Written by Samuel Denmeade, MD, Professor of Oncology, Urology and Pharmacology The Johns Hopkins University School of Medicine, Baltimore, MD

Presentation Overview:
•Androgen and Androgen Signaling 101
•Rationale For Bipolar Androgen Therapy (BAT)
•Results from the RESTORE study testing BAT in Castration Resistant Prostate Cancer
•The multi-center TRANSFORMER Trial
•Future Directions
•Results of BATMAN trial testing BAT as part of Intermittent Hormone Therapy strategy

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Written by Majed Alghamdi, MD, Amandeep Taggar, MD, Derek Tilley, MSc, Marc Kerba, MD, Xanthoula Kostaras, MSc, Geoffrey Gotto, MD, Michael Sia, MD

Prostate cancer (PCa) is the most common cancer among men in North America. According to Canadian Cancer Statistics, approximately 21 600 men will be diagnosed with PCa and 4000 men will die in 2016 due to PCa, accounting for 10% of cancer mortality in men. Treatment is guided by risk stratification, which uses Gleason score (GS), prostate-specific antigen (PSA), and clinical exam (T-stage) to classify patients into high-, intermediate- and low-risk groups. High risk disease (HR-PCa) represents 20–30% of all patients and is defined as ≥T3a, GS ≥8, or PSA >20. Four randomized, controlled trials (RCTs) established the combination of radiation therapy (RT) and androgen-deprivation therapy (ADT) as a standard treatment for men with HR-PCa. These trials showed that RT + ADT is associated with higher overall survival rates compared to RT or ADT alone. However, several retrospective studies suggested that radical prostatectomy (RP) may provide comparable outcomes to RT + ADT, but no RCT has compared them directly. Therefore, the optimal treatment approach to HR-PCa remains controversial. Urologists are usually the first specialists to see these patients and may or may not elect to refer patients for a discussion of RT + ADT. In Alberta, Canada, an interdisciplinary team including urologists, as well as radiation and medical oncologists, developed an evidence-based clinical practice guideline (CPG) for the management of PCa in January 2005. The guideline, which has been regularly updated, recommends that patients with HR-PCa be referred to a radiation oncologist (RO) prior to surgery and that the preferred treatment is RT + ADT. These recommendations are consistent with other national and international guidelines. This is a report on the impact of the CPG on clinical practice since its publication. We hypothesized that RO referral rates would increase from 2005 to 2012. The primary and secondary endpoints are RO referral rate and treatment

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Written by Amandeep Taggar, MD; Majed Alghamdi, MD; Derek Tilly, MD; Xanthoula Kostaras, MD; Marc Kerba, MD; Siraj Husain, MD; Geoff Gotto, MD; Michael Sia, MD

In 2015, 24 000 new cases of prostate cancer diagnosis are anticipated in Canada (Canadian Cancer Stats 2015). Of these patients, approximately 50% will undergo radical prostatectomy (RP). Despite improvements in surgical techniques, some patients will have high-risk features (HRF) (i.e., positive margins [M+], extracapsular extension [ECE], and seminal vesicle invasion [SVI]) post-resection without biochemical evidence of disease. Phase 3 randomized, controlled trials (RCT) have shown that adjuvant radiation therapy (aRT) for patients with HRF improves biochemical relapse-free survival and recurrence-free survival. The update of the Southwest Oncology Group (SWOG) 8794 trial with median followup of 12.9 years has also shown an improvement in metastasis-free survival and overall survival. Similarly, the 10-year followup data from the European Organization for Research and Treatment of Cancer (EORTC) 22911 trial confirms biochemical progression-free survival benefit and reports a clinical progression-free survival benefit with patients who underwent aRT. Following publication of these trials and a meta-analysis, the Genitourinary Radiation Oncologists of Canada (GUROC) issued a consensus statement advising a consultation with a radiation oncologist (RO) early in the postoperative period to discuss benefits and side effects of aRT in those with HRF. The American Urological Association (AUA) and American Society for Therapeutic Radiation Oncology (ASTRO) have also issued similar recommendations in their guidelines. Furthermore, the American Society of Clinical Oncology has also endorsed these recommendations.10 The Alberta Health Services Cancer Control clinical practice guidelines, initially published in 2005 and updated yearly thereafter, reflect the phase 3 RCT evidence and recommendation of GUROC. The goal of this study is to assess referral pattern to RO post-RP in order to determine the impact of published recommendations

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Written by J. Dunn PhD, Professor, Chief Executive Officer | C. Casey Consumer, Founding Support Group Leader | D. Sandoe Consumer, Founding Support Group Leader, National Chairman | M.K. Hyde PhD, Senior Research Fellow | M-C. Cheron-Sauer B Soc Work, MA Policy and Applied Social Research, MA Management, Director Support Programs | A. Lowe PhD, Associate Professor, Chief Executive Officer | J.L. Oliffe RN, PhD, Professor | S.K. Chambers RN, PhD, Professor, Director

Across Australia, prostate cancer support groups (PCSG) have emerged to fill a gap in psychosocial care for men and their families. However, an understanding of the triggers and influencers of the PCSG movement is absent. We interviewed 21 SG leaders (19 PC survivors, two partners), of whom six also attended a focus group, about motivations, experiences, past and future challenges in founding and leading PCSGs. Thematic analysis identified four global themes: illness experience; enacting a supportive response; forming a national collective and challenges. Leaders described men’s feelings of isolation and neglect by the health system as the impetus for PCSGs to form and give/receive mutual help. Negotiating health care systems was an early challenge. National affiliation enabled leaders to build a united voice in the health system and establish a group identity and collective voice. Affiliation was supported by a symbiotic relationship with tensions between independence, affiliation and governance. Future challenges were group sustainability and inclusiveness. Study findings describe how a grassroots PCSG movement arose consistent with an embodied health movement perspective. Health care organisations who seek to leverage these community resources need to be cognisant of SG values and

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Written by Alison M. Rasper, MD, Ryan P. Terlecki, MD, FACS, Wake Forest Baptist Health, Winston-Salem, NC

Prostate cancer is the most common malignancy among the male survivorship population in the United States, representing 44% of approximately 7 million survivors. In the era of modern medicine and value-based care, successfully treating only the cancer is not sufficient. The cancer survivor represents an individual in need of restoration and protection against future events. A well-designed and well-supported survivorship program not only meets a mandate for accreditation, it logically translates into better patient care. This review summarizes the history of the survivorship movement, outlines some key elements of a survivorship program, and highlights the opportunity to apply these principles to improve cancer-related care, develop relationships with colleagues that may allow increased identification of men at risk, and expand both the experience and outcomes of individual specialists within men’s health.

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Written by Stacy Loeb, New York University

The prostate cancer screening controversy has reached a critical turning point. There has been a 50% reduction in prostate cancer mortality in the United States, and screening is estimated to account for 45% to 70%. On the other hand, screening may result in significant harms, including unnecessary biopsies with potential associated adverse effects, overdiagnosis, and resultant overtreatment.

Where should we go from here? In 2012, the US Preventive Services Task Force issued a gradeDrecommendation against prostatespecific antigen (PSA) screening for men of all ages. Early data suggest that this has been associated with a reduction in the diagnosis of lowrisk disease but that the proportion of high-risk cases has increased. Mathematical models project that abandoning screening altogether, as suggested, would eliminate overdiagnosis but also would result in a doubling of patients presenting with metastatic disease and a 13% to 20% increase in prostate cancer deaths by 2025. Thus, completely eliminating screening is not a good option, because it will also reverse the substantial progress that has been made in reducing suffering and death from advanced disease.

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Written by AB Weiner, RS Matulewicz, SE Eggener and EM Schaeffer

Over the past decade, there has been substantial shifts in PSA screening practices in response to randomized trial data and US Preventive Services Task Force (USPSTF) recommendations in 2008 and 2012. This has resulted in reduced screening with associated declines in overall prostate cancer incidence. Using data from a large cancer registry from 2004 through 2013, we sought to analyze the temporal relationship between relaxed screening and increases in yearly incidence of advanced or metastatic prostate cancer.

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Written by Stewart Campbell

In a trial, a photosynthesis-based therapy eliminates cancer in over 80% of patients – and could be used to attack other cancers, too

Scientists at the Weizmann Institute may have found the cure for prostate cancer, at least if it is caught in its early stages – via a drug that doctors inject into cancerous cells and treat with infrared laser illumination.

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Written by Stewart Campbell

In Canada, prostate cancer is the most common male malignancy and the third most common cause of cancer death in men. From March 1-3, 2016, Calgarians were introduced to vastly divergent views concerning the use of the prostate-specific antigen (PSA) test and PSA screening prior to a cancer diagnosis to assess a man’s risk of prostate cancer.

This latest discourse about PSA screening followed publication by Dr. Dickenson from the University of Calgary and co-authors of the article “Trends in prostate cancer incidence and mortality in Canada during the era of prostate-specific antigen screening” in the Canadian Medical Association Journal OPEN (Dickenson, 2016). The article presented data depicting prostate cancer incidence and mortality in Canada from 1969 – 2007 in relation to the introduction of the PSA test.

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UBC Public Affairs

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The Globe and Mail

More men with suspicious prostate test results are being monitored for changes in disease progression instead of undergoing immediate treatment, according to a new study in the Canadian Medical Association Journal.

Nearly one-third of patients who underwent monitoring were eventually treated for prostate cancer, the study found.

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UBC Public Affairs

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Jelena Lukovic, George Rodrigues

A majority of patients with castrate-resistant prostate cancer ultimately develop distant metastases, with bone being the most common site of spread. Classically, systemic therapy has been considered the standard of care for patients with metastatic cancer. Emerging evidence, however, suggests that an intermediate oligometastatic state, between limited disease and widespread metastases, exists; theoretically, with locally ablative treatment, patients may be curable. In this case report, we describe a complete PSA response following aggressive management of an oligometastatic lesion in the setting of castrate-resistant prostate cancer.

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Murray Krahn MD MSc

Prostate cancer is the most commonly diagnosed cancer affecting Canadian men. One in eight men will be diagnosed with this disease in their lifetime.1 Men who receive a diagnosis of prostate cancer face considerable anxiety, especially when it comes to their treatment options. This is exacerbated by the fact that while many prostate cancer tumours are slow-growing and may not require immediate treatment, others can be quite aggressive requiring prompt surgery and/or radiation and systemic therapy.

For this and other reasons, caring for men with prostate cancer is challenging. While surgery, chemotherapy, radiation and hormonal therapy can all be effective in targeting the tumour, the potential side effects of treatment, such as urinary incontinence and sexual dysfunction can significantly affect men’s quality of life, even as they survive their disease.

Research has improved the understanding of factors that help inform choices about treatment. Clinicians are better able to predict how likely it is that a specific cancer will respond to treatment, and to determine men’s risk for recurrence of the disease after treatment. But despite these and other advances, prostate cancer is still the third leading cause of cancer deaths in Canada.1

Until now, there had been little comparable pan-Canadian information available on how well cancer systems across the country are doing with regards to diagnosing, treating and providing follow-up and supportive care to prostate cancer patients. The 2015 Prostate Cancer Control in Canada: A System Performance Spotlight Report sheds light on specific topics relevant to the control and management of prostate cancer across the country. It also includes the Special Feature, Reflections of Canadian Men with Prostate Cancer, and considers the person-centred perspective throughout the dimensions of the cancer control continuum—from diagnosis and treatment through survivorship and palliative care.

This report is organized along the dimensions of the cancer control continuum. Indicator results are generally compared by province or territory, age group and sex. Where appropriate, comparisons with international jurisdictions are discussed, highlighting potential best practices and benchmarks. Commentary on emerging evidence or studies either nationally or internationally is also provided.

The report was produced in close collaboration with partners at the national, provincial and territorial levels. Provincial cancer agencies and programs provided the data needed to develop and calculate many of the indicators included in the report. Our national partners at Statistics Canada, the Canadian Institute for Health Information, the National Research Corporation Canada, and the Canadian Cancer Research Alliance also contributed data and/or analysis.

Subject matter expertise was provided by the Prostate Cancer Expert Panel comprising clinicians, epidemiologists and researchers with specific expertise in various aspects of prostate cancer—from population health to pathology, and from radiation oncology to urology and psychology. A number of prostate cancer survivors and family members from across the country brought their own unique experiences and perspectives to the panel’s deliberations.

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Murray Krahn MD MSc

In a linked guideline, the Canadian Task Force on Preventive Health Care summarizes its updated recommendations not to use the prostate-specific antigen (PSA) test for prostate cancer screening.1 The task force's guideline is an excellent example of health care decisions being made from the perspective of evidencebased medicine. The task force focused on clinically meaningful outcomes and rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. However, it paid insufficient attention to patient values, patient preferences and costs.

A story: In the mid-1990s, I participated in a PSA guideline group for Cancer Care Ontario. The "usual" literature search was conducted, which focused on the evidence of mortality benefit and the potential harms of screening. I had been building decision models of PSA screening2 and measuring cost and quality-of-life outcomes for years. I was slightly chagrined that none of my papers turned up in the search. It made me ask, "Why are the rest of the committee and I seeing this problem so differently?" My model suggested that there might be a mortality benefit but overall a loss of quality-adjusted life expectancy. This meant that the way in which patients valued health outcomes was a key part of the screening decision. In other words, this was a "preference-sensitive" decision. Moreover, it seemed too obvious to mention that cost was a relevant concern in a publicly funded health system. The rest of the committee, though, did not see evidence on quality of life, patient preferences or cost as relevant. They also did not see modelling as a serious scientific endeavour that might illumine the key trade-offs (mortality v. quality of life). They saw the problem as one of whether PSA screening reduced mortality.

Flash forward roughly 20 years. Plus ça change… We have more data but the same dilemma. Trials of PSA screening have been reported and show a possible but small mortality benefit. The adverse effects of prostate cancer treatment are known. Modelling studies predict a small mortality gain and a questionable overall health benefit.3,4 There is more evidence about cost5 and patient preferences.6,7 Yet guideline panels such as the US Preventive Services Task Force and the Canadian Task Force on Preventive Health Care are still basing their recommendations only on the trial evidence.

I have come to believe that there are at least three paradigms at work in the interpretation of scientific evidence: evidence-based medicine; health economics and decision science; and social science and bioethics. Researchers who work mainly within one of these paradigms ask slightly different questions. What inferences can be drawn from the evidence? What is the best decision given the evidence we have? What decision fits with patient and social values? Each paradigm privileges different things: clinical outcomes; outcomes, costs and preferences; patient experiences, power relationships and ethical principles. Each is a lens that subtly conditions what we consider to be evidence, how we integrate evidence and how we recommend a course of action.

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Canadian Task Force on Preventive Health Care

Prostate cancer is the most commonly diagnosed non–skin cancer in men and the third leading cause of cancer-related death among men in Canada.1 The current estimated lifetime risk of diagnosis is 14.3%, whereas the lifetime risk of death from prostate cancer is 3.6%.2 The prevalence of undiagnosed prostate cancer at autopsy is high and increases with age (> 40% among men aged 40–49 yr to > 70% among men aged 70–79 yr).3 Most cases of diagnosed prostate cancer have a good prognosis; the 10-year estimated relative survival ratio is now 95%, the highest among all cancers in men.

In Canada, the age-standardized rate of death from prostate cancer rose from 1969 to 1991, followed by a decline of 37.5% from 1992 to 2009, at an average rate of 2.6% per year. In 1990, the estimated age-standardized mortality was 30 cases per 100 000, and in 2010 it was just below 20 per 100 000. However, over the same period, the number of cases and the age-standardized incidence of prostate cancer both increased. Subsequent to the introduction and adoption of prostate-specific antigen (PSA) testing, the incidence of prostate cancer increased rapidly from 1990 to a peak in 1993 and a second, less-pronounced peak in 2001. Much of the excess incidence represents overdiagnosis, that is, the detection of cancers that would not progress to cause symptoms or death.

There is no conclusive evidence to determine what proportion of the decline in prostate cancer mortality is due to screening versus improved treatment, or other factors; it is likely that both screening and treatment have contributed. If PSA screening were the primary reason for the decrease in mortality, the steep increase in incidence due to early case detection associated with screening should have been followed by a sharp reduction in mortality. Instead, the reduction in prostate cancer mortality over time has been relatively steady and began too soon after the test's introduction to be attributed mainly to PSA screening.

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Question

While on call over the weekend, I looked after one of my partner's patients who is approaching death from advanced, refractory ovarian cancer. She ended up in the ICU with what was believed to be a bowel perforation and sepsis, and I and the intensivists on the case felt that she could die within a few days. She was completely lucid despite her condition, and refused to discuss any treatment limitations, despite the fact that all of the physicians involved in her care agreed that her prognosis was terminal. When I tried to discuss these issues with her, she asked me not to talk about anything negative with her, because she needed to find something hopeful to hang on to. Decisions need to be made—should I just remain silent about them at her request? We can't really make any decisions without discussing negative things.

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The Case

A 46-year-old man sought consultation for an abnormal prostate-specific antigen (PSA) level of 9 ng/mL and one prior negative biopsy. Five months ago, while traveling, he had presented to an urgent care facility with a 24-hour history of fever, chills, nausea, and vomiting. He required intravenous hydration, and a urinalysis suggested a urinary tract infection. Subsequent culture grew > 100,000 Escherichia coli organisms. He was treated with ciprofloxin (Cipro) and had relief of symptoms. On his return home he saw his primary care doctor. A PSA level was obtained and was 13 ng/mL. He was referred to a urologist, who performed a digital rectal exam and felt some asymmetry; to follow up, he ordered a CT scan and scheduled a biopsy. The transrectal ultrasound (TRUS) identified a 34-gram gland with no abnormalities; 12 core biopsies were obtained. The cores showed areas of inflammation but no suspicion of cancer.

One month later, the patient's asymmetry had improved; however, his PSA level was still elevated. An infectious disease consult was obtained to rule out the presence of a granulomatous process such as tuberculosis; the evaluation was negative. The PSA level was 9 ng/mL.

It was recommended that he follow up with the urologist in 6 months. He was a little concerned about his PSA level and sought evaluation at our institution. He appeared healthy; he had some mild urinary obstructive symptoms and normal sexual function. Results of a urinalysis were normal, and on rectal exam, the prostate was normal. A Progensa prostate cancer antigen 3 (PCA3) test was obtained, and the PCA3 score (ratio of PCA3 RNA to PSA RNA) was 53 (normal, less than 25); his PSA level at this point was 6.1 ng/mL. Because of concerns raised by results of both the PSA and PCA3 tests, the paraffin(Drug information on paraffin) blocks from his 12 core biopsies were obtained for the performance of a molecular marker test called ConfirmMDx. The ConfirmMDx test identified three areas of concern in the right apex and right base of the patient's gland. An endorectal coil MRI also suggested abnormalities in the apex, base, and midprostate. TRUS-directed biopsies were performed and confirmed the presence of Gleason 3+3=6 in the right apex and base. A standard set of 12 core biopsies also detected "xanthogranulomatous inflammation." The patient was relieved to know the diagnosis and was scheduled for a nerve-sparing radical prostatectomy.

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Brief

The majority of patients with systemic prostate cancer treated with androgen deprivation therapy (ADT) will develop castration-resistant prostate cancer (CRPC). CRPC is defined by prostate-specific antigen (PSA) or radiographic progression in the context of castrate levels of testosterone.[1] CRPC patients may or may not have obvious metastases. Like all stages of prostate cancer, the natural history of nonmetastatic or metastatic CRPC is heterogeneous, and clinical decisions must be made in the context of an individual's disease pace, symptoms, age, medical condition, and goals.

When a patient initially transitions to CRPC, it's advisable to confirm that serum testosterone is castrate (less than 50 ng/dL by convention). Rarely, the serum testosterone level with medical castration (LHRH agonists/antagonists) may be higher than 50 ng/dL and can be lowered with an adjustment in the dose of the therapeutic agent, proper administration of the agent, or orchiectomy. CRPC can be categorized as nonmetastatic or metastatic. In nonmetastatic CRPC, I generally categorize patients as slow progressors or rapid progressors based on their initial response to ADT and the PSA doubling time (PSAdt). A trial of denosumab (Xgeva) in nonmetastatic CRPC (PSAdt 10 months) gives us the best estimate of time to development of metastases and overall survival (OS) in these patients.[1] Patients who had nonmetastatic CRPC with short (< 10 months) PSAdt developed metastases in 29 to 33 months and had an OS of about 44 months.[2] Patients with established metastatic CRPC (no prior chemotherapy) have life expectancy in the range of 27 to 32 months and may need more frequent cancer staging and interventions.[3] Patients with nonmetastatic CRPC should be re-imaged at regular intervals (3 to 6 months) in order to be able to take advantage, as early as possible, of the option for therapies that require metastases.

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Question

I was asked to see a patient with widely metastatic renal cell carcinoma in the ICU. He is a 47-year-old man who had a large, clear-cell primary renal cell carcinoma resected 21 months ago; had a recurrence in retroperitoneal lymph nodes, bones, and lungs; and was treated with three lines of therapy but had no response and continued to progress. In the 6 weeks prior to the current hospital admission, he became progressively more debilitated, was eventually wheelchair-bound, and became increasingly short of breath. When he was admitted, he was in florid respiratory failure from compression of his inferior vena cava and right atrium and compression of his left lower lobe bronchus. He was immediately intubated and sedated; he eventually became paralyzed because of progressive worsening of his respiratory status. I saw him as a consult and visited nearly every day for 5 days. His wife, who is his primary spokesperson, has continued to demand that I provide him with sorafenib(Drug information on sorafenib) (Nexavar), since she read that it works in kidney cancer and it is one of the treatments he has not tried. She says that he was always "a fighter," competing in triathlons even after his diagnosis. Should I provide the patient with sorafenib, just to satisfy his wife, since it is unlikely to do much harm?

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Purpose

The Gleason scoring system has been the traditional basis for studies on the assessment and treatment of prostate cancer. Recent reports of long-term prostate cancer outcomes stratified by Gleason score based on the 2005 ISUP (International Society of Urological Pathology) update suggest that important aspects of the biology of prostate cancer correlate with commonly available histopathological information. In this review we present a conceptual framework for the possible existence of distinct but interrelated developmental pathways in the context of the Gleason score in considering various biological and clinical aspects of prostate cancer. This may be useful in characterizing prostate cancer as an indolent condition in some and an aggressive disease in others, in decision making for treatment, and in the interpretation of the biological course and treatment outcomes.

Materials and Methods

A comprehensive review of clinical, pathological and investigational biological literature on this topic was conducted. In addition, the biological behavior of prostate cancer as interpreted from this survey was compared to that of other solid neoplasms in developing a schema for characterizing the pathogenesis of various forms of the disease.

Results

The Gleason scoring system has been found to have fundamental value in predicting the behavior of prostate cancer and assessing outcomes of its treatment. Increasingly, the proportion of Gleason pattern 4 in a prostatectomy specimen is being recognized as a critical factor in predicting the rates of biochemical recurrence and prostate cancer specific mortality. Under the current Gleason classification, a Gleason 3 + 3 = 6 cancer carries a minimal long-term risk of progression or mortality. Risk of biochemical recurrence and prostate cancer specific mortality increases with increasing proportions of the Gleason 4 component in the prostatectomy specimen, from 3 + 3 = 6 with tertiary 4 (i.e. less than 5% of a 4 component) to 3 + 4 = 7, 4 + 3 = 7 and 4 + 4 = 8. Assuming that the Gleason 4 component increases in volume more rapidly with time than well differentiated components, it can be inferred that a smaller proportion of Gleason 4 could mean that the cancer has been identified at an earlier phase in the natural history of the disease. This could explain the improved prognosis on the basis of length and lead time biases, and conceivably on the basis of a decreased likelihood of cancer cells having metastasized. Correspondingly, increasing amounts of Gleason 4 cancer in a prostate specimen might be explained in 2 ways, as the preferential growth of a single clone of Gleason 4 cells, possibly with intraprostatic spread, or the evolution of Gleason 3 cancer cells to become Gleason 4. These hypotheses have been examined by genetic analysis of metastatic deposits and by comparisons of multiple foci of cancer within individual prostates. The clinical significance of these concepts in regard to disease status at diagnosis, treatment selection, outcomes of treatment, and implications for future research on the basis of clinical and molecular observations are the basis of the developmental schemata we propose.

Conclusions

Given the relatively benign nature of homogeneous, low volume Gleason 3 tumors, and the progressive risk of biochemical recurrence and prostate cancer specific mortality with increasing quantities of Gleason 4 components, we propose that Gleason 4 (and 5) cancers constitute cancer diatheses distinct from that of Gleason 3 cancer. This distinction may contribute to the understanding of the prognosis intrinsic to these biological behavioral patterns, and help guide the translation of findings at molecular and histological levels to a more precise selection of treatments.

Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Purpose

Although androgen deprivation therapy leads to weight gain within the first year in men with prostate cancer, longer term changes and the relationship to patient age are not well characterized.

We examined long-term weight gain by age group in men on androgen deprivation therapy for up to 36 months.

Materials and Methods

Three cohorts matched by age and education were recruited in this prospective study, including men in whom continuous androgen deprivation therapy was initiated, controls with prostate cancer and healthy controls. All patients with prostate cancer had nonmetastatic disease. We performed age stratified (less than 65 vs 65 years or greater) comparisons. Univariate and multivariable associations with weight change with time were evaluated using linear regression.

Results

We included 257 men with a mean age of 69.1 years. At baseline the cohorts were similar in age, education, body mass index, weight and comorbidity. Androgen deprivation therapy was associated with weight gain from baseline at 6, 12, 18, 24, 30 and 36 months compared to controls with prostate cancer and healthy controls (p = 0.006, 0.015, 0.028, 0.003, 0.014 and 0.0004, respectively). The proportion of men who gained weight was higher among androgen deprivation therapy users than controls with prostate cancer and healthy controls at most time points. Age stratified analyses showed that younger patients (age less than 65 years) on androgen deprivation therapy had significantly greater weight gain with time than older patients (4.7 vs 1.4 kg, p = 0.005). However, age did not appear to affect weight change with time in men not on androgen deprivation therapy (p = 0.37).

Conclusions

Androgen deprivation therapy was associated with an increase in weight during 36 months and weight gain was significantly higher in patients younger than 65 years.

Written by

Timilshina N, Breunis H, Alibhai SM.
Department of Medicine, University Health Network, Toronto, Ontario, Canada.

Purpose

The Gleason scoring system has been the traditional basis for studies on the assessment and treatment of prostate cancer. Recent reports of long-term prostate cancer outcomes stratified by Gleason score based on the 2005 ISUP (International Society of Urological Pathology) update suggest that important aspects of the biology of prostate cancer correlate with commonly available histopathological information. In this review we present a conceptual framework for the possible existence of distinct but interrelated developmental pathways in the context of the Gleason score in considering various biological and clinical aspects of prostate cancer. This may be useful in characterizing prostate cancer as an indolent condition in some and an aggressive disease in others, in decision making for treatment, and in the interpretation of the biological course and treatment outcomes.

Materials and Methods

A comprehensive review of clinical, pathological and investigational biological literature on this topic was conducted. In addition, the biological behavior of prostate cancer as interpreted from this survey was compared to that of other solid neoplasms in developing a schema for characterizing the pathogenesis of various forms of the disease.

Results

The Gleason scoring system has been found to have fundamental value in predicting the behavior of prostate cancer and assessing outcomes of its treatment. Increasingly, the proportion of Gleason pattern 4 in a prostatectomy specimen is being recognized as a critical factor in predicting the rates of biochemical recurrence and prostate cancer specific mortality. Under the current Gleason classification, a Gleason 3 + 3 = 6 cancer carries a minimal long-term risk of progression or mortality. Risk of biochemical recurrence and prostate cancer specific mortality increases with increasing proportions of the Gleason 4 component in the prostatectomy specimen, from 3 + 3 = 6 with tertiary 4 (i.e. less than 5% of a 4 component) to 3 + 4 = 7, 4 + 3 = 7 and 4 + 4 = 8. Assuming that the Gleason 4 component increases in volume more rapidly with time than well differentiated components, it can be inferred that a smaller proportion of Gleason 4 could mean that the cancer has been identified at an earlier phase in the natural history of the disease. This could explain the improved prognosis on the basis of length and lead time biases, and conceivably on the basis of a decreased likelihood of cancer cells having metastasized. Correspondingly, increasing amounts of Gleason 4 cancer in a prostate specimen might be explained in 2 ways, as the preferential growth of a single clone of Gleason 4 cells, possibly with intraprostatic spread, or the evolution of Gleason 3 cancer cells to become Gleason 4. These hypotheses have been examined by genetic analysis of metastatic deposits and by comparisons of multiple foci of cancer within individual prostates. The clinical significance of these concepts in regard to disease status at diagnosis, treatment selection, outcomes of treatment, and implications for future research on the basis of clinical and molecular observations are the basis of the developmental schemata we propose.

Conclusions

Given the relatively benign nature of homogeneous, low volume Gleason 3 tumors, and the progressive risk of biochemical recurrence and prostate cancer specific mortality with increasing quantities of Gleason 4 components, we propose that Gleason 4 (and 5) cancers constitute cancer diatheses distinct from that of Gleason 3 cancer. This distinction may contribute to the understanding of the prognosis intrinsic to these biological behavioral patterns, and help guide the translation of findings at molecular and histological levels to a more precise selection of treatments.

Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Prostate cancer is the leading cancer type diagnosed in American men and is the second leading cancer diagnosed in men worldwide.

Although studies have been conducted to investigate the association between prostate cancer and exposure to pesticides and/or farming, the results have been inconsistent. We performed a meta-analysis to summarize the association of farming and prostate cancer. The PubMed database was searched to identify all published case-control studies that evaluated farming as an occupational exposure by questionnaire or interview and prostate cancer. Ten published and two unpublished studies were included in this analysis, yielding 3,978 cases and 7,393 controls. Prostate cancer cases were almost four times more likely to be farmers compared with controls with benign prostate hyperplasia (BPH; meta odds ratio [OR], crude = 3.83, 95% confidence interval [CI] = 1.96-7.48, Q-test p value = .352; two studies); similar results were obtained when non-BPH controls were considered, but with moderate heterogeneity between studies (meta OR crude = 1.38, 95% CI = 1.16-1.64, Q-test p value = .216, I2 = 31% [95% CI = 0-73]; five studies). Reported pesticide exposure was inversely associated with prostate cancer (meta OR crude = 0.68, 95% CI = 0.49-0.96, Q-test p value = .331; four studies), whereas no association with exposure to fertilizers was observed. Our findings confirm that farming is a risk factor for prostate cancer, but this increased risk may not be due to exposure to pesticides.

Sipuleucel-T (Provenge) autologous vaccine approved for treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer.

Sipuleucel-T (Provenge) (Sip-T) is first -in class as a therapeutic autologous vaccine approved for the treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer. This product is the culmination of decades of basic immunological and prostate cancer investigations and 13 y of clinical trial investigations. Sip-T represents a paradigm shift in cancer therapeutics and represents the first approved autologous therapeutic cancer vaccine, which has demonstrated a survival benefit. The potential benefit of this product is the excellent risk to benefit ratio, which will allow for the combination of this approach with other more toxic therapies. The favorable risk to benefit will also afford the opportunity for trials investigating this product earlier in the disease state and in combination with local therapies. The ability to target more localized or lower volume disease will maximize the therapeutic benefit over a longer period of time. The novelty of the platform of this approach could be used to treat any cancer with a tumor-specific cell surface target. The main product of Sip-T is the re-infusion of a patient's antigen presenting cells from leukapheresis after ex-vivo exposure to a chimeric protein of human GM-CSF and PAP. In metastatic CRPC patients three infusions of these activated cells over a month lead to statistically significant 4.1 mo increase in median survival and a 22.5% reduction in risk of death. The main side effect from this re-infusion of activated immune cells is a "flu-like" syndrome that includes chills, fatigue, fevers, back pain, nausea, joints aches and headaches in decreasing order of frequency. Immune monitoring during the clinical trials also demonstrated a specific cellular and antibody immune response, suggesting the proposed mechanism of adoptive immunotherapy to PAP was behind this survival benefit. This product also serves as a proof of principle for targeted immunotherapy for others cancers with defined cell surface markers. In summary, the approval of Sip-T based on a survival benefit and very tolerable safety profile will 1) enhance our ability to care for men with advanced prostate cancer, 2) allow for further investigations of this approach in combination with others therapies with different mechanisms of action and non-overlapping toxicities, and 3) allow further investigations earlier in the course of the disease.