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1.  Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer 
The New England journal of medicine  2014;370(10):932-942.
Radical prostatectomy reduces mortality among men with localized prostate cancer; however, important questions regarding long-term benefit remain.
Between 1989 and 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy and followed them through the end of 2012. The primary end points in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) were death from any cause, death from prostate cancer, and the risk of metastases. Secondary end points included the initiation of androgen-deprivation therapy.
During 23.2 years of follow-up, 200 of 347 men in the surgery group and 247 of the 348 men in the watchful-waiting group died. Of the deaths, 63 in the surgery group and 99 in the watchful-waiting group were due to prostate cancer; the relative risk was 0.56 (95% confidence interval [CI], 0.41 to 0.77; P = 0.001), and the absolute difference was 11.0 percentage points (95% CI, 4.5 to 17.5). The number needed to treat to prevent one death was 8. One man died after surgery in the radical-prostatectomy group. Androgen-deprivation therapy was used in fewer patients who underwent prostatectomy (a difference of 25.0 percentage points; 95% CI, 17.7 to 32.3). The benefit of surgery with respect to death from prostate cancer was largest in men younger than 65 years of age (relative risk, 0.45) and in those with intermediate-risk prostate cancer (relative risk, 0.38). However, radical pros-tatectomy was associated with a reduced risk of metastases among older men (relative risk, 0.68; P = 0.04).
Extended follow-up confirmed a substantial reduction in mortality after radical prostatectomy; the number needed to treat to prevent one death continued to decrease when the treatment was modified according to age at diagnosis and tumor risk. A large proportion of long-term survivors in the watchful-waiting group have not required any palliative treatment. (Funded by the Swedish Cancer Society and others.)
PMCID: PMC4118145  PMID: 24597866
2.  Results From the Scandinavian Prostate Cancer Group Trial Number 4: A Randomized Controlled Trial of Radical Prostatectomy Versus Watchful Waiting 
In the Scandinavian Prostate Cancer Group Trial Number 4 (SPCG-4), 347 men were randomly assigned to radical prostatectomy and 348 to watchful waiting. In the most recent analysis (median follow-up time = 12.8 years), the cumulative mortality curves had been stable over the follow-up. At 15 years, the absolute risk reduction of dying from prostate cancer was 6.1% following randomization to radical prostatectomy, compared with watchful waiting. Hence, 17 need to be randomized to operation to avert one death. Data on self-reported symptoms, stress from symptoms, and quality of life were collected at 4 and 12.2 years of median follow-up. These questionnaire studies show an intricate pattern of symptoms evolving after surgery, hormonal treatments, signs of tumor progression, and also from natural aging. This article discusses some of the main findings of the SPCG-4 study.
PMCID: PMC3540876  PMID: 23271778
3.  Prostate cancer (early) 
BMJ Clinical Evidence  2006;2006:1805.
Prostate cancer is the sixth most common cancer in the world, and 85% of cases are diagnosed in men over the age of 65 years. In men with well to moderately differentiated prostate cancer that remains within the capsule, clinical progression-free survival is 70% at 5 years, and 40% at 10 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for early prostate cancer? We searched: Medline, Embase, The Cochrane Library and other important databases up to February 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 25 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding hormone therapy to external beam radiation therapy, or to brachytherapy; adding neoadjuvant hormone therapy to surgery alone, or to surgery plus adjuvant hormone therapy; brachytherapy alone; external beam radiation therapy alone; hormone therapy plus standard care; immediate hormone therapy; radical prostatectomy; and watchful waiting.
Key Points
Prostate cancer is the sixth most common cancer in the world and 85% of cases are diagnosed in men over the age of 65 years. Subclinical prostate cancer is thought to be very common and increases with age, with an estimated prevalence of 30% in men aged 30-39 years, increasing to over 75% in men aged over 85 years.Risk factors include black ethnic origin, family history of prostate cancer and diet.In men with well to moderately differentiated prostate cancer that remains within the capsule, clinical progression free survival is 70% at 5 years and 40% at 10 years.Age adjusted mortality rates for prostate cancer do not seem to be affected by national PSA screening and treatment rates.
This review focuses on clinically localised disease that has not extended beyond the prostate capsule (TNM classification system T0, T1, T2, and American Urologic Staging system stages A and B).
Radical prostatectomy may reduce mortality compared with watchful waiting in men with clinically localised prostate cancer, but the benefits in quality adjusted life expectancy seem to be moderate. Radical prostatectomy may reduce overall and prostate cancer mortality and metastasis, but increases the risk of urinary and sexual dysfunction.
The benefits of external beam radiation therapy (EBRT) or brachytherapy compared with watchful waiting or radical prostatectomy are unknown. EBRT increases the risk of erectile dysfunction and toxicity to the surrounding tissues. Long term survival after EBRT depends on pre-treatment PSA level and tumour differentiation.
Hormone therapy may be used as neoadjuvant therapy before surgery or radiotherapy, concurrently with radiation therapy, or as an adjuvant to other treatments or usual care. Evidence of benefit from hormone therapy in early prostate cancer is very limited. Neoadjuvant hormone therapy may improve biochemical free survival when used with EBRT, but not when given before surgery plus adjuvant hormonal therapy. Immediate hormone therapy in men with clinically localised prostate cancer may reduce disease progression but may not reduce overall mortality, although few adequate studies have been found. Adjuvant hormonal therapy may reduce disease progression but may not improve overall survival compared with placebo.Hormone therapy is associated with increased rates of gynaecomastia and breast pain.
PMCID: PMC2907626  PMID: 19454100
4.  The Prostate Cancer Intervention Versus Observation Trial:VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): Design and Baseline Results of a Randomized Controlled Trial Comparing Radical Prostatectomy With Watchful Waiting for Men With Clinically Localized Prostate Cancer 
Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer death in men. In the United States, 90% of men with prostate cancer are more than age 60 years, diagnosed by early detection with the prostate-specific antigen (PSA) blood test, and have disease believed confined to the prostate gland (clinically localized). Common treatments for clinically localized prostate cancer include watchful waiting (WW), surgery to remove the prostate gland (radical prostatectomy), external-beam radiation therapy and interstitial radiation therapy (brachytherapy), and androgen deprivation. Little is known about the relative effectiveness and harms of treatments because of the paucity of randomized controlled trials. The Department of Veterans Affairs/National Cancer Institute/Agency for Healthcare Research and Quality Cooperative Studies Program Study #407:Prostate Cancer Intervention Versus Observation Trial (PIVOT), initiated in 1994, is a multicenter randomized controlled trial comparing radical prostatectomy with WW in men with clinically localized prostate cancer. We describe the study rationale, design, recruitment methods, and baseline characteristics of PIVOT enrollees. We provide comparisons with eligible men declining enrollment and men participating in another recently reported randomized trial of radical prostatectomy vs WW conducted in Scandinavia. We screened 13 022 men with prostate cancer at 52 US medical centers for potential enrollment. From these, 5023 met initial age, comorbidity, and disease eligibility criteria, and a total of 731 men agreed to participate and were randomized. The mean age of enrollees was 67 years. Nearly one-third were African American. Approximately 85% reported that they were fully active. The median PSA was 7.8ng/mL (mean 10.2ng/mL). In three-fourths of men, the primary reason for biopsy leading to a diagnosis of prostate cancer was a PSA elevation or rise. Using previously developed tumor risk categorizations incorporating PSA levels, Gleason histologic grade, and tumor stage, it was found that approximately 40% had low-risk, 34% had medium-risk, and 21% had high-risk prostate cancer based on local histopathology. Comparison to our national sample of eligible men declining PIVOT participation as well as to men enrolled in the Scandinavian trial indicated that PIVOT enrollees are representative of men being diagnosed and treated in the United States and quite different from men in the Scandinavian trial. PIVOT enrolled an ethnically diverse population representative of men diagnosed with prostate cancer in the United States. Results will yield important information regarding the relative effectiveness and harms of surgery compared with WW for men with predominately PSA-detected clinically localized prostate cancer.
PMCID: PMC3540866  PMID: 23271771
5.  Factors associated with initial treatment and survival for clinically localized prostate cancer: results from the CDC-NPCR Patterns of Care Study (PoC1) 
BMC Cancer  2010;10:152.
Despite the large number of men diagnosed with localized prostate cancer, there is as yet no consensus concerning appropriate treatment. The purpose of this study was to describe the initial treatment patterns for localized prostate cancer in a population-based sample and to determine the clinical and patient characteristics associated with initial treatment and overall survival.
The analysis included 3,300 patients from seven states, diagnosed with clinically localized prostate cancer in 1997. We examined the association of sociodemographic and clinical characteristics with four treatment options: radical prostatectomy, radiation therapy, hormone therapy, and watchful waiting. Diagnostic and treatment information was abstracted from medical records. Socioeconomic measures were derived from the 2000 Census based on the patient's residence at time of diagnosis. Vital status through December 31, 2002, was obtained from medical records and linkages to state vital statistics files and the National Death Index. Multiple logistic regression analysis and Cox proportional hazards models identified factors associated with initial treatment and overall survival, respectively.
Patients with clinically localized prostate cancer received the following treatments: radical prostatectomy (39.7%), radiation therapy (31.4%), hormone therapy (10.3%), or watchful waiting (18.6%). After multivariable adjustment, the following variables were associated with conservative treatment (hormone therapy or watchful waiting): older age, black race, being unmarried, having public insurance, having non-screen detected cancer, having normal digital rectal exam results, PSA values above 20, low Gleason score (2-4), comorbidity, and state of residence. Among patients receiving definitive treatment (radical prostatectomy or radiation therapy), older age, being unmarried, PSA values above 10, unknown Gleason score, state of residence, as well as black race in patients under 60 years of age, were associated with receipt of radiation therapy. Overall survival was related to younger age, being married, Gleason score under 8, radical prostatectomy, and state of residence. Comorbidity was only associated with risk of death within the first three years of diagnosis.
In the absence of clear-cut evidence favoring one treatment modality over another, it is important to understand the factors that inform treatment selection. Since state of residence was a significant predictor of both treatment as well as overall survival, true regional differences probably exist in how physicians and patients select treatment options. Factors affecting treatment choice and treatment effectiveness need to be further explored in future population-based studies.
PMCID: PMC2876077  PMID: 20403178
6.  Radical Prostatectomy versus Observation for Localized Prostate Cancer 
The New England journal of medicine  2012;367(3):203-213.
The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known.
From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality.
During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P = 0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P = 0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P = 0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P = 0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death.
Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT number, NCT00007644.)
PMCID: PMC3429335  PMID: 22808955
7.  Risk Assessment for Prostate Cancer Metastasis and Mortality at the Time of Diagnosis 
Although many tools for the assessment of prostate cancer risk have been published, most are designed to predict only biochemical recurrence, usually after a single specified treatment. We assessed the accuracy of the Cancer of the Prostate Risk Assessment (CAPRA) score, which was validated previously to predict pathological and biochemical outcomes after radical prostatectomy, to predict metastases, prostate cancer–specific mortality, and all-cause mortality.
We studied 10 627 men with clinically localized prostate cancer in the Cancer of the Prostate Strategic Urologic Research Endeavor registry, who underwent primary radical prostatectomy, radiation therapy (external beam or interstitial), androgen deprivation monotherapy, or watchful waiting/active surveillance, and had at least 6 months of follow-up after treatment. CAPRA scores were calculated at diagnosis from the prostate-specific antigen level, Gleason score, percentage of biopsy cores that were positive for cancer, clinical tumor stage, and age at diagnosis. Survival was studied with Kaplan–Meier analyses. Associations between increasing CAPRA scores and bone metastasis, cancer-specific mortality, and all-cause mortality were examined by use of proportional hazards regression, with adjustment for primary treatment; for all-cause mortality, the analysis also included adjustment for age and comorbidity. Accuracy of the CAPRA score was assessed with the concordance (c)-index.
Among the 10 627 patients, 311 (2.9%) men developed bone metastases, 251 (2.4%) died of prostate cancer, and 1582 (14.9%) died of other causes. Each single-point increase in the CAPRA score was associated with increased bone metastases (hazard ratio [HR] for bone metastases = 1.47, 95% confidence interval [CI] = 1.39 to 1.56), cancer-specific mortality (HR for prostate cancer death = 1.39, 95% CI = 1.31 to 1.48), and all-cause mortality (HR for death = 1.13, 95% CI = 1.10 to 1.16). The CAPRA score was accurate for predicting metastases (c-index = 0.78), cancer-specific mortality (c-index = 0.80), and all-cause mortality (c-index = 0.71).
In a large cohort of patients with clinically localized prostate cancer who were managed with one of five primary modalities, the CAPRA score predicted clinical prostate cancer endpoints with good accuracy. These results support the value of the CAPRA score as a risk assessment and stratification tool for both research studies and clinical practice.
PMCID: PMC2697208  PMID: 19509351
8.  The Natural History of Men Treated With Deferred Androgen Deprivation Therapy in Whom Metastatic Prostate Cancer Developed Following Radical Prostatectomy 
The Journal of urology  2007;179(1):156-162.
We report on the natural history and factors influencing the prognosis of a cohort of hormone naïve, prostate specific antigen era patients in whom metastatic prostate cancer developed after radical prostatectomy who were followed closely and treated with deferred androgen deprivation therapy at the time of metastasis.
Materials and Methods
A total of 3,096 men underwent radical prostatectomy performed by a single surgeon at Johns Hopkins Hospital between 1987 and 2005. Of these men 422 had prostate specific antigen failure. Distant metastasis developed in 123 patients, of whom 91 with complete data formed the study cohort initially treated during the prostate specific antigen era (1987 to 2005) and receiving androgen deprivation therapy after documented metastasis. A total of 41 men died of prostate cancer. Median survival times were estimated by Kaplan-Meier analysis. Prognostic impact was estimated as the hazard ratio derived from the Cox proportional hazards model.
Median followup from radical prostatectomy was 120 months (range 24 to 216). Kaplan-Meier median (range) times to failure were 24 months (12 to 144) from radical prostatectomy to prostate specific antigen failure, 36 months (0 to 132) from prostate specific antigen failure to metastasis, 84 months (12 to 180) from metastasis to death and 168 months (24 to 216) from radical prostatectomy to death. Statistically significant univariate risk factors for prostate cancer specific mortality at the time of metastasis were pain at diagnosis of metastases (p = 0.002), time from radical prostatectomy to metastasis (p = 0.024) and prostate specific antigen doubling time less than 3 months during the 24 months before metastasis (p = 0.016). Multivariable analysis demonstrated independent predictors of prostate cancer specific mortality at the time of metastasis, namely pain (HR 3.5, p = 0.003) and prostate specific antigen doubling time less than 3 months (HR 3.4, p = 0.017).
Men treated with deferred androgen deprivation therapy for the development of metastasis after radical prostatectomy may have a long life span, 169 months after radical prostatectomy (range 24 to 216). The presence of pain and short prostate specific antigen doubling time predicted an unfavorable outcome.
PMCID: PMC4342043  PMID: 18001801
prostatic neoplasms; prostatectomy; neoplasm metastasis; androgens; pain
9.  Robotic-Assisted Minimally Invasive Surgery for Gynecologic and Urologic Oncology 
Executive Summary
An application was received to review the evidence on the ‘The Da Vinci Surgical System’ for the treatment of gynecologic malignancies (e.g. endometrial and cervical cancers). Limitations to the current standard of care include the lack of trained physicians on minimally invasive surgery and limited access to minimally invasive surgery for patients. The potential benefits of ‘The Da Vinci Surgical System’ include improved technical manipulation and physician uptake leading to increased surgeries, and treatment and management of these cancers.
The demand for robotic surgery for the treatment and management of prostate cancer has been increasing due to its alleged benefits of recovery of erectile function and urinary continence, two important factors of men’s health. The potential technical benefits of robotic surgery leading to improved patient functional outcomes are surgical precision and vision.
Clinical Need
Uterine and cervical cancers represent 5.4% (4,400 of 81,700) and 1.6% (1,300 of 81,700), respectively, of incident cases of cancer among female cancers in Canada. Uterine cancer, otherwise referred to as endometrial cancer is cancer of the lining of the uterus. The most common treatment option for endometrial cancer is removing the cancer through surgery. A surgical option is the removal of the uterus and cervix through a small incision in the abdomen using a laparoscope which is referred to as total laparoscopic hysterectomy. Risk factors that increase the risk of endometrial cancer include taking estrogen replacement therapy after menopause, being obese, early age at menarche, late age at menopause, being nulliparous, having had high-dose radiation to the pelvis, and use of tamoxifen.
Cervical cancer occurs at the lower narrow end of the uterus. There are more treatment options for cervical cancer compared to endometrial cancer, however total laparoscopic hysterectomy is also a treatment option. Risk factors that increase the risk for cervical cancer are multiple sexual partners, early sexual activity, infection with the human papillomavirus, and cigarette smoking, whereas barrier-type of contraception as a risk factor decreases the risk of cervical cancer.
Prostate cancer is ranked first in men in Canada in terms of the number of new cases among all male cancers (25,500 of 89,300 or 28.6%). The impact on men who develop prostate cancer is substantial given the potential for erectile dysfunction and urinary incontinence. Prostate cancer arises within the prostate gland, which resides in the male reproductive system and near the bladder. Radical retropubic prostatectomy is the gold standard treatment for localized prostate cancer. Prostate cancer affects men above 60 years of age. Other risk factors include a family history of prostate cancer, being of African descent, being obese, consuming a diet high in fat, physical inactivity, and working with cadium.
The Da Vinci Surgical System
The Da Vinci Surgical System is a robotic device. There are four main components to the system: 1) the surgeon’s console, where the surgeon sits and views a magnified three-dimensional image of the surgical field; 2) patient side-cart, which sits beside the patient and consists of three instrument arms and one endoscope arm; 3) detachable instruments (endowrist instruments and intuitive masters), which simulate fine motor human movements. The hand movements of the surgeon’s hands at the surgeon’s console are translated into smaller ones by the robotic device and are acted out by the attached instruments; 4) three-dimensional vision system: the camera unit or endoscope arm. The main advantages of use of the robotic device are: 1) the precision of the instrument and improved dexterity due to the use of “wristed” instruments; 2) three-dimensional imaging, with improved ability to locate blood vessels, nerves and tissues; 3) the surgeon’s console, which reduces fatigue accompanied with conventional laparoscopy surgery and allows for tremor-free manipulation. The main disadvantages of use of the robotic device are the costs including instrument costs ($2.6 million in US dollars), cost per use ($200 per use), the costs associated with training surgeons and operating room personnel, and the lack of tactile feedback, with the trade-off being increased visual feedback.
Research Questions
For endometrial and cervical cancers,
1. What is the effectiveness of the Da Vinci Surgical System vs. laparoscopy and laparotomy for women undergoing any hysterectomy for the surgical treatment and management of their endometrial and cervical cancers?
2. What are the incremental costs of the Da Vinci Surgical System vs. laparoscopy and laparotomy for women undergoing any hysterectomy for the surgical treatment and management of their endometrial and cervical cancers?
For prostate cancer,
3. What is the effectiveness of robotically-assisted radical prostatectomy using the Da Vinci Surgical System vs. laparoscopic radical prostatectomy and retropubic radical prostatectomy for the surgical treatment and management of prostate cancer?
4. What are the incremental costs of robotically-assisted radical prostatectomy using the Da Vinci Surgical System vs. laparoscopic radical prostatectomy and retropubic radical prostatectomy for the surgical treatment and management of prostate cancer?
Research Methods
Literature Search
Search Strategy
A literature search was performed on May 12, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, Wiley Cochrane, CINAHL, Centre for Reviews and Dissemination/International Agency for Health Technology Assessment for studies published from January 1, 2000 until May 12, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language articles (January 1, 2000-May 12, 2010)
Journal articles that report on the effectiveness or cost-effectiveness for the comparisons of interest using a primary data source (e.g. obtained in a clinical setting)
Journal articles that report on the effectiveness or cost-effectiveness for the comparisons of interest using a secondary data source (e.g. hospital- or population-based registries)
Study design and methods must be clearly described
Health technology assessments, systematic reviews, randomized controlled trials, non-randomized controlled trials and/or cohort studies, case-case studies, regardless of sample size, cost-effectiveness studies
Exclusion Criteria
Duplicate publications (with the more recent publication on the same study population included)
Non-English papers
Animal or in-vitro studies
Case reports or case series without a referent or comparison group
Studies on long-term survival which may be affected by treatment
Studies that do not examine the cancers (e.g. advanced disease) or outcomes of interest
Outcomes of Interest
For endometrial and cervical cancers,
Primary outcomes:
Morbidity factors
- Length of hospitalization
- Number of complications*
Peri-operative factors
- Operation time
- Amount of blood loss*
- Number of conversions to laparotomy*
Number of lymph nodes recovered
For prostate cancer,
Primary outcomes:
Morbidity factors
- Length of hospitalization
- Amount of morphine use/pain*
Peri-operative factors
- Operation time
- Amount of blood loss*
- Number of transfusions*
- Duration of catheterization
- Number of complications*
- Number of anastomotic strictures*
Number of lymph nodes recovered
Oncologic factors
- Proportion of positive surgical margins
Long-term outcomes
- Urinary continence
- Erectile function
Summary of Findings
Robotic use for gynecologic oncology compared to:
Laparotomy: benefits of robotic surgery in terms of shorter length of hospitalization and less blood loss. These results indicate clinical effectiveness in terms of reduced morbidity and safety, respectively, in the context of study design limitations.
The beneficial effect of robotic surgery was shown in pooled analysis for complications, owing to increased sample size.
More work is needed to clarify the role of complications in terms of safety, including improved study designs, analysis and measurement.
Laparoscopy: benefits of robotic surgery in terms of shorter length of hospitalization, less blood loss and fewer conversions to laparotomy likely owing to the technical difficulty of conventional laparoscopy, in the context of study design limitations.
Clinical significance of significant findings for length of hospitalizations and blood loss is low.
Fewer conversions to laparotomy indicate clinical effectiveness in terms of reduced morbidity.
Robotic use for urologic oncology, specifically prostate cancer, compared to:
Retropubic surgery: benefits of robotic surgery in terms of shorter length of hospitalization and less blood loss/fewer individuals requiring transfusions. These results indicate clinical effectiveness in terms of reduced morbidity and safety, respectively, in the context of study design limitations. There was a beneficial effect in terms of decreased positive surgical margins and erectile dysfunction. These results indicate clinical effectiveness in terms of improved cancer control and functional outcomes, respectively, in the context of study design limitations.
Surgeon skill had an impact on cancer control and functional outcomes.
The results for complications were inconsistent when measured as either total number of complications, pain management or anastomosis. There is some suggestion that robotic surgery is safe with respect to less post-operative pain management required compared to retropubic surgery, however improved study design and measurement of complications need to be further addressed.
Clinical significance of significant findings for length of hospitalizations is low.
Laparoscopy: benefits of robotic surgery in terms of less blood loss and fewer individuals requiring transfusions likely owing to the technical difficulty of conventional laparoscopy, in the context of study design limitations.
Clinical significance of significant findings for blood loss is low.
The potential link between less blood loss, improved visualization and improved functional outcomes is an important consideration for use of robotics.
All studies included were observational in nature and therefore the results must be interpreted cautiously.
Economic Analysis
The objective of this project was to assess the economic impact of robotic-assisted laparoscopy (RAL) for endometrial, cervical, and prostate cancers in the province of Ontario.
A budget impact analysis was undertaken to report direct costs associated with open surgery (OS), endoscopic laparoscopy (EL) and robotic-assisted laparoscopy (RAL) based on clinical literature review outcomes, to report a budget impact in the province based on volumes and costs from administrative data sets, and to project a future impact of RAL in Ontario. A cost-effectiveness analysis was not conducted because of the low quality evidence from the clinical literature review.
Hospital costs were obtained from the Ontario Case Costing Initiative (OCCI) for the appropriate Canadian Classification of Health Intervention (CCI) codes restricted to selective ICD-10 diagnostic codes after consultation with experts in the field. Physician fees were obtained from the Ontario Schedule of Benefits (OSB) after consultation with experts in the field. Fees were costed based on operation times reported in the clinical literature for the procedures being investigated. Volumes of procedures were obtained from the Ministry of Health and Long-Term Care (MOHLTC) administrative databases.
Direct costs associated with RAL, EL and OS included professional fees, hospital costs (including disposable instruments), radiotherapy costs associated with positive surgical margins in prostate cancer and conversion to OS in gynecological cancer. The total cost per case was higher for RAL than EL and OS for both gynecological and prostate cancers. There is also an acquisition cost associated with RAL. After conversation with the only supplier in Canada, hospitals are looking to spend an initial 3.6M to acquire the robotic surgical system
Previous volumes of OS and EL procedures were used to project volumes into Years 1-3 using a linear mathematical expression. Burden of OS and EL hysterectomies and prostatectomies was calculated by multiplying the number of cases for that year by the cost/case of the procedure.
The number of procedures is expected to increase in the next three years based on historical data. RAL is expected to capture this market by 65% after consultation with experts. If it’s assumed that RAL will capture the current market in Ontario by 65%, the net impact is expected to be by Year 3, 3.1M for hysterectomy and 6.7M for prostatectomy procedures respectively in the province.
RAL has diffused in the province with four surgical systems in place in Ontario, two in Toronto and two in London. RAL is a more expensive technology on a per case basis due to more expensive robot specific instrumentation and physician labour reflected by increased OR time reported in the clinical literature. There is also an upfront cost to acquire the machine and maintenance contract. RAL is expected to capture the market at 65% with project net impacts by Year 3 of 3.1M and 6.7M for hysterectomy and prostatectomy respectively.
PMCID: PMC3382308  PMID: 23074405
10.  Individualized Estimation of the Benefit of Radical Prostatectomy from the Scandinavian Prostate Cancer Group Randomized Trial 
European Urology  2012;62(2):204-209.
Although there is randomized evidence that radical prostatectomy improves survival, there are few data on how benefit varies by baseline risk.
We aimed to create a statistical model to calculate the decrease in risk of death associated with surgery for an individual patient, using stage, grade, prostate-specific antigen, and age as predictors.
Design, setting, and participants
A total of 695 men with T1 or T2 prostate cancer participated in the Scandinavian Prostate Cancer Group 4 trial (SPCG-4).
Patients in SPCG-4 were randomized to radical prostatectomy or conservative management.
Outcome measurements and statistical analysis
Competing risk models were created separately for the radical prostatectomy and the watchful waiting group, with the difference between model predictions constituting the estimated benefit for an individual patient.
Results and limitations
Individualized predictions of surgery benefit varied widely depending on age and tumor characteristics. At 65 yr of age, the absolute 10-yr risk reduction in prostate cancer mortality attributable to radical prostatectomy ranged from 4.5% to 17.2% for low- versus high-risk patients. Little expected benefit was associated with surgery much beyond age 70. Only about a quarter of men had an individualized benefit within even 50% of the mean. A limitation is that estimates from SPCG-4 have to be applied cautiously to contemporary patients.
Our model suggests that it is hard to justify surgery in patients with Gleason 6, T1 disease or in those patients much above 70 yr of age. Conversely, surgery seems unequivocally of benefit for patients who have Gleason 8, or Gleason 7, stage T2. For patients with Gleason 6 T2 and Gleason 7 T1, treatment is more of a judgment call, depending on patient preference and other clinical findings, such as the number of positive biopsy cores and comorbidities.
PMCID: PMC3389180  PMID: 22541389
Prostatic neoplasms; Statistics and research design; Randomized controlled trial; Prostatectomy
11.  Immediate Risk for Cardiovascular Events and Suicide Following a Prostate Cancer Diagnosis: Prospective Cohort Study 
PLoS Medicine  2009;6(12):e1000197.
Katja Fall and Fang Fang and colleagues find that men newly diagnosed with prostate cancer are at increased risk of cardiovascular events and suicide.
Stressful life events have been shown to be associated with altered risk of various health consequences. The aim of the present study was to investigate whether the emotional stress evoked by a prostate cancer diagnosis increases the immediate risks of cardiovascular events and suicide.
Methods and Findings
We conducted a prospective cohort study by following all men in Sweden who were 30 y or older (n = 4,305,358) for a diagnosis of prostate cancer (n = 168,584) and their subsequent occurrence of cardiovascular events and suicide between January 1, 1961 and December 31, 2004. We used Poisson regression models to calculate relative risks (RRs) and 95% confidence intervals (CIs) of cardiovascular events and suicide among men who had prostate cancer diagnosed within 1 y to men without any cancer diagnosis. The risks of cardiovascular events and suicide were elevated during the first year after prostate cancer diagnosis, particularly during the first week. Before 1987, the RR of fatal cardiovascular events was 11.2 (95% CI 10.4–12.1) during the first week and 1.9 (95% CI 1.9–2.0) during the first year after diagnosis. From 1987, the RR for cardiovascular events, nonfatal and fatal combined, was 2.8 (95% CI 2.5–3.2) during the first week and 1.3 (95% CI 1.3–1.3) during the first year after diagnosis. While the RR of cardiovascular events declined, the RR of suicide was stable over the entire study period: 8.4 (95% CI 1.9–22.7) during the first week and 2.6 (95% CI 2.1–3.0) during the first year after diagnosis. Men 54 y or younger at cancer diagnosis demonstrated the highest RRs of both cardiovascular events and suicide. A limitation of the present study is the lack of tumor stage data, which precluded possibilities of investigating the potential impact of the disease severity on the relationship between a recent diagnosis of prostate cancer and the risks of cardiovascular events and suicide. In addition, we cannot exclude residual confounding as a possible explanation.
Men newly diagnosed with prostate cancer are at increased risks for cardiovascular events and suicide. Future studies with detailed disease characteristic data are warranted.
Please see later in the article for the Editors' Summary
Editors' Summary
Prostate cancer—a type of tumor that develops in a walnut-sized structure in the male reproductive system—is the commonest cancer (excluding skin cancer) among men in developed countries. In the USA and the UK, for example, one in six men will develop prostate cancer during their lifetime. Most prostate cancers develop in elderly men and, because these tumors usually grow relatively slowly, many men die with prostate cancer rather than as a result of it. Nevertheless, some prostate cancers are fast-growing and aggressive and prostate cancer is the second leading cause of cancer-related death among men. The symptoms of prostate cancer include problems urinating and excessive urination during the night. Nowadays, however, most prostate cancers are detected before they produce any symptoms by measuring the amount of a protein called the prostate-specific antigen (PSA) in the blood.
Why Was This Study Done?
Widespread PSA screening was introduced 20 years ago in the hope that early detection of prostate cancer would save lives. But, although many more prostate cancers are detected nowadays, the number of prostate cancer deaths has not changed significantly. Experts are divided, therefore, about whether the potential benefits of PSA screening outweigh its risks. Treatments for prostate cancer (for example, surgical removal of the prostate) may be more effective if they are started early but they can cause impotence and urinary incontinence, so should men be treated whose cancer might otherwise never affect their health? In addition, receiving a diagnosis of prostate cancer is stressful and there is growing evidence that stressful life events can increase an individual's risk of becoming ill or dying from a heart attack, stroke, or other “cardiovascular” events and of becoming mentally ill. In this study, therefore, the researchers investigate whether men diagnosed with prostate cancer in Sweden have increased risks of cardiovascular events and suicide during the first week and first year after their diagnosis.
What Did the Researchers Do and Find?
The researchers identified nearly 170, 000 men diagnosed with prostate cancer between 1961 and 2004 among Swedish men aged 30 years or older by searching the Swedish Cancer Register. They obtained information on subsequent fatal and nonfatal cardiovascular events and suicides from the Causes of Death Register and the Inpatient Register (in Sweden, everyone has a unique national registration number that facilitates searches of different health-related Registers). Before 1987, men with prostate cancer were about 11 times as likely to have a fatal cardiovascular event during the first week after their diagnosis as men without prostate cancer; during the first year after their diagnosis, men with prostate cancer were nearly twice as likely to have a cardiovascular event as men without prostate cancer (a relative risk of 1.9). From 1987, the relative risk of combined fatal and nonfatal cardiovascular events associated with a diagnosis of prostate cancer was 2.8 during the first week and 1.3 during the first year after diagnosis. The relative risk of suicide associated with a diagnosis of prostate cancer was 8.4 during the first week and 2.6 during the first year after diagnosis throughout the study period. Finally, men younger than 54 years at diagnosis had higher relative risks of both cardiovascular events and suicide.
What Do These Findings Mean?
These findings suggest that men newly diagnosed with prostate cancer have an increased risk of cardiovascular events and suicide. Because there is no information on tumor size or aggressiveness in the Cancer Register, the researchers could not look at the relationship between disease severity and the likelihood of a cardiovascular event or suicide. Furthermore, because of the study design, men who received a diagnosis of prostate cancer may have had additional characteristics in common that contributed to their increased risk of cardiovascular events and suicide. Nevertheless, these findings strongly suggest that the stress of the diagnosis itself rather than any subsequent treatment has deleterious effects on the health of men receiving a diagnosis of prostate cancer. Thus, strategies should be developed to reduce the risks of cardiovascular events and suicide—increased clinical and psychological monitoring—after a diagnosis of prostate cancer, particularly among young men, and this new information should be considered in the ongoing debate about the risks and benefits of PSA screening.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Cancer Institute provides information on all aspects of prostate cancer, (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on prostate cancer, including Prostate Cancer Screening, A Decision Guide (some information in multiple languages)
The UK National Health Service Choices Web site provides detailed information on prostate cancer
The UK-based Samaritans charity provides confidential nonjudgmental emotional support, 24 hours a day, for people who are experiencing feelings of distress or despair, including those which could lead to suicide
Outside the UK, Befrienders provides information on help lines for those experiencing distress
PMCID: PMC2784954  PMID: 20016838
12.  Outcomes in Localized Prostate Cancer: National Prostate Cancer Register of Sweden Follow-up Study 
Treatment for localized prostate cancer remains controversial. To our knowledge, there are no outcome studies from contemporary population-based cohorts that include data on stage, Gleason score, and serum levels of prostate-specific antigen (PSA).
In the National Prostate Cancer Register of Sweden Follow-up Study, a nationwide cohort, we identified 6849 patients aged 70 years or younger. Inclusion criteria were diagnosis with local clinical stage T1–2 prostate cancer from January 1, 1997, through December 31, 2002, a Gleason score of 7 or less, a serum PSA level of less than 20 ng/mL, and treatment with surveillance (including active surveillance and watchful waiting, n = 2021) or curative intent (including radical prostatectomy, n = 3399, and radiation therapy, n = 1429). Among the 6849 patients, 2686 had low-risk prostate cancer (ie, clinical stage T1, Gleason score 2-6, and serum PSA level of <10 ng/mL). The study cohort was linked to the Cause of Death Register, and cumulative incidence of death from prostate cancer and competing causes was calculated.
For the combination of low- and intermediate-risk prostate cancers, calculated cumulative 10-year prostate cancer–specific mortality was 3.6% (95% confidence interval [CI] = 2.7% to 4.8%) in the surveillance group and 2.7% (95% CI = 2.1% to 3.45) in the curative intent group. For those with low-risk disease, the corresponding values were 2.4% (95% CI = 1.2% to 4.1%) among the 1085 patients in the surveillance group and 0.7% (95% CI = 0.3% to 1.4%) among the 1601 patients in the curative intent group. The 10-year risk of dying from competing causes was 19.2% (95% CI = 17.2% to 21.3%) in the surveillance group and 10.2% (95% CI = 9.0% to 11.4%) in the curative intent group.
A 10-year prostate cancer–specific mortality of 2.4% among patients with low-risk prostate cancer in the surveillance group indicates that surveillance may be a suitable treatment option for many patients with low-risk disease.
PMCID: PMC2897875  PMID: 20562373
13.  Recent Time Trends in the Epidemiology of Stage IV Prostate Cancer in the United States: Analysis of Data From the Surveillance, Epidemiology, and End Results Program* 
Urology  2009;75(6):1396-1404.
To describe recent epidemiologic trends in stage IV prostate cancer. Although advances in screening and diagnostic techniques have led to earlier detection of prostate cancer, a portion of patients still present with late-stage disease.
Population-based cancer registry data from the Surveillance, Epidemiology, and End Results Program (cases from 1988 to 2003, follow-up through 2005) were used to calculate annual age-adjusted incidence rates of stage IV prostate cancer (overall and for the subset presenting with distant metastases) and to assess time trends in patient, tumor, and treatment characteristics and survival.
From 1988 to 2003, the age-adjusted incidence of stage IV prostate cancer significantly declined by 6.4% each year. The proportion of men diagnosed at younger ages, with poorly differentiated tumors, or who underwent a radical prostatectomy significantly increased over time. Five-year relative survival improved across the study period (from 41.6% to 62.3%), particularly in those diagnosed at younger ages or with moderately to well-differentiated tumors. Later years of diagnosis were independently associated with a decreased risk of death (from all causes and from prostate cancer specifically) after controlling for important patient, tumor, and treatment characteristics. Tumor grade and receipt of radical prostatectomy appeared to be the strongest independent prognostic indicators. Temporal trends were similar in the subset presenting with distant metastases, except that no significant improvement in survival was observed.
As younger men may expect to live longer with advanced prostate cancer, there remains a need to widen the range of therapeutic and supportive care options.
PMCID: PMC4249683  PMID: 19969335
14.  Long term results of HDR brachytherapy in men older than 75 with localized carcinoma of the prostate 
Prostate cancer is an illness with a high incidence, especially among older men. The choice of a treatment option among men above 75 years is, however, not clear. Radical prostatectomy in this age group is connected with a relatively high morbidity. A further possibility of curative treatment is radiotherapy which can be administered in the form of external beam or in combination with high dose rate (HDR) brachytherapy.
The aim of our work was to evaluate how HDR brachytherapy is tolerated among men older than 75 and how associated diseases can influence the tolerance to this treatment. Of interest to us were the treatment results and mortality from other diseases.
Materials and methods
We analyzed a sample of 20 men above 75 years old (median 77 years) who were undergoing treatment by a combination of external radiotherapy and brachytherapy. Sixteen (80%) of them had prostate cancer with an intermediate and high risk of recurrence, four had low risk prostate cancer. Most patients, 14 (70%), had less than two comorbidities.
The median observation period was 57 months. No perioperative complications were recorded. Acute genitourinary toxicity (GU) to a maximum grade of 1–2 manifested in 60% of cases. Acute gastrointestinal toxicity (GIT) was observed only at grade 1 and in 25% of cases. Late GU toxicity occurred in 35% of patients, with only one showing grade 3; late GIT toxicity was recorded at grade 1 only in 3 patients (15%). 70% of the men lived longer than 3 years after treatment, at present, 50% lived more than 5 years. Long-term biochemical remission was achieved in 18 patients (90%).
HDR BRT is possible and well-tolerated in older men above 75 years in good condition and without serious intercurrence.
Well-selected older patients with higher-risk tumours and without serious comorbidities undoubtedly benefit from radical treatment when compared with watchful waiting.
PMCID: PMC3863282  PMID: 24381742
Localized prostate cancer; High dose rate (HDR) brachytherapy; Older man
15.  Long-Term Functional Outcomes after Treatment for Localized Prostate Cancer 
The New England journal of medicine  2013;368(5):436-445.
The purpose of this analysis was to compare long-term urinary, bowel, and sexual function after radical prostatectomy or external-beam radiation therapy.
The Prostate Cancer Outcomes Study (PCOS) enrolled 3533 men in whom prostate cancer had been diagnosed in 1994 or 1995. The current cohort comprised 1655 men in whom localized prostate cancer had been diagnosed between the ages of 55 and 74 years and who had undergone either surgery (1164 men) or radiotherapy (491 men). Functional status was assessed at baseline and at 2, 5, and 15 years after diagnosis. We used multivariable propensity scoring to compare functional outcomes according to treatment.
Patients undergoing prostatectomy were more likely to have urinary incontinence than were those undergoing radiotherapy at 2 years (odds ratio, 6.22; 95% confidence interval [CI], 1.92 to 20.29) and 5 years (odds ratio, 5.10; 95% CI, 2.29 to 11.36). However, no significant between-group difference in the odds of urinary incontinence was noted at 15 years. Similarly, although patients undergoing prostatectomy were more likely to have erectile dysfunction at 2 years (odds ratio, 3.46; 95% CI, 1.93 to 6.17) and 5 years (odds ratio, 1.96; 95% CI, 1.05 to 3.63), no significant between-group difference was noted at 15 years. Patients undergoing prostatectomy were less likely to have bowel urgency at 2 years (odds ratio, 0.39; 95% CI, 0.22 to 0.68) and 5 years (odds ratio, 0.47; 95% CI, 0.26 to 0.84), again with no significant between-group difference in the odds of bowel urgency at 15 years.
At 15 years, no significant relative differences in disease-specific functional outcomes were observed among men undergoing prostatectomy or radiotherapy. Nonetheless, men treated for localized prostate cancer commonly had declines in all functional domains during 15 years of follow-up. (Funded by the National Cancer Institute.)
PMCID: PMC3742365  PMID: 23363497
16.  Treatment Decisions for Localized Prostate Cancer 
To identify what factors men consider important when choosing treatment for prostate cancer, and to assess why men reject watchful waiting as a treatment option.
One hundred two consecutive men with newly diagnosed localized prostate cancer identified from hospital and community-based urology practice groups.
Patients were asked open-ended questions about likes and dislikes of all treatments considered, how they chose their treatment, and reasons for rejecting watchful waiting. The interviews were conducted in person, after the men had made a treatment decision but before they received the treatment.
The most common reasons for liking a treatment were removal of tumor for radical prostatectomy (RP) (n = 15), evidence for external beam radiation (EBRT) (n = 6), and short duration of therapy for brachytherapy (seeds) (n = 25). The most frequently cited dislikes were high risk of incontinence for RP (n = 46), long duration of therapy for EBRT (n = 29), and lack of evidence for seeds (n = 16). Only 12 men chose watchful waiting. Fear of future consequences, cited by 64% (n = 90) of men, was the most common reason to reject watchful waiting.
In discussing treatment options for localized prostate cancer, clinicians, including primary care providers, should recognize that patients' decisions are often based on specific beliefs regarding each therapy's intrinsic characteristics, supporting evidence, or pattern of complications. Even if patients do not recall a physician recommendation against watchful waiting, this option may not be chosen because of fear of future consequences.
PMCID: PMC1495597  PMID: 11089712
localized prostate cancer; treatment; decision making
17.  Limitations of PSADT following Biochemical Recurrence after Radical Prostatectomy: Results from The SEARCH Database 
The Journal of urology  2008;179(5):1785-1790.
PSA doubling time (PSADT) following biochemical recurrence after radical prostatectomy is a powerful predictor of prostate cancer-specific and overall death. To calculate PSADT requires multiple PSA determinations unaltered by secondary therapy separated by sufficient time. Physicians and patients may be unwilling to wait before starting secondary therapy, especially for high-risk recurrences. Hence, those with calculable PSADT may represent a select lower-risk group relative to all men with biochemical recurrence.
We compared clinical and pathological features between patients with and without calculable PSADT and assessed time trends in the proportion with calculable PSADT among 535 patients with biochemical recurrence after radical prostatectomy at 5 VA medical centers comprising the SEARCH Database between 1988 and 2003.
PSADT was not calculable in 187 (35%) patients, most commonly due to receipt of secondary therapy (155/187 (83%)). Over time, the proportion of patients with calculable PSADT declined significantly (p<0.001). The presence of adverse pathological features, faster time to recurrence, higher body mass index and differing surgical centers were associated with not having a calculable PSADT. Among all men who recurred in the most recent year of analysis the adjusted probability of having a calculable PSADT was only 43%: 61% in patients with favorable pathology, yet only 30% with seminal vesicle invasion.
Those with calculable PSADT represented a select, lower-risk cohort and the proportion of patients with calculable PSADT declined over time. This highlights the need for alternative markers for men with recurrent prostate cancer as one of our best current markers, PSADT, is only available in a limited number of patients.
PMCID: PMC3179690  PMID: 18343434
Prostate neoplasms; radical prostatectomy; prostate specific antigen; tumor markers
18.  Is Radical Prostatectomy a Useful Therapeutic Option for High-Risk Prostate Cancer in Older Men? 
The Oncologist  2012;17(Suppl 1):4-8.
This article discusses radical prostatectomy as a treatment option for high-risk prostate cancer in men older than 70 years.
Prostate cancer affects a high proportion of men over 70 years of age, who are likely to have high-risk disease and a substantial risk of prostate-cancer-specific death. With life expectancy increasing worldwide, the burden of prostate cancer is also expected to rise. Thus, effective management of this high-risk senior patient group is increasingly important. Radical prostatectomy can increase survival and decrease the risk of metastatic progression. Postsurgery complications are affected more by comorbidity than by age. In patients without comorbidities, surgery is associated with a low risk of mortality. Advanced age may increase the likelihood of incontinence following radical prostatectomy, but patients with higher risk disease are no more likely to experience this complication compared with lower risk groups. Treatment decisions should be made after considering the health status and life expectancy of the individual patient. If eligible, the patient should be offered radical prostatectomy as a potentially curative treatment, without a rigid restriction to a certain chronological age.
PMCID: PMC3593781  PMID: 23015679
Curative therapy; Cancer-specific mortality; Localized disease; High risk
19.  Predicting Prostate Cancer Biochemical Recurrence Using a Panel of Serum Proteomic Biomarkers 
The Journal of urology  2009;181(3):1407-1414.
The pathological state of the prostate may be reflected by serum proteome in a man. We hypothesized that biomarkers are present in preoperative serum, which may be used to predict the probability of biochemical recurrence following radical prostatectomy.
Materials and Methods
Mass spectrometry analysis was used to compare 52 men who experienced biochemical recurrence with 52 who remained biochemical recurrence-free for approximately 5 years after radical retropubic prostatectomy. A total of 30 matched pairs of recurrent and nonrecurrent serum samples were randomly selected as a training set for biomarker discovery and model development. Selected mass spectrometry peaks were combined with pre-radical retropubic prostatectomy prostate specific antigen in a multivariate algorithm to predict recurrence. The algorithm was evaluated using the remaining 22 recurrent and 22 nonrecurrent subjects as test samples. Protein identities of the selected mass spectrometry peaks were investigated.
Two serum biomarkers for recurrence, P1 and P2, were combined with preoperative prostate specific antigen to predict biochemical recurrence. The ROC AUC for prostate specific antigen and the predicted outcome was 0.606 and 0.691 in the testing data, respectively. Using a single cutoff the samples were divided into 2 groups that were predictive of biochemical recurrence (p = 0.026). In contrast, preoperative prostate specific antigen did not differ between recurrent and nonrecurrent cases (Wilcoxon matched pairs test p = 0.07). The protein identity of P1 was determined to be a truncated form of C4a (C4a des-Arg). Preliminary data indicated that P2 was an N-terminal fragment of protein C inhibitor.
In the current study population, which was matched on Gleason score and TNM staging, pre-radical retropubic prostatectomy prostate specific antigen retained no independent power to predict recurrence. However, by adding 2 proteomic biomarkers to preoperative prostate specific antigen the combined model demonstrated statistically significant value for predicting prostate cancer recurrence in men who underwent radical retropubic prostatectomy.
PMCID: PMC4130150  PMID: 19157448
prostate; prostatic neoplasms; neoplasm recurrence; complement C4a; protein C inhibitor
20.  Effects of Screening on Radical Prostatectomy Efficacy: The Prostate Cancer Intervention Versus Observation Trial 
The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) trial showed that radical prostatectomy (RP) reduced prostate cancer deaths with an absolute mortality difference (AMD) between the RP and watchful waiting arms of 6.1% (95% confidence interval [CI] = 0.2% to 12.0%) after 15 years. In the United States, the Prostate Cancer Intervention Versus Observation Trial (PIVOT) produced an AMD of 3% (95% CI = −1.1% to 6.5%) after 12 years. It is not known whether a higher frequency of screen detection in PIVOT explains the lower AMD.
We assumed the SPCG-4 trial represents RP efficacy and prostate cancer survival in an unscreened population. Given the fraction of screen-detected prostate cancers in PIVOT, we adjusted prostate cancer survival using published estimates of overdiagnosis and lead time to project the effect of screen detection on disease-specific deaths.
On the basis of published estimates, we assumed that 32% of screen-detected cancers were overdiagnosed and a mean lead time among non-overdiagnosed cancers of 7.7 years. When we adjusted prostate cancer survival for the 76% of case patients in PIVOT who were screen detected, we projected that the AMD after 12 years would be 2.0% (95% CI = −1.6% to 5.6%) based on variation in published estimates of overdiagnosis and mean lead time in the United States.
If RP efficacy and prostate cancer survival in the absence of screening are similar to that in the SPCG-4 trial, then overdiagnosis and lead time largely explain the lower AMD in PIVOT. If these artifacts of screening are the correct explanation, then there is a subset of case subjects that should not be treated with RP, and identifying this subset should lead to a clearer understanding of the benefit of RP in the remaining cases.
PMCID: PMC3691943  PMID: 23411592
21.  Risk Stratification for Biochemical Recurrence among Men with Positive Surgical Margins or Extracapsular Disease after Radical Prostatectomy: Results from the SEARCH Database 
The Journal of urology  2008;179(5):1791-1796.
Among men with either extracapsular disease or positive surgical margins after radical prostatectomy, immediate adjuvant therapy decreases the risk of biochemical recurrence at the cost of increased toxicity. We sought to further stratify these men into a low-risk group in whom watchful waiting after surgery may be preferred and a high-risk cohort in whom adjuvant therapy may be preferred.
Materials and Methods
We performed a retrospective analysis of 902 men treated by radical prostatectomy in the SEARCH database between 1988 and 2007 with positive surgical margins and/or extracapsular disease without seminal vesicle invasion or lymph node metastasis. The significant independent predictors of biochemical recurrence were determined using a multivariate Cox proportional hazards model. Based upon the recurrence risk generated from the multivariate Cox proportional hazards regression model, we generated tables to estimate the risk of recurrence at 1, 3 and 5 years after surgery.
After a median of 3 years of follow-up, 346 (39%) patients developed a biochemical recurrence. On multivariate analysis, the significant predictors of biochemical recurrence included age >60 years, PSA >10 ng/ml, Gleason score 4+3 and 8–10, 2 or more sites of positive surgical margins and prostate specimen weight ≤30 grams. The overall predictive accuracy of the model as determined by the Concordance Index C was 0.67, which compared to 0.60 for the post-operative “Kattan nomogram” for this patient population.
We have developed a simple instrument, which once validated, may aid in the postoperative decision making process for men with intermediate risk of recurrence after prostatectomy.
PMCID: PMC3179686  PMID: 18343426
Prostate cancer; radical prostatectomy; biochemical recurrence
22.  Prostate Cancer–Specific Survival Following Salvage Radiotherapy vs Observation in Men With Biochemical Recurrence After Radical Prostatectomy 
Biochemical disease recurrence after radical prostatectomy often prompts salvage radiotherapy, but no studies to date have had sufficient numbers of patients or follow-up to determine whether radiotherapy improves survival, and if so, the subgroup of men most likely to benefit.
To quantify the relative improvement in prostate cancer–specific survival of salvage radiotherapy vs no therapy after biochemical recurrence following prostatectomy, and to identify subgroups for whom salvage treatment is most beneficial.
Design, Setting, and Patients
Retrospective analysis of a cohort of 635 US men undergoing prostatectomy from 1982–2004, followed up through December 28, 2007, who experienced biochemical and/or local recurrence and received no salvage treatment (n=397), salvage radiotherapy alone (n=160), or salvage radiotherapy combined with hormonal therapy (n=78).
Main Outcome Measure
Prostate cancer–specific survival defined from time of recurrence until death from disease.
With a median follow-up of 6 years after recurrence and 9 years after prostatectomy, 116 men (18%) died from prostate cancer, including 89 (22%) who received no salvage treatment, 18 (11%) who received salvage radiotherapy alone, and 9 (12%) who received salvage radiotherapy and hormonal therapy. Salvage radiotherapy alone was associated with a significant 3-fold increase in prostate cancer–specific survival relative to those who received no salvage treatment (hazard ratio [HR], 0.32 [95% confidence interval {CI}, 0.19–0.54]; P<.001). Addition of hormonal therapy to salvage radiotherapy was not associated with any additional increase in prostate cancer–specific survival (HR, 0.34 [95% CI, 0.17–0.69]; P=.003). The increase in prostate cancer–specific survival associated with salvage radiotherapy was limited to men with a prostate-specific antigen doubling time of less than 6 months and remained after adjustment for pathological stage and other established prognostic factors. Salvage radiotherapy initiated more than 2 years after recurrence provided no significant increase in prostate cancer–specific survival. Men whose prostate-specific antigen level never became undetectable after salvage radiotherapy did not experience a significant increase in prostate cancer–specific survival. Salvage radiotherapy also was associated with a significant increase in overall survival.
Salvage radiotherapy administered within 2 years of biochemical recurrence was associated with a significant increase in prostate cancer–specific survival among men with a prostate-specific antigen doubling time of less than 6 months, independent of other prognostic features such as pathological stage or Gleason score. These preliminary findings should be validated in other settings, and ultimately, in a randomized controlled trial.
PMCID: PMC3076799  PMID: 18560003
23.  The clinical burden of prostate cancer in Canada: forecasts from the Montreal Prostate Cancer Model 
OBJECTIVES: The incidence of prostate cancer is increasing, as is the number of diagnostic and therapeutic interventions to manage this disease. We developed a Markov state-transition model--the Montreal Prostate Cancer Model--for improved forecasting of the health care requirements and outcomes associated with prostate cancer. We then validated the model by comparing its forecasted outcomes with published observations for various cohorts of men. METHODS: We combined aggregate data on the age-specific incidence of prostate cancer, the distribution of diagnosed tumours according to patient age, clinical stage and tumour grade, initial treatment, treatment complications, and progression rates to metastatic disease and death. Five treatments were considered: prostatectomy, radiation therapy, hormonal therapies, combination therapies and watchful waiting. The resulting model was used to calculate age-, stage-, grade- and treatment-specific clinical outcomes such as expected age at prostate cancer diagnosis and death, and metastasis-free, disease-specific and overall survival. RESULTS: We compared the model's forecasts with available cohort data from the Surveillance, Epidemiology and End Results (SEER) Program, based on over 59,000 cases of localized prostate cancer. Among the SEER cases, the 10-year disease-specific survival rates following prostatectomy for tumour grades 1, 2 and 3 were 98%, 91% and 76% respectively, as compared with the model's estimates of 96%, 92% and 84%. We also compared the model's forecasts with the grade-specific survival among patients from the Connecticut Tumor Registry (CTR). The 10-year disease-specific survival among the CTR cases for grades 1, 2 and 3 were 91%, 76% and 54%, as compared with the model's estimates of 91%, 73% and 37%. INTERPRETATION: The Montreal Prostate Cancer Model can be used to support health policy decision-making for the management of prostate cancer. The model can also be used to forecast clinical outcomes for individual men who have prostate cancer or are at risk of the disease.
PMCID: PMC1232349  PMID: 10763395
24.  Metastasis After Radical Prostatectomy or External Beam Radiotherapy for Patients With Clinically Localized Prostate Cancer: A Comparison of Clinical Cohorts Adjusted for Case Mix 
Journal of Clinical Oncology  2010;28(9):1508-1513.
We assessed the effect of radical prostatectomy (RP) and external beam radiotherapy (EBRT) on distant metastases (DM) rates in patients with localized prostate cancer treated with RP or EBRT at a single specialized cancer center.
Patients and Methods
Patients with clinical stages T1c-T3b prostate cancer were treated with intensity-modulated EBRT (≥ 81 Gy) or RP. Both cohorts included patients treated with salvage radiotherapy or androgen-deprivation therapy for biochemical failure. Salvage therapy for patients with RP was delivered a median of 13 months after biochemical failure compared with 69 months for EBRT patients. DM was compared controlling for patient age, clinical stage, serum prostate-specific antigen level, biopsy Gleason score, and year of treatment.
The 8-year probability of freedom from metastatic progression was 97% for RP patients and 93% for EBRT patients. After adjustment for case mix, surgery was associated with a reduced risk of metastasis (hazard ratio, 0.35; 95% CI, 0.19 to 0.65; P < .001). Results were similar for prostate cancer–specific mortality (hazard ratio, 0.32; 95% CI, 0.13 to 0.80; P = .015). Rates of metastatic progression were similar for favorable-risk disease (1.9% difference in 8-year metastasis-free survival), somewhat reduced for intermediate-risk disease (3.3%), and more substantially reduced in unfavorable-risk disease (7.8% in 8-year metastatic progression).
Metastatic progression is infrequent in men with low-risk prostate cancer treated with either RP or EBRT. RP patients with higher-risk disease treated had a lower risk of metastatic progression and prostate cancer–specific death than EBRT patients. These results may be confounded by differences in the use and timing of salvage therapy.
PMCID: PMC3731893  PMID: 20159826
25.  Is it necessary to cure prostate cancer when it is possible? (Understanding the role of prostate inflammation resolution to prostate cancer evolution) 
Clinical Interventions in Aging  2007;2(1):153-161.
Definitive therapy with radical prostatectomy, cryotherapy, or radiation therapy generally follows the initial diagnosis of prostate cancer, particularly when men have at least 10 additional years of life expectancy. There is growing concern regarding the optimal conservative treatment for patients who decline or do not otherwise qualify for such definitive curative treatment. For those patients who choose a watchful waiting approach, it would be beneficial to know what specific dietary and nutritional methods could potentially slow the progression of their disease. In this prospective study, it was our goal to analyze the efficacy and safety of treating prostate cancer conservatively using the principles of a Mediterranean diet in association with a specific prostate nutritional supplement.
Twenty-three men aged 43–74 (median age: 64) with biopsy proven, organ-confined prostate cancer who had already declined immediate hormonal therapy and attempts at a curative cancer treatment agreed to participate in a Chronic Disease Management (CDM) protocol highlighted by diet with a specific prostate nutritional supplement. The diet recommended was a modified Mediterranean diet while a patented nutritional prostatitis formula (Peenuts®) was the supplement common to all patients. Prostate specific antigen (PSA), a recognized marker of prostate disease and prostate cancer activity, was the primary indicator to validate exacerbation or suppression of disease. All men were followed with serial PSA testing, a digital rectal exam, an International Prostate Symptom Score index (IPSS-Index) and an expressed prostatic secretion (EPS) examination. The primary Gleason sum/score represented in this study was 6 (n = 11), while Gleason sum patterns 5, 5/6, 6/7, and 7 were also evaluated. Referencing the Partin Tables, organ confinement was predicted to be 66%.
Eighty-seven percent of men (n = 20) noted a 58% reduction (range of improvement: 13%–90%) in PSA over an average of 38.5 months (range: 13–84 months). The remaining 13% of men included three men who experienced a mild elevation in PSA of 0.3 ng/ml, 0.7 ng/ml, and 0.9 ng/ml over 14 months, 42 months, and 34 months, respectively. Fifteen men had completed an initial and secondary IPSS-Index while 14 men had undergone an initial and secondary EPS. The mean percentage reduction in IPSS-Index was 61% (range: 20%–100% with a median of 55%), while men evaluated with EPS examinations noted a mean percentage reduction in white blood cells of 77.5% (range: 33%–99% with a median of 82%). These results were evaluated using the t-test, Wilcoxon Analysis and the Null Hypothesis and found to be statistically significant.
Clearly there is a need to develop effective alternative conservative therapies for the increasing numbers of prostate cancer patients who will not tolerate definitive curative measures or simply choose a conservative approach. Although this prospective study had no control arm, was of limited duration and included only 23 participants, it did appear to show significant benefit to the majority of prostate cancer patients treated with selective nutritional and dietary therapy alone. Such treatments may provide a safe and effective long-term treatment alternative for some patients. Further study is encouraged.
PMCID: PMC2684075  PMID: 18044088
Prostate cancer; prostatitis; prostate cancer nutrition; PSA; EPS; Gleason score; voiding symptoms; Mediterranean diet

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