate cancer and metastases to lymph nodes only were reviewed. Lymph nodes of 8 mm or more in size were considered to be enlarged. RESULTS: The medial external iliac (obturator) nodes were most commonly enlarged (75% of patients) followed by nodes in the para-aortic region (26%) and anterior internal iliac region (24%). Para-aortic lymph-node enlargement was uncommon in the absence of pelvic lymphadenopathy. Midline pre-sacral lymph-node enlargement was not observed. Incidence of enlarged lymph nodes in the lateral external iliac group was 18%, an area which may not be routinely included during radiotherapy. CONCLUSION: There is a case for studying further the role of including lateral external iliac lymph nodes in the pelvic radiotherapy volume, as there may be an appreciable risk of lymph-node spread to this area.

The utility of digital rectal examination after radical radiotherapy for prostate cancer.

AIMS: The aim of the current study was to determine the utility of routine digital rectal examination (DRE) after radical radiotherapy for prostate cancer. MATERIALS AND METHODS: Between 1990 and 1999, 899 patients with clinically localised prostatic adenocarcinoma (T1-4, N0/Nx, M0/Mx) underwent neoadjuvant androgen deprivation and radical radiotherapy at the Royal Marsden Hospital. Patients were followed with serum prostate-specific antigen (PSA) test and DRE carried out at 6-monthly intervals for the first 2 years, and then annually. RESULTS: At a median follow-up of 5 years, 39 out of 899 cases (4.3%) had local recurrence detected on DRE. DRE failed to detect any local recurrences in the absence of a rising PSA. The lowest serum PSA concentration at the time of clinically detectable local recurrence was 1.7 ng/ml. CONCLUSIONS: These findings question the standard model of follow-up after radiotherapy for prostate cancer, and suggest that alternatives, such as telephone clinics, should be considered.

Tumour staging using magnetic resonance imaging in clinically localised prostate cancer: relationship to biochemical outcome after neo-adjuvant androgen deprivation and radical radiotherapy.

AIMS: To evaluate the prognostic significance of magnetic resonance imaging (MRI) tumour stage in clinically localised prostate cancer. MATERIALS AND METHODS: Between 1988 and 1999, 199 men with clinically localised prostate cancer (T -T4, N0/Nx, M0) were treated with neo-adjuvant androgen deprivation and radical radiotherapy, and were staged using MRI. Concordance between clinical tumour (cT) stage, as determined by digital rectal examination, and MRI tumour (mT) stage was assessed. Univariate and multivariate analyses using the Cox proportional hazards model were used to study the prognostic role of cT stage and mT stage in addition to established prognostic factors. RESULTS: Of these 199 patients, 103 (52%) were upstaged on MRI, seven (3%) were downstaged, and in 89 (45%) cT and mT stages were concordant. With median follow-up of 3.8 years, 5-year freedom from prostate-specific antigen (PSA) failure was 48% (95% confidence interval (CI) 39-56%). On univariate analysis, freedom from PSA failure was associated with mT stage (P = 0.009) as well as Gleason score (P < 0.001) and initial PSA (P < 0.001), but not cT stage (P = 0.449). On multivariate analysis, Gleason score (P = 0.001), initial PSA (P < 0.001), but not mT stage (P = 0.112) remained independent determinants of freedom from PSA failure. For the subgroup of 149 patients with cT1-2 disease, mT stage was a significant predictor of increased risk of PSA failure on univariate analysis (P = 0.005), but not multivariate analysis (P = 0.19). CONCLUSION: Freedom from PSA failure was more closely associated with mT stage than cT stage. Future studies are warranted to determine whether mT stage is an independent determinant of treatment outcome.

The utility of the non-human primate; model for studying gene by environment interactions in behavioral research.

Variation in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) has been associated with anxiety and harm avoidance and is weakly associated with a number of neuropsychiatric disorders, including Type II alcoholism, which has a high rate of comorbidity with antisocial personality disorder. Studies have also demonstrated interactions between 5-HTLPR variation and environmental stress on the incidence of depression. As in humans, there is a serotonin transporter gene promoter length polymorphism in rhesus macaques that produces similar decreases in transcriptional efficiency. Macaques with histories of early-life stress have been shown to exhibit impulsive aggression, incompetent social behavior and increased behavioral and endocrine responsivity to stress. In this paper, we review studies performed previously in our lab and present preliminary data examining interactions between early rearing and serotonin transporter gene promoter variation on the incidences of play behavior and aggression in infant rhesus macaques. The data presented here highlight the importance of considering gene-environment interactions when studying childhood risk factors for aggression, anxiety and related neuropsychiatric disorders and support the use of the nonhuman primate for studing gene by environment interactions in behavioral research.

Radical radiotherapy for prostate cancer.

External beam radiotherapy is one of the curative treatment options for localised prostate cancer. This article will describe recent advances in prostate radiotherapy, focussing on the results of randomised trials which have addressed the role of radiation dose escalation and of adjuvant hormone therapy. Current controversies will then be considered, including the merits of radiotherapy in comparison with alternative approaches to early prostate cancer, and the possible role of adjuvant radiation following surgery. Finally, future developments will be described, including hypofractionation and dose individualisation, which have the potential to further improve the outcome of external beam radiotherapy for prostate cancer.

The effect of cholesterol-lowering agents on hepatic and plasma cholesterol in Niemann-Pick disease type C.

Niemann-Pick disease type C (NP-C) is a neurovisceral lipidosis characterized by defective intracellular trafficking of cholesterol and lysosomal accumulation of unesterified cholesterol, believed to be an offending metabolite. We studied the effect of cholesterol-lowering agents on hepatic and plasma cholesterol levels in NP-C by randomly assigning 25 patients with NP-C to one of five treatment regimens containing different combinations of cholestyramine, lovastatin, nicotinic acid, or dimethyl sulfoxide (DMSO). Unesterified cholesterol content was measured in liver biopsies before and after 4 months' treatment. All drug regimens except DMSO alone reduced hepatic and plasma cholesterol levels. Toxicity was limited and did not prevent any patient from completing the study. The combination of cholestyramine, lovastatin, and nicotinic acid lowered cholesterol levels in liver and blood with minimal side effects. A controlled clinical study will be necessary to determine if this regimen influences the rate of neurologic progression.

The management of PSA failure after radical radiotherapy for localized prostate cancer.

An asymptomatic rising serum prostate-specific antigen (PSA) level is the most common form of failure after radical radiotherapy for localized prostate cancer, but there is no consensus as to how it should be managed. This review addresses the following three questions concerning men with PSA failure after radiotherapy: (i) what is the course of the disease without further intervention?; (ii) what is the role of radical treatment, such as salvage prostatectomy?; and (iii) should androgen deprivation be started immediately or should it be delayed until clinical progression occurs? An algorithm for the management of PSA failure after radical radiotherapy for localized prostate cancer is proposed.