David Robert Siemens

Augmenting Detection of Prostate Cancer in Transrectal Ultrasound Images Using SVM and RF Time Series

We propose a novel and accurate method based on ultrasound RF time series analysis and an extended version of support vector machine classification for generating probabilistic cancer maps that can augment ultrasound images of prostate and enhance the biopsy process. To form the RF time series, we record sequential ultrasound RF echoes backscattered from tissue while the imaging probe and the tissue are stationary in position. We show that RF time series acquired from agar-gelatin-based tissue mimicking phantoms, with difference only in the size of cell-mimicking microscopic glass beads, are distinguishable with statistically reliable accuracies up to 80.5%. This fact indicates that the differences in tissue microstructures affect the ultrasound RF time series features. Based on this phenomenon, in an ex vivo study involving 35 prostate specimens, we show that the features extracted from RF time series are significantly more accurate and sensitive compared to two other established categories of ultrasound-based tissue typing methods. We report an area under receiver operating characteristic curve of 0.95 in tenfold cross validation and 0.82 in leave-one-patient-out cross validation for detection of prostate cancer.

Curative therapy for bladder cancer in routine clinical practice: A population-based outcomes study

AIMS Definitive therapy of bladder cancer involves cystectomy or radiotherapy; controversy exists regarding optimal management. Here we describe the management and outcomes of patients treated in routine practice. MATERIALS AND METHODS Treatment records were linked to the Ontario Cancer Registry to identify all cases of bladder cancer in Ontario treated with cystectomy or radiotherapy in 1994-2008. Practice patterns are described in three study periods: 1994-1998, 1999-2003, 2004-2008. Logistic regression, Cox model and propensity score analyses were used to evaluate factors associated with treatment choice and survival. RESULTS In total, 3879 cases (74%) underwent cystectomy and 1380 (26%) were treated with primary radiotherapy. Cystectomy use increased over time (66, 75, 78%), whereas radiotherapy decreased (34, 25, 22%), P < 0.001. There was substantial regional variation in the proportion of cases undergoing radiotherapy (range 16-51%). Five year cancer-specific survival (CSS) and overall survival were 40 and 36% for surgical cases and 35 and 26% for radiotherapy cases (P < 0.001). In multivariate Cox model and propensity score analyses, there was no significant difference in CSS between surgery and radiotherapy (hazard ratio 0.99, 95% confidence interval 0.91-1.08); radiotherapy was associated with slightly inferior overall survival (hazard ratio 1.08, 95% confidence interval 1.00-1.16). CONCLUSION Utilisation of cystectomy for bladder cancer in routine practice has increased over time with no evidence of a significant difference in CSS between radiotherapy and cystectomy.

Patterns of referral for perioperative chemotherapy among patients with muscle-invasive bladder cancer: A population-based study

PURPOSE Reasons for low uptake of perioperative chemotherapy for muscle-invasive bladder cancer are not well described. Herein, we report referral patterns from urology to medical oncology (MO) in Ontario, Canada, and subsequent use of chemotherapy. METHODS Electronic treatment records were linked to the Ontario Cancer Registry to describe referral patterns and use of neoadjuvant/adjuvant chemotherapy (NACT/ACT) among patients with muscle-invasive bladder cancer treated with cystectomy in Ontario from 1994 to 2008. Logistic regression identified factors associated with referral to MO and use of NACT/ACT. RESULTS Overall, 18% (520/2,944) of patients were seen by MO before cystectomy, and 25% (128/520) of referred cases were treated with NACT. Among patients not treated with NACT or radiation, 39% (1,085/2,809) were seen by MO following cystectomy; 51% (548/1,085) of referred patients had ACT. There was wide geographic variation in MO referral rates before (range: 5%-40%) and after cystectomy (range: 26%-59%). Patients seen by MO from 2004 to 2008 were more likely to receive ACT (57%) compared with patients in earlier years (41% in 1994-1998 and 46% in 1999-2003, P<0.001). CONCLUSIONS Lack of referral to MO is an important barrier to use of NACT/ACT. Upstream decision making by urologists is an important target in future knowledge translation.

Detection of Prostate Cancer from RF Ultrasound Echo Signals Using Fractal Analysis

In this paper we propose a new feature, average Higuchi dimension of RF time series (AHDRFT), for detection of prostate cancer using ultrasound data. The proposed feature is extracted from RF echo signals acquired from prostate tissue in an in vitro setting and is used in combination with texture features extracted from the corresponding B-scan images. In a novel approach towards RF data collection, we continuously recorded backscattered echoes from the prostate tissue to acquire time series of the RF signals. We also collected B-scan images and performed a detailed histopathologic analysis on the tissue. To compute AHDRFT, the Higuchi fractal dimensions of the RF time series were averaged over a region of interest. AHDRFT and texture features extracted from corresponding B-scan images were used to classify regions of interest, as small as 0.028 cm of the prostate tissue in cancerous and normal classes. We validated the results based on our histopathologic maps. A combination of image statistical moments and features extracted from co-occurrence matrices of the B-scan images resulted in classification accuracy of around 87%. When AHDRFT was added to the feature vectors, the classification accuracy was consistently over 95% with best results of over 99% accuracy. Our results show that the RF time series backscattered from prostate tissues contain information that can be used for detection of prostate cancer

Delivery of perioperative chemotherapy for bladder cancer in routine clinical practice.

BACKGROUND Few articles have documented regimens and timing of perioperative chemotherapy for bladder cancer in routine practice. Here, we describe practice patterns in the general population of Ontario, Canada. METHODS In this retrospective cohort study, treatment and physician billing records were linked to the Ontario Cancer Registry to describe use of neoadjuvant (NACT) and adjuvant (ACT) chemotherapy among all patients with muscle-invasive bladder cancer treated with cystectomy in Ontario 1994-2008. Time to initiation of ACT (TTAC) was measured from cystectomy. Multivariate Cox regression was used to identify factors associated with overall (OS) and cancer-specific survival (CSS). RESULTS Of 2944 patients undergoing cystectomy, 4% (129/2944) and 19% (571/2944) were treated with NACT and ACT, respectively. Five-year OS was 25% [95% confidence interval (CI) 17% to 34%] for NACT, 29% (95% CI 25% to 33%) for ACT cases. Among patients with identifiable drug regimens, cisplatin was used in 82% (253/308) and carboplatin in 14% (43/308). The most common regimens were gemcitabine-cisplatin (54%, 166/308) and methotrexate, vinblastine, doxorubicin, cisplatin (MVAC) (21%, 66/308). Mean TTAC was 10 weeks; 23% of patients had TTAC >12 weeks. TTAC >12 weeks was associated with inferior OS [hazard ratio (HR) 1.28, 95% CI 1.00-1.62] and CSS (HR 1.30, 95% CI 1.00-1.69). In adjusted analyses, OS and CSS were lower among patients treated with carboplatin compared with those treated with cisplatin; OS HR 2.14 (95% CI 1.40-3.29) and CSS HR 2.06 (95% CI 1.26-3.37). CONCLUSIONS Most patients in the general population receive cisplatin, and this may be associated with superior outcomes to carboplatin. Initiation of ACT beyond 12 weeks is associated with inferior survival. Patients should start ACT as soon as they are medically fit to do so.BACKGROUND Few articles have documented regimens and timing of perioperative chemotherapy for bladder cancer in routine practice. Here, we describe practice patterns in the general population of Ontario, Canada. METHODS In this retrospective cohort study, treatment and physician billing records were linked to the Ontario Cancer Registry to describe use of neoadjuvant (NACT) and adjuvant (ACT) chemotherapy among all patients with muscle-invasive bladder cancer treated with cystectomy in Ontario 1994-2008. Time to initiation of ACT (TTAC) was measured from cystectomy. Multivariate Cox regression was used to identify factors associated with overall (OS) and cancer-specific survival (CSS). RESULTS Of 2944 patients undergoing cystectomy, 4% (129/2944) and 19% (571/2944) were treated with NACT and ACT, respectively. Five-year OS was 25% [95% confidence interval (CI) 17% to 34%] for NACT, 29% (95% CI 25% to 33%) for ACT cases. Among patients with identifiable drug regimens, cisplatin was used in 82% (253/308) and carboplatin in 14% (43/308). The most common regimens were gemcitabine-cisplatin (54%, 166/308) and methotrexate, vinblastine, doxorubicin, cisplatin (MVAC) (21%, 66/308). Mean TTAC was 10 weeks; 23% of patients had TTAC >12 weeks. TTAC >12 weeks was associated with inferior OS [hazard ratio (HR) 1.28, 95% CI 1.00-1.62] and CSS (HR 1.30, 95% CI 1.00-1.69). In adjusted analyses, OS and CSS were lower among patients treated with carboplatin compared with those treated with cisplatin; OS HR 2.14 (95% CI 1.40-3.29) and CSS HR 2.06 (95% CI 1.26-3.37). CONCLUSIONS Most patients in the general population receive cisplatin, and this may be associated with superior outcomes to carboplatin. Initiation of ACT beyond 12 weeks is associated with inferior survival. Patients should start ACT as soon as they are medically fit to do so.

Why is perioperative chemotherapy for bladder cancer underutilized

Despite clinical evidence and recommendations from international treatment guidelines, the use of perioperative chemotherapy for muscle-invasive bladder cancer in routine practice remains low. Although multiple studies have described underutilization, there is an urgent need to better understand the elements contributing to the observed gaps in care. In this commentary, we explore what is known about the factors contributing to underutilization of perioperative chemotherapy for muscle-invasive bladder cancer. We also propose a framework to guide future knowledge translation activities in an effort to improve the care and outcomes of patients with this disease.

Quality of care indicators and their related outcomes: A population-based study in prostate cancer patients treated with radiotherapy

BACKGROUND AND PURPOSE We describe variations across the regional cancer centres in Ontario, Canada for five prostate cancer radiotherapy (RT) quality indicators: incomplete pre-treatment assessment, follow-up care, leg immobilization, bladder filling, and portal film target localization. Along with cancer centre volume, we examined each indicators association with relevant outcomes: long-term cause-specific survival, urinary incontinence, and gastrointestinal and genitourinary late morbidities. MATERIALS AND METHODS We conducted a population-based retrospective cohort study of 924 prostate cancer patients diagnosed between 1990 and 1998 who received RT within 9 months of diagnosis. Data sources included treating charts and registry and administrative data. The associations between indicators and outcomes were analysed using regression techniques to control for potential confounders. RESULTS Practice patterns varied across the regional cancer centres for all indicators (p<0.0001). Incomplete pre-treatment assessment was associated with worse cause-specific survival although this result was not significant when adjusted for confounding (adjusted RR=1.78, 95% CI=0.79-3.98). Treatment without leg immobilization (adjusted RR=1.72, 95% CI=1.16-2.56) and with an empty bladder (adjusted RR=1.98, 95% CI=1.08-3.63) was associated with genitourinary late morbidities. Treatment without leg immobilization was also associated with urinary incontinence (adjusted RR=2.18, 95% CI=1.23-3.87). CONCLUSIONS We documented wide variations in practice patterns. We demonstrated that measures of quality of care can be shown to be associated with clinically relevant outcomes in a population-based sample of prostate cancer patients.

Discrete Fourier Analysis of Ultrasound RF Time Series for Detection of Prostate Cancer

In this paper, we demonstrate that a set of six features extracted from the discrete Fourier transform of ultrasound radio-frequency (RF) time series can be used to detect prostate cancer with high sensitivity and specificity. Ultrasound RF time series refer to a series of echoes received from one spatial location of tissue while the imaging probe and the tissue are fixed in position. Our previous investigations have shown that at least one feature, fractal dimension, of these signals demonstrates strong correlation with the tissue microstructure. In the current paper, six new features that represent the frequency spectrum of the RF time series have been used, in conjunction with a neural network classification approach, to detect prostate cancer in regions of tissue as small as 0.03 cm2. Based on pathology results used as gold standard, we have acquired mean accuracy of 91%, mean sensitivity of 92% and mean specificity of 90% on seven human prostates.

Serum follicle-stimulating hormone levels predict time to development of castration resistant prostate cancer

INTRODUCTION Treatment of advancing prostate cancer focuses on blocking the activation of the androgen receptor with resultant prolonged perturbation of the hypothalamic-pituitary-gonadal axis. Androgen deprivation therapy (ADT) is marked, however, by eventual progression to castration- resistant prostate cancer (CRPC). Emerging evidence has postulated that follicle-stimulating hormone (FSH) may lead to proliferative and mutagenic responses of prostate cancer. We investigated the association of serum FSH and time to castration resistance. METHODS This was a single-centre retrospective study assessing serum FSH levels of patients undergoing ADT for advancing prostate cancer. The primary outcome was time of ADT initiation to the development of CRPC. For each patient on treatment and with castrate levels of testosterone, the maximum FSH value between ADT commencement and CRPC was identified and recorded. FSH was analyzed as a continuous and categorical variable. Cox multivariate regression in a step-wise fashion was used to explore the association between FSH levels and time to CRPC. RESULTS From a database of 323 prostate cancer patients actively managed with ADT, 103 men had a documented FSH value while castrate, with 45 men progressing to CRPC. The mean ± standard deviation maximum FSH value of these patients was 6.66 ± 4.22 mIU/mL (range: 1.5-28.1). The mean duration from ADT commencement to CRPC was 3.03 ± 0.34 years (range: 0.36-9.71). Univariate analysis suggested a trend of a negative correlation between FSH values and time to castrate resistance. A FSH value of less than or equal to the lowest tertile (4.8 mIU/mL) was associated with a longer time to CRPC (hazard ratio 0.46; p = 0.006). In the Cox regression analysis, elevated FSH was associated with a shorter duration time to CRPC (p = 0.03). CONCLUSIONS This retrospective, single-centre study would suggest there may be an association between serum FSH levels and time to CRPC for men treated palliatively with ADT for advancing prostate cancer. Further clinical investigation in a larger cohort of men is required to determine any clinical utility of FSH as a biomarker of progression or target for therapy.

Impact of Enzalutamide Compared with Bicalutamide on Quality of Life in Men with Metastatic Castration-resistant Prostate Cancer: Additional Analyses from the TERRAIN Randomised Clinical Trial

BACKGROUND Improving health-related quality of life (HRQoL) is an important goal in metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE To examine the impact of enzalutamide versus bicalutamide on HRQoL in mCRPC. DESIGN, SETTING, AND PARTICIPANTS TERRAIN is a multinational, phase 2, randomised, double-blind study in asymptomatic/mildly symptomatic men with mCRPC (ClinicalTrials.gov, NCT01288911). Patients were randomised (1:1) via an interactive voice and web response system to enzalutamide 160mg/d (n=184) or bicalutamide 50mg/d (n=191), with androgen deprivation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS HRQoL was assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P), European Quality of Life 5-Domain Scale (EQ-5D), and Brief Pain Inventory, Short-form questionnaires every 12 wk. Primary and secondary analyses utilised mixed models for repeated measures and pattern mixture models, respectively. RESULTS AND LIMITATIONS At 61 wk, 84 (46%) enzalutamide and 39 (20%) bicalutamide patients in the study were assessed. At 61 wk, changes from baseline favoured enzalutamide versus bicalutamide on three FACT-P domains in mixed models for repeated measures analyses and seven in pattern mixture models analyses. There were no differences in changes for EQ-5D index/visual analogue scale scores. Risk of first deterioration was lower with enzalutamide for FACT-P total (hazard ratio: 0.64, 95% confidence interval: 0.46-0.89, p=0.007), FACT-G total (hazard ratio: 0.70, 95% confidence interval: 0.50-0.98, p=0.04), PCS pain (hazard ratio: 0.74, 95% confidence interval: 0.54-1.00, p=0.048), and EQ-5D index (hazard ratio: 0.66, 95% confidence interval: 0.47-0.93, p=0.02) scores versus bicalutamide. Brief Pain Inventory, Short-form scores increased in both groups. There was no difference in time-to-pain progression. Study limitations include the exploratory nature of the HRQoL analyses, lack of multiple comparisons corrections, and unknown effects of anxiety/depression on HRQoL. CONCLUSIONS In patients with asymptomatic/mildly symptomatic mCRPC, enzalutamide provides HRQoL benefit versus bicalutamide. PATIENT SUMMARY Enzalutamide treatment was associated with better health-related quality of life in several domains versus bicalutamide in asymptomatic/mildly symptomatic metastatic castration-resistant prostate cancer. This likely relates to previously reported lower rates of symptomatic disease progression.