PSA Testing, Combined With Other Relevant Patient Data Can Reduce Unnecessary Prostate Biopsies

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Separate study suggests combining urine test with PSA can aid cancer diagnosis

Prostate cancer screening that combines an adjusted blood test with other factors including the size of the gland, the patient’s overall weight and family history, can help up to one-quarter of men avoid biopsies and the risks associated with them, a Beth Israel Deaconess Medical Center-led research team says.
Writing in a study published online by the journal Cancer, the team led by Martin G. Sanda, MD, Director of the Prostate Center at Beth Israel Deaconess Medical Center and Professor of Urology at Harvard Medical School, suggests that instead of using “one-size-fits-all” levels of PSA to determine who should have a biopsy, considering other factors such as prostate size can substantially improve the ability of PSA testing to identify aggressive prostate cancers for which treatment is warranted, while avoiding detection of indolent cancers that are better undiagnosed because they do not require treatment.

A second study led by Sanda, and published online in the journal Urologic Oncology, suggests the presence or absence of genes commonly found in the urine of men, when combined with a PSA test, can also be used to determine whether a biopsy is necessary.
The new suggested approaches come as the United States Preventive Services Task Force expert panel concluded that current PSA-based prostate cancer screening saves few or no lives, but causes harm through treatment or further invasive testing such as biopsies. That’s because prostate cancers can vary in aggressiveness and more men die of other causes aside from that cancer – and because the PSA test alone cannot determine how dangerous any particular cancer may be.

“The US Preventative Services Task Force threw the baby out with the bathwater by their blanket recommendation against prostate cancer screening,” says Sanda, noting that PSA screening can instead be refined to more selectively identify only aggressive cancer for which treatment is indicated by adjusting PSA results for other considerations such as family history, obesity, and prostate size.

Results from the multi-center study that suggest that PSAD levels of less than 0.1 – in contrast to the unadjusted level of between 2.5 and 4 – can be a better benchmark of a potential cancer. The density, determined by a digital rectal exam, enables physicians to take into account other factors like benign prostatic hyperplasia, an enlargement of the gland that affects all men as they age.

Combining the PSAD with the digital exam, a look at the patient’s family history and a body mass index of 25 of less – the calculation used to define obesity – would avoid biopsy in approximately one-quarter of biopsy-eligible men, the researchers found.
“Urological practice, patient outcome and cost-effectiveness of health care would each benefit from new targeted strategies, such as nomograms (a predictive tool) that improve prediction of aggressive cancers, to enable selective identification of candidate for prostate biopsy that would improve the yield of clinically significant, histologically aggressive cancers warranting subsequent definitive treatment,” researchers wrote.

In a separate multicenter study published in Urologic Oncology, researchers said a test looking for two specific genetic biomarkers – TMPRSS2:ERG and PCA3 – taken after a digital rectal exam, could help limit biopsies to men who possess both genes and whose PSA readings range between 2 and 10, potentially sparing one-third of men from biopsies.

“Urine testing for prostate cancer is in its infancy,” says Sanda, noting next steps are underway as a result of study funded by a $3.1 million grant from the National Institutes of Health , that is evaluating new urine and blood test for prostate cancer in more 2,400 men over the next five years with a goal of improving upon the problems of over-diagnosis and over-treatment.

A focal point of the proposed work involves a community outreach effort led by BIDMC primary care physician J. Jacques Carter, MD, MPH, Medical Director of the Dana Farber Cancer Institute Prostate Cancer Screening and Education Program and an Assistant Professor of Medicine at Harvard Medical School. A key component of this study will be African-American men, who appear to develop prostate cancer more frequently, and who are at increased risk of dying from prostate cancer.

Panel endorses active monitoring and delay of treatment for low-risk prostate cancer

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An independent panel convened this week by the National Institutes of Health has concluded that many men with localized, low-risk prostate cancer should be closely monitored, permitting treatment to be delayed until warranted by disease progression. However, monitoring strategies—such as active surveillance—have not been uniformly studied and available data do not yet point to clear follow-up protocols. The panel recommended standardizing definitions and conducting additional studies to clarify which monitoring strategies are most likely to optimize patient outcomes.

“It’s clear that many men would benefit from delaying treatment, but there is no consensus on what constitutes observational strategies and what criteria should be used to determine when treatment might ultimately be needed among closely-monitored men,” said Dr. Patricia A. Ganz, conference panel chairperson and director of the Division of Cancer Prevention and Control Research at the Jonsson Comprehensive Cancer Center at the University of California in Los Angeles.

Prostate cancer is the most common non-skin cancer in men in the United States. It is estimated that in 2011, approximately 240,000 men will be newly diagnosed with prostate cancer and 33,000 will die of the disease. More than half of these cancers are localized (confined to the prostate), not aggressive at diagnosis, and unlikely to become life-threatening. However, approximately 90 percent of patients receive immediate treatment, such as surgery or radiation therapy. For many of these patients, treatment has substantial short- and long-term side effects, such as diminished sexual function and loss of urinary control, without clear benefits, such as improved survival. Identifying appropriate management strategies for different subgroups of patients is critical to improving survival and reducing the burden of adverse effects.

Currently, clinicians often describe two alternatives to immediate treatment of low-risk prostate cancer: observation with and without the intent to cure. Observation without intent to cure, sometimes referred to as watchful waiting, is a passive approach, with treatment provided to alleviate symptoms if they develop. Observation with intent to cure, often referred to as active surveillance, involves proactive patient follow-up in which blood samples, digital rectal exams, and repeat prostate biopsies are conducted on a regular schedule, and curative treatment is initiated if the cancer progresses.

The panel identified emerging consensus in the medical community on a definition for low-risk prostate cancer: a prostate-specific antigen (PSA) level less than 10 ng/mL and a Gleason score of 6 or less. Using this definition, the panel estimated that more than 100,000 men diagnosed with prostate cancer each year would be candidates for active monitoring rather than immediate treatment. Importantly, however, the panel found that protocols to manage active monitoring still vary widely, hampering the evaluation and comparison of research findings.

Prostate cancer affects some 30-40 percent of men over the age of 50. Some of these men will benefit from immediate treatment, others will benefit from observation. We need to standardize definitions, group patients by their risks, and conduct additional research to determine the best protocols for managing low-risk disease,” stated Dr. Ganz.

The panel further recommended that disease terminology should be refined as a result of changes in the patient population with prostate cancer due to prostate-specific antigen (PSA) testing. Because of the very favorable prognosis of PSA-detected, low-risk prostate cancer, the panel recommended that strong consideration be given to removing the anxiety-provoking term “cancer” for this condition.

The panel also found that clinicians’ framing of disease management options is an important factor in patient decision-making. Other influential factors include views of family members, cancer experiences of family and friends, lifestyle priorities, and personal philosophy. Findings from studies in communication sciences and behavioral economics could be applied in clinical settings to promote informed, shared decision-making. While research continues to fill knowledge gaps and develop consensus, the decisions faced by men and their providers following a diagnosis of localized, low-risk prostate cancer should be highly individualized, and include the consideration of biological, psychological, social, and cultural factors.

With regard to future research, the panel recommended against future federal funding for single-institutional site studies, and emphasized instead the importance of supporting multisite clinical research studies. The panel also supports the establishment of registry-based cohort studies that collect longitudinal data on active monitoring participants, including clinical and patient-reported outcomes.

An updated version of the panel's draft statement, which incorporates public comments received in an open conference session this morning, will be posted later today at http://consensus.nih.gov.

The panel will hold a press telebriefing to discuss their findings today at 2 p.m. eastern time. To participate, call 888-428-7458(inside the United States) or 201-604-5177 (International) and reference the NIH State-of-the-Science Conference. Audio playback will be available shortly after conclusion of the telebriefing and can be accessed by calling 888-632-8973 (US) or 201-499-0429(International) and entering replay code 11996437.

The state-of-the-science conference was sponsored by the NIH Office of Medical Applications of Research, the National Cancer Institute, and the Centers for Disease Control and Prevention, along with other NIH and U.S. Department of Health and Human Services components. This conference was conducted under the NIH Consensus Development Program, which convenes conferences to assess the available scientific evidence and develop objective statements on controversial medical issues.

The 14-member state-of-the-science panel included experts in the fields of cancer prevention and control, urology, pathology, epidemiology, genetics, transplantation, bioethics, economics, health services research, shared decision-making, health communication, and community engagement. A complete listing of the panel members and their institutional affiliations is included in the draft conference statement. Additional materials, including panel biographies, photos, and other related resources, are available at http://consensus.nih.gov/2011/prostatemedia.htm. Interviews with panel members can be arranged by contacting Elizabeth Neilson at 301-496-4999 or NeilsonE@od.nih.gov.

The conference was webcast live and will be archived shortly. Links to the archived webcast will be available at http://consensus.nih.gov/2011/prostate.htm.

IQ can rise or fall significantly during adolescence

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The findings may have implications for testing and streaming of children during their school years

IQ, the standard measure of intelligence, can increase or fall significantly during our teenage years, according to research funded by the Wellcome Trust, and these changes are associated with changes to the structure of our brains. The findings may have implications for testing and streaming of children during their school years.

Across our lifetime, our intellectual ability is considered to be stable, with Intelligence Quotient (IQ) scores taken at one point in time used to predict educational achievement and employment prospects later in life. However, in a study published today in the journal Nature, researchers at the Wellcome Trust Centre for Neuroimaging at UCL (University College London) and the Centre for Educational Neuroscience show for the first time that in fact our IQ is not constant.

The researchers, led by Professor Cathy Price, tested thirty-three healthy adolescents in 2004 when they were between the ages of 12 and 16 years. They then repeated the tests four years later when the same subjects were between 15 and 20 years old. On both occasions, the researchers took structural brains scans of the subjects using magnetic resonance imaging (MRI).

Professor Price and colleagues found significant changes in the IQ scores measured in 2008 compared to the 2004 scores. Some subjects had improved their performance relative to people of a similar age by as much as 20 points on the standardised IQ scale; in other cases, however, performance had fallen by a similar amount. In order to test whether these changes were meaningful, the researchers analysed the MRI scans to see if there was a correlation with changes in the structure of the subjects' brains.

"We found a considerable amount of change in how our subjects performed on the IQ tests in 2008 compared to four years earlier," explains Sue Ramsden, first author of the study. "Some subjects performed markedly better but some performed considerably worse. We found a clear correlation between this change in performance and changes in the structure of their brains and so can say with some certainty that these changes in IQ are real."

The researchers measured each subject's verbal IQ, which includes measurements of language, arithmetic, general knowledge and memory, and their non-verbal IQ, such as identifying the missing elements of a picture or solving visual puzzles. They found a clear correlation with particular regions of the brain. An increase in verbal IQ score correlated with an increase in the density of grey matter – the nerve cells where the processing takes place – in an area of the left motor cortex of the brain that is activated when articulating speech. Similarly, an increase in non-verbal IQ score correlated with an increase in the density of grey matter in the anterior cerebellum, which is associated with movements of the hand. However, an increase in verbal IQ did not necessarily go hand-in-hand with an increase in non-verbal IQ.

According to Professor Price, a Wellcome Trust Senior Research Fellow, it is not clear why IQ should have changed so much and why some people's performance improved whilst others' decline. It is possible that the differences are due to some of the subjects being early or late developers, but it is equally possible that education played a role in changing IQ, and this has implications for how schoolchildren are assessed.

"We have a tendency to assess children and determine their course of education relatively early in life, but here we have shown that their intelligence is likely to be still developing," says Professor Price. "We have to be careful not to write off poorer performers at an early stage when in fact their IQ may improve significantly given a few more years.

"It's analogous to fitness. A teenager who is athletically fit at 14 could be less fit at 18 if they stopped exercising. Conversely, an unfit teenager can become much fitter with exercise. "

Other studies from the Wellcome Trust Centre for Neuroimaging and other research groups have provided strong evidence that the structure of the brain remains 'plastic' even throughout adult life. For example, Professor Price showed recently that guerrillas in Columbia who had learned to read as adults had a higher density of grey matter in several areas of the left hemisphere of the brain than those who had not learned to read. Professor Eleanor Maguire, also from the Wellcome Trust Centre, showed that part of a brain structure called the hippocampus, which plays an important role in memory and navigation, has greater volume in licensed London taxi drivers.

"The question is, if our brain structure can change throughout our adult lives, can our IQ also change?" adds Professor Price. "My guess is yes. There is plenty of evidence to suggest that our brains can adapt and their structure changes, even in adulthood."

'Understanding the brain' is one of the Wellcome Trust's key strategic challenges. It funds a significant portfolio of neuroscience and mental health research, ranging from studies of molecular and cellular components to work on cognition and higher systems. At the Wellcome Trust Centre for Neuroimaging, clinicians and scientists study higher cognitive function to understand how thought and perception arise from brain activity, and how such processes break down in neurological and psychiatric disease.

"This interesting study highlights how 'plastic' the human brain is," said Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust. "It will be interesting to see whether structural changes as we grow and develop extend beyond IQ to other cognitive functions. This study challenges us to think about these observations and how they may be applied to gain insight into what might happen when individuals succumb to mental health disorders."

Age a Big Factor in Prostate Cancer Deaths

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Contrary to common belief, men age 75 and older are diagnosed with late-stage and more aggressive prostate cancer and thus die from the disease more often than younger men, according to a University of Rochester analysis published online this week by the journal, Cancer.

The study is particularly relevant in light of the recent controversy about prostate cancer screening. Earlier this month a government health panel said that healthy men age 50 and older should no longer be routinely tested for prostate cancer because the screening test in its current form does not save lives and sometimes leads to needless suffering and overtreatment. Patient advocates and many clinicians disagreed with the finding.

Although the Rochester study does not address screening directly it does raise questions about the benefits of earlier detection among the elderly.

“Especially for older people, the belief is that if they are diagnosed with prostate cancer it will grow slowly and they will die of something else,” said lead author Guan Wu, M.D., Ph.D., assistant professor of Urology and of Pathology and Laboratory Medicine at the University of Rochester Medical Center.

“We hope our study will raise awareness of the fact that older men are actually dying at high rates from prostate cancer,” he said. “With an aging population it is important to understand this, as doctors and patients will be embarking on more discussions about the pros and cons of treatment.”

Wu and colleagues studied the largest national cohort of cancer patients, called the Surveillance, Epidemiology, and End Results (SEER) database. They analyzed 464,918 records of men diagnosed with prostate cancer between 1998 and 2007, known as the “PSA era” because of a strong inclination to recommend the PSA test during that time.

(The prostate-specific antigen or PSA is a protein produced by the prostate gland, which can be measured in the blood. An elevated PSA is associated with cancer and other noncancerous prostate conditions.)

The analysis showed that when age groups are broken down into smaller sections, men 75 or older represented only 16 percent of the male population above age 50 and 26 percent of all cases of prostate cancer -- but 48 percent of cases of metastatic disease at diagnosis and 53 percent of all deaths. In general, higher grade cancer seemed to increase with age, the study said.

Researchers were looking for associations between age, metastasis and death because in clinical practice, Wu said, several URMC urologists observed that many otherwise healthy older men were presenting with very advanced disease at diagnosis, and reporting that they had never had a PSA test.

Indeed, older men have largely been excluded from prior clinical trials of the benefits of early detection, the study said. This is based on the idea that older men wouldn’t benefit from early detection because of a shorter remaining life expectancy.

But Wu and colleagues contend that overall health, more than age, impacts life expectancy following a cancer diagnosis, and that more studies are needed to identify ways to manage the disease in older patients.

“Due to a lot of natural variation in the biology of prostate cancer,” Wu said, “the URMC study should stimulate the need to develop an algorithm to identify healthy, elderly men who might benefit from an earlier diagnosis.”

Screening For Prostate Cancer

A Review of the Evidence for the U.S. Preventive Services Task Force

Release Date: October 2011

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By Roger Chou, MD; Jennifer M. Croswell, MD, MPH; Tracy Dana, MLS; Christina Bougatsos, BS; Ian Blazina, MPH; Rongwei Fu, PhD; Ken Gleitsmann, MD, MPH; Helen C. Koenig, MD, MPH; Clarence Lam, MD, MPH; Ashley Maltz, MD, MPH; J. Bruin Rugge, MD, MPH; and Kenneth Lin, MD

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The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.

This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

This article was first published in Annals of Internal Medicine on October 7, 2011 (www.annals.org).

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Contents

Abstract

Introduction

Methods

Data Synthesis

Discussion

References

Abstract

Background: Screening can detect prostate cancer in earlier, asymptomatic stages when treatments might be more effective.

Purpose: To update the 2002 and 2008 U.S. Preventive Services Task Force evidence reviews on screening and treatments for prostate cancer.

Data Sources: MEDLINE (2002 to July 2011) and the Cochrane Library Database (through second quarter of 2011).

Study Selection: Randomized trials of prostate-specific antigen–based screening, randomized trials and cohort studies of prostatectomy or radiation therapy versus watchful waiting, and large observational studies of perioperative harms.

Data Extraction: Investigators abstracted and checked study details and quality using predefined criteria.

Data Synthesis: Of 5 screening trials, the 2 largest and highest-quality studies reported conflicting results. One found screening was associated with reduced prostate cancer–specific mortality compared with no screening in a subgroup of men age 55 to 69 years after 9 years (relative risk, 0.80 [95% CI, 0.65 to 0.98]; absolute risk reduction, 0.07 percentage point). The other found no statistically significant effect after 10 years (relative risk, 1.1 [CI, 0.80 to 1.5]). After 3 or 4 screening rounds, 12% to 13% of screened men had false-positive results. Serious infections or urinary retention occurred after 0.5% to 1.0% of prostate biopsies. There were 3 randomized trials and 23 cohort studies of treatments. One good-quality trial found that prostatectomy for localized prostate cancer decreased risk for prostate cancer–specific mortality compared with watchful waiting through 13 years of follow-up (relative risk, 0.62 [CI, 0.44 to 0.87]; absolute risk reduction, 6.1%). Benefits appeared limited to men younger than 65 years of age. Treating approximately 3 men with prostatectomy or 7 men with radiation therapy instead of watchful waiting would each result in 1 additional case of erectile dysfunction. Treating approximately 5 men with prostatectomy would result in 1 additional case of urinary incontinence. Prostatectomy was associated with perioperative death (about 0.5%) and cardiovascular events (0.6% to 3%), and radiation therapy was associated with bowel dysfunction.

Limitation: Only English-language articles were included. Few studies evaluated newer therapies.

Conclusion: Prostate-specific antigen–based screening results in small or no reduction in prostate cancer–specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary.

Primary Funding Source: Agency for Healthcare Research and Quality

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Introduction

Prostate cancer is the most commonly diagnosed cancer in U.S. men (1-3). Prostate-specific antigen (PSA)–based screening can detect prostate cancers in earlier, asymptomatic stages, when treatments might be more effective.

The U.S. Preventive Services Task Force (USPSTF) last reviewed the evidence on prostate cancer screening (4) and issued recommendations in 2008 (5). Since then, large trials of prostate cancer screening have been published (6, 7). Benefits and harms of treatments for prostate cancer were last reviewed by the USPSTF in 2002 (8). This article summarizes 2 recent reviews commissioned by the USPSTF to synthesize the current evidence on screening (9) and treatments (10) for localized prostate cancer.

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Methods

Scope of the Review

We followed a standardized protocol and developed an analytic framework that focused on the following key questions:

1. Does PSA-based screening decrease prostate cancer–specific or all-cause mortality?


2. What are the harms of PSA-based screening for prostate cancer?


3. What are the benefits of treatment of early-stage or screening-detected prostate cancer?


4. What are the harms of treatment of early-stage or screening-detected prostate cancer?
   
   

Detailed methods and data for the review, including search strategies, multiple evidence tables with quality ratings of individual studies, and pooled analyses of some harms data, are available in the full report (10). Also of note, androgen deprivation therapy, cryotherapy, and high-intensity focused ultrasonography are reviewed in the full report (10) but are not presented in this manuscript.

Data Sources and Searches

We searched OVID MEDLINE from 2002 to July 2011, PubMed from 2007 to July 2011, and the Cochrane Database through the second quarter of 2011 and reviewed reference lists to identify relevant articles published in the English language.

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Study Selection

At least 2 reviewers independently evaluated each study to determine inclusion eligibility. We restricted inclusion to published studies. We included randomized trials of screening for prostate cancer in asymptomatic men (including those with chronic, mild lower urinary tract symptoms) that incorporated 1 or more PSA measurements, with or without additional methods, such as digital rectal examination, and reported all-cause or prostate cancer–specific mortality or harms associated with screening. We also included randomized trials and cohort studies of men with screening-detected prostate cancer that compared radical prostatectomy or radiation therapy (the most common primary treatments for localized prostate cancer [11, 12]) with watchful waiting and reported all-cause mortality, prostate cancer–specific mortality, or prespecified harms (quality of life or functional status, urinary incontinence, bowel dysfunction, erectile dysfunction, psychological effects, and surgical complications). We included studies of clinically localized (T1 or T2) prostate cancer because more than 90% of screening-detected prostate cancers are localized (6, 7, 13). We included only studies that reported risk estimates for mortality adjusted at a minimum for age at diagnosis and tumor grade (no study reported adjusted risk estimates for treatment harms). We also included large (n>1000) uncontrolled observational studies of perioperative mortality and surgical complications.

We classified “no treatment,” “observation,” or “deferred treatment” as watchful waiting because patients probably received at least watchful waiting. We also grouped watchful waiting with active surveillance because studies of active surveillance provided insufficient information to determine whether more active follow-up actually occurred (14), and older studies used these terms interchangeably.

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Data Extraction and Quality Assessment

One investigator abstracted details about the patient population, study design, analysis, duration of follow-up, and results. A second investigator reviewed data abstraction for accuracy. Two investigators independently applied criteria developed by the USPSTF (15) to rate the quality of each study as good, fair, or poor. Discrepancies were resolved through a consensus process.

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Data Synthesis and Analysis

We assessed the aggregate internal validity (quality) of the body of evidence for each key question (good, fair, and poor) using methods developed by the USPSTF on the basis of the number, quality, and size of studies; consistency of results between studies; and directness of evidence (15). We synthesized results of treatment studies descriptively, using medians and ranges, because few randomized, controlled trials (RCTs) were available and studies varied in the populations and interventions evaluated, methodologic quality, duration of follow-up, and other factors. We stratified results according to study type and qualitatively assessed effects of study quality, duration of follow-up, year of publication, and mean age on results.

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Role of the Funding Source

This study was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. Agency staff and USPSTF members helped develop the scope of this work and reviewed draft manuscripts. The draft systematic reviews were reviewed by external peer reviewers not affiliated with the USPSTF, then revised for the final version. Agency approval was required before this manuscript could be submitted for publication, but the authors are solely responsible for the content and the decision to submit.

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Data Synthesis

Appendix Figure 1 and Appendix Figure 2 show the results of the search and study selection process.

We identified 2 fair-quality (6, 7) and 3 poor-quality (16-20) randomized trials of PSA-based screening (Appendix Table 1). We also included a report describing results from a single center (21) participating in a fair-quality trial (7). Sample sizes ranged from 9026 to 182,160 and maximum follow-up from 11 to 20 years (median, 6 to 14 years).

We identified 11 studies (2 RCTs [22-29] and 9 cohort studies [30-38]) on benefits of prostate cancer treatments and 16 studies (2 RCTs [39-42] and 14 cohort studies [43-58]) on harms (Appendix Table 2). Sample sizes ranged from 72 to 44,630 and duration of follow-up from 1 to 23 years. Four studies were rated good quality (23, 42, 52, 56, 58), 1 poor quality (29), and the remainder fair quality. Frequent methodologic shortcomings were failure to describe loss to follow-up (6 cohort studies and all 3 RCTs met this criterion) and inadequate blinding of outcome assessors (no cohort studies and 1 RCT met this criterion). Only 2 studies (33, 40) clearly described the control group intervention (Appendix Table 1). We also included 6 observational studies (59-64) of surgical complications after prostatectomy.

Key Question 1: Does PSA-Based Screening Decrease Prostate Cancer–Specific or All-Cause Mortality?

The fair-quality U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial randomly assigned 76,693 men between 55 and 74 years of age to annual PSA screening in combination with digital rectal examination versus usual care (6). After 7 years' (complete) follow-up, screening was associated with increased prostate cancer incidence (relative risk [RR], 1.2 [95% CI, 1.2 to 1.3]) but no effect on prostate cancer–specific (RR, 1.1 [CI, 0.75 to 1.7]) or all-cause (RR, 0.98 [CI, 0.92 to 1.0]) mortality. Similar results were observed after 10 years (67% of sample; RR, 1.1 [CI, 0.80 to 1.5]). Up to 52% of men assigned to usual care underwent a PSA test at some point during the trial, and 44% of trial participants had undergone PSA screening before entry.

The fair-quality European Randomized Study of Screening for Prostate Cancer (ERSPC) randomly assigned 182,000 men age 50 to 74 years from 7 countries to PSA testing every 2 to 7 years (depending on center and year) or to usual care (7). Data from 2 other study centers were excluded for reasons not specified in the study protocol. Levels of PSA for diagnostic evaluation ranged from 2.5 to 4.0 mcg/L (1 center used 10 mcg/L for several years). Recruitment and randomization procedures and age eligibility also varied. After a median of 9 years, prostate cancer incidence was higher in the screened group (net increase, 34 per 1000 men), but there was no statistically significant difference in prostate cancer–specific mortality (RR, 0.85 [CI, 0.73 to 1.0]). A prespecified subgroup analysis of 162,243 men age 55 to 69 years found that screening was associated with reduced prostate cancer–specific mortality (RR, 0.80 [CI, 0.65 to 0.98]; absolute risk reduction, 0.07 percentage point), for an estimated 1410 men invited to screening and 48 treated to prevent 1 prostate cancer–specific death.

After the publication of the main ERSPC results, 1 participating center (Göteborg, Sweden) reported results separately (21). It found PSA screening (threshold, 2.5 to 3.0 mcg/L) every 2 years in 20,000 men age 50 to 64 years to be associated with increased prostate cancer incidence (hazard ratio [HR], 1.6 [CI, 1.5 to 1.8]) and decreased risk for prostate cancer–specific mortality (RR, 0.56 [CI, 0.39 to 0.82]; absolute risk reduction, 0.34 percentage point) after a median of 14 years. Outcomes for 60% of participants were included in the main ERSPC report (7). Although no other center separately reported results, only exclusion of the Swedish center data from the overall ERSPC analysis resulted in loss of the statistically significant effect of screening on prostate cancer–specific mortality (RR, 0.84 [CI, 0.70 to 1.01]), suggesting better results than the other centers (7).

Three poor-quality trials (number of men invited to screening ranged from 1494 to 31,333) found no difference between screening-invited and control groups in prostate cancer–specific mortality risk (16, 17, 20). Two of the trials (17, 19) were included in the 2008 USPSTF review (4); results after 5 years' additional follow-up are now available from 1 of the trials (20). Methodologic shortcomings in these trials included failure to describe adequate randomization or allocation concealment methods, poorly described loss to follow-up, and unclear masking of outcomes assessors. One trial used a high PSA cut-point (10 mcg/L) (16).

Key Question 2: What Are the Harms of PSA-Based Screening for Prostate Cancer?

Direct harms of PSA-based screening were reported in the ERSPC and PLCO trials (6, 7). The Finnish center of the ERSPC trial found that 12% of men received at least 1 false-positive result after 3 rounds of PSA testing (cutoff, 4.0 mcg/L) (65). For the entire ERPSC trial, 76% of prostate biopsies for an elevated PSA level identified no cancer (7). In the PLCO trial, the cumulative risk for at least 1 false-positive result was 13% after 4 PSA tests (cutoff, 4.0 mcg/L), with a 5.5% risk for undergoing at least 1 biopsy due to a false-positive test result (66).

Physical harms of screening in the PLCO trial included bleeding or pain from digital rectal examination (0.3 event per 10,000 screened); bruising or fainting due to venipuncture (26 events per 10,000 screened); and biopsy complications, such as infection, bleeding, and urinary difficulties (68 events per 10,000 evaluations) (6). The Rotterdam, Netherlands, center of the ERSPC trial reported that among 5802 biopsies performed, 200 men (3.5%) developed a fever, 20 (0.4%) experienced urinary retention, and 27 (0.5%) required hospitalization for signs of prostatitis or urosepsis (67).

None of the RCTs of PSA-based screening provided information on potential psychological harms, such as anxiety or adverse effects on health-related quality of life. The 2008 USPSTF review found evidence that false-positive PSA test results are associated with adverse psychological effects but could not estimate their magnitude (4).

Key Question 3: What Are the Benefits of Treatment of Early-Stage or Screening-Detected Prostate Cancer?

Prostatectomy

Prostatectomy was compared with watchful waiting in 1 good-quality RCT (n=695) of men with localized (stage T1b, T1c, or T2) prostate cancer (Appendix Table 3) (22-24, 28). It did not specifically enroll men with screening-detected prostate cancer, and about 75% of cancers were palpable (stage T2). By comparison, 36% of localized cancers in the ERSPC screening trial were stage T2 (7). The 2002 USPSTF review included results through 6 years of follow-up (28). Data now available through 15 years showed a sustained decrease in risk for prostate cancer–specific mortality (15% vs. 21%; RR, 0.62 [CI, 0.44 to 0.87]; absolute difference, 6.1 percentage points [CI, 0.2 to 12 percentage points]) and all-cause mortality (RR, 0.75 [CI, 0.61 to 0.92]; absolute difference, 6.6 percentage points [CI, −1.3 to 14 percentage points]) (23). In subgroup analyses, benefits were restricted to men younger than 65 years of age (RR, 0.49 [CI, 0.31 to 0.79] for prostate cancer–specific mortality; RR, 0.52 [CI, 0.37 to 0.73] for all-cause mortality). One other small (n=142), poor-quality RCT found no difference between prostatectomy and no prostatectomy for localized prostate cancer on overall survival through 23 years (29). It did not report prostate cancer–specific mortality.

Eight cohort studies (median n=2264 [range, 316 to 25,900]) with duration of follow-up ranging from 4 to 13 years consistently found prostatectomy for localized prostate cancer to be associated with decreased risk for all-cause mortality (6 studies; median adjusted HR, 0.46 [range, 0.32 to 0.67] [31, 33-37]) and prostate cancer–specific mortality (5 studies; median adjusted HR, 0.32 [range, 0.25 to 0.50] [30, 33, 35, 36, 38]) compared with watchful waiting (Appendix Table 3). The largest was a fair-quality, propensity-adjusted analysis of data from the U.S. Surveillance, Epidemiology, and End Results (SEER) program (n=25,900) of men 65 to 80 years of age that found decreased risk for all-cause mortality after 12 years (adjusted HR, 0.50 [CI, 0.66 to 0.72]) (37). Another large (n=22,385), fair-quality Swedish cohort study also found prostatectomy to be associated with decreased risk for all-cause mortality after 4 years of follow-up, after adjustment for age, Gleason score, and PSA level (adjusted HR, 0.41 [CI, 0.36 to 0.48]) (31).

Radiation Therapy

No RCTs compared radiation therapy versus watchful waiting. Five cohort studies (median n=3441 [range, 334 to 30,857]) with follow-up ranging from 4 to 13 years consistently found that radiation therapy (external-beam radiation therapy or unspecified modality) for localized prostate cancer was associated with decreased risk for all-cause mortality (5 studies; median adjusted HR, 0.68 [range, 0.62 to 0.81] [31, 35-38]) and prostate cancer–specific mortality (5 studies; median adjusted HR, 0.66 [range, 0.63 to 0.70]) compared with watchful waiting (Appendix Table 3) (30, 35-38). The largest study, a previously described analysis of SEER data, found radiation therapy to be associated with decreased propensity-adjusted risk for all-cause mortality (adjusted HR, 0.81 [CI, 0.78 to 0.85]) (37). A large Swedish cohort study (also described earlier) found radiation therapy to be associated with decreased risk for all-cause mortality (adjusted HR, 0.62 [CI, 0.54 to 0.71]) (31).

Key Question 4: What Are the Harms of Treatment of Early-Stage or Screening-Detected Prostate Cancer?

Prostatectomy

Urinary Incontinence and Erectile Dysfunction. Prostatectomy was associated with increased risk for urinary incontinence compared with watchful waiting in 1 RCT (RR, 2.3 [CI, 1.6 to 3.2]) (41) and 4 cohort studies (median RR, 4.0 [range, 2.0 to 11]) (Appendix Table 4) (47, 49, 53, 56). In the RCT, the absolute increase in risk for urinary incontinence with surgery was 28 percentage points (49% versus 21%) (41). In the cohort studies, the median rate of urinary incontinence with watchful waiting was 6% (range, 3% to 10%), with prostatectomy associated with a median increase in absolute risk of 18 percentage points (range, 8 to 40 percentage points) (47, 49, 53, 56).

Prostatectomy was also associated with an increased risk for erectile dysfunction compared with watchful waiting in 1 RCT (RR, 1.8 [CI, 1.5 to 2.2]) (41) and 5 cohort studies (median RR, 1.5 [range, 1.3 to 2.1]) (Appendix Table 4) (47, 49, 53, 54, 56). In the RCT, the absolute increase in risk for erectile dysfunction with surgery was 36 percentage points (81% versus 45%) (41). In the cohort studies, the median rate of erectile dysfunction with watchful waiting was 52% (range, 26% to 68%), with prostatectomy associated with a median increase in absolute risk of 26 percentage points (range, 21 to 29 percentage points) (47, 49, 53, 54, 56).

Differences in study quality, duration of follow-up, or year of publication did not appear to explain differences in estimates across studies. The studies provided few details about the specific surgical procedures evaluated, although open retropubic radical prostatectomy was the dominant procedure when most of the studies were conducted (68). One observational study stratified estimates for erectile dysfunction and urinary incontinence by use of nerve-sparing (n=494; 68% and 9.4%, respectively) versus non–nerve-sparing (n=476; 87% and 15%, respectively) techniques (56).

Consistent with the studies reporting dichotomous outcomes, 8 cohort studies that evaluated urinary and sexual function outcomes by using continuous scales found that prostatectomy was associated with worse outcomes compared with watchful waiting (Appendix Table 4 [43, 46, 48, 51, 53, 55-57].)

Quality of Life. Nine studies reported generic quality of life (43, 46, 48, 50, 51, 53, 55, 56). Two studies reported very similar Short-Form 36 (SF-36) physical and mental component summary scores after prostatectomy and watchful waiting (Appendix Table 5) (43, 56). On specific SF-36 subscales, prostatectomy was associated with better physical function (6 studies; median difference, 9 points [range, 2 to 16 points]) (43, 46, 48, 50, 51, 53, 55, 56) and emotional role function subscale scores (7 studies; median difference, 8 points [range, 5 to 13 points]) (43, 46, 48, 50, 51, 53, 55, 56), with small or no clear differences on other SF-36 subscales.

Surgical Complications. The largest (n=101,604) study of short-term (≤30-day) complications after prostatectomy reported a 30-day perioperative mortality rate of 0.5% in Medicare claimants (60); 3 other large observational studies reported similar findings (59, 61, 62). Advanced age and increased number of serious comorbid conditions were associated with higher perioperative mortality, although absolute rates were less than 1% even in men at higher risk. In the Medicare database study, perioperative rates of serious cardiovascular events were 3% and rates of vascular events (including pulmonary embolism and deep venous thrombosis) were 2% (60). In 2 other studies (n=1243 [63] and 11,010 [59]), rates of cardiovascular events were 0.6% and 3% and rates of vascular events 1% and 2%, respectively. Serious rectal or ureteral injury due to surgery ranged from 0.3% to 0.6% (60, 63).

Other Harms. Five studies (reported in 6 publications) found no clear differences between prostatectomy and watchful waiting in risk for bowel dysfunction (41, 42, 46, 47, 49, 56). One RCT found no difference between prostatectomy and watchful waiting in risk for high levels of anxiety, depression, or worry after 4 years (42).

Radiation Therapy

Urinary Incontinence and Erectile Dysfunction. Radiation therapy was associated with increased risk for urinary incontinence compared with watchful waiting in 1 small RCT, but the estimate was very imprecise (RR, 8.3 [CI, 1.1 to 63]) because of small numbers of events (1 in the watchful waiting group) (Appendix Table 4) (39). There was no clear increase in risk in 4 (total n=1910) cohort studies (median RR, 1.1 [range, 0.71 to 2.0]) (47, 49, 53, 56).

Radiation therapy was associated with increased risk for erectile dysfunction compared with watchful waiting in 6 cohort studies, with similar estimates across studies (median RR, 1.3 [range, 1.1 to 1.5]) (Appendix Table 4) (47, 49, 53, 54, 56, 58). Rates of erectile dysfunction ranged from 26% to 68% (median, 50%) with watchful waiting; radiation therapy was associated with a median increase in pooled absolute risk of 14 percentage points (range, 7 to 22 percentage points).

Five of the six studies did not provide details about the type of radiation therapy (for example, external-beam radiation therapy [EBRT] versus brachytherapy) or dosing regimen. One good-quality cohort study reported a 7.0% rate of urinary incontinence after high-dose brachytherapy (n=47), 5.4% after low-dose brachytherapy (n=58), and 2.7% after EBRT (n=123) (56). Rates of erectile dysfunction were 72%, 36%, and 68%, respectively.

Consistent with the studies reporting dichotomous outcomes, 8 cohort studies found radiation therapy to be associated with worse sexual function compared with watchful waiting based on continuous scales, although no clear differences were seen in sexual bother scores and measures of urinary function (Appendix Table 4) (40, 43, 46, 48, 51, 53, 55, 56-58).

Quality of Life. Ten studies reported generic quality of life (40, 43, 46, 48, 50, 51, 53, 55, 58). Three studies found no differences between radiation therapy and watchful waiting in SF-36 physical (median difference, 0 points [range, −3 to 0 points]) or mental (median difference, 0 points [range, −2 to 1 points]) component summary scores (Appendix Table 4) (43, 56, 58). Results favored watchful waiting on the physical role function subscale (7 studies; median difference, −9 points [range, −22 to 1 points]) (43, 46, 48, 51, 53, 55, 58), with no clear differences on other SF-36 subscales.

Other Harms. Six cohort studies consistently found radiation therapy associated with worse Prostate Cancer Index bowel bother (median difference, −6 points [range, −10 to −2 points]) and function (median difference, −8 points [range, −15 to −3 points]) compared with watchful waiting (43, 48, 51, 53, 56). In studies that evaluated bowel function serially, effects appeared most pronounced in the first few months after radiation therapy and gradually improved (40, 46, 51, 57). This might help explain the inconsistent results among studies that reported dichotomous outcomes. Although 1 study found radiation therapy associated with substantially increased risk for bowel urgency after 2 years (3.2% vs. 0.4%; RR, 7.5 [CI, 1.0 to 56]) (47), 2 studies with longer duration of follow-up (5.6 [49] and 3 years [56]) found no increased risk.

One cohort study reported similar effects of EBRT and brachytherapy on Prostate Cancer Index bowel function and bother (43). One other study found low-dose brachytherapy to be associated with smaller effects on bowel bother (about 3-point change from baseline) compared with high-dose brachytherapy (9-point change) or EBRT (8-point change) (56).

No study reported effects of radiation therapy versus watchful waiting on anxiety or depression.

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Discussion

The Table depicts our summary of the evidence. Screening based on PSA identifies additional prostate cancers, but most trials found no statistically significant effect on prostate cancer–specific mortality. Recent meta-analyses of randomized trials included in this review found no pooled effect of screening on prostate cancer–specific mortality (69, 70). However, the 2 largest and highest-quality trials reported conflicting results (6, 7). The ERSPC trial found PSA screening every 2 to 7 years to be associated with a 20% relative reduction in risk for death from prostate cancer in a prespecified subgroup of men age 55 to 69 years (7), whereas the PLCO trial found no effect (6). High rates of previous PSA screening and contamination in the control group of the PLCO trial may have reduced its ability to detect benefits, although these factors do not explain the trend toward increased risk for prostate cancer–specific mortality in the screened group. The proportion of men in the PLCO trial who initially chose active surveillance or expectant management instead of curative treatment was lower than in the ERSPC trial (10% versus 19%), and the PLCO trial evaluated a shorter screening interval (annual versus every 4 years), suggesting that more conservative screening and treatment strategies might be more effective than more aggressive ones. Chance could also explain the apparent discrepancy between the 2 trials because the risk estimate confidence intervals overlapped. Additional follow-up might help resolve the discrepancy, given the long lead time (10 to 15 years) that may be necessary to fully understand the effect of PSA-based screening.

Treatment studies can help inform screening decisions by providing information about potential benefits of interventions once prostate cancer is detected. However, only 1 good-quality randomized trial compared an active treatment for localized prostate cancer versus watchful waiting (23). It found that prostatectomy was associated with decreased risk for all-cause and prostate cancer–specific mortality after 15 years of follow-up, although benefits appeared limited to younger men based on subgroup analyses. Because the RCT did not enroll men specifically with screening-detected prostate cancers, its applicability to screening is uncertain. Although cohort studies consistently found prostatectomy and radiation therapy to be associated with decreased risk for all-cause and prostate cancer–specific mortality compared with watchful waiting, estimates are susceptible to residual confounding, even after statistical adjustment.

Screening is associated with potential harms, including serious infections or urinary retention in about 1 of 200 men who undergo prostate biopsy as a result of an abnormal screening test result. False-positive screening results occurred in 12% to 13% of men randomly assigned to PSA-based screening (65, 66), with 1 trial reporting no prostate cancers in three quarters of screening-triggered biopsies (7). Screening also is likely to result in overdiagnosis because of the detection of low-risk cancers that would not have caused morbidity or death during a man's lifetime, and overtreatment of such cancers, which exposes men to unnecessary harms (71). Over three quarters of men with localized prostate cancer (about 90% of screening-detected cancers are localized) undergo prostatectomy or radiation therapy (11, 12). On the basis of data from the ERSPC trial, the rate of overdiagnosis with screening was estimated to be as high as 50% (72), and 48 men received treatment for every prostate cancer–specific death prevented (7). Treating approximately 3 men with prostatectomy or 7 with radiation therapy instead of watchful waiting would each result in 1 additional case of erectile dysfunction, and treating approximately 5 men with prostatectomy instead of watchful waiting would result in 1 additional case of urinary incontinence. Prostatectomy and radiation therapy were not associated with worse outcomes on most measures related to general health-related quality of life compared with watchful waiting, suggesting that negative effects related to specific harms may be offset by positive effects (perhaps related to less worry about untreated prostate cancer). Prostatectomy was also associated with perioperative (30-day) mortality (about 0.5%) and cardiovascular events (0.6% to 3%), and radiation therapy was associated with bowel dysfunction.

The evidence on treatment-related harms reviewed for this report appeared most applicable to open retropubic radical prostatectomy and EBRT, although details about specific surgical techniques or radiation therapy techniques and dosing regimens were frequently lacking. We found little evidence with which to evaluate newer techniques for prostatectomy (including nerve-sparing approaches that use laparoscopy, either robotic-assisted or free-hand) compared with watchful waiting, but found no pattern suggesting that more recent studies reported different risk estimates than older studies. Limited data suggest that low-dose brachytherapy may be associated with fewer harms than high-dose brachytherapy or EBRT (56). A potential harm of radiation therapy not addressed in this review is secondary post-treatment carcinogenic effects (73, 74).

Other treatments used for localized prostate cancer are reviewed in the full report, available on the USPSTF Web site (10). Although androgen deprivation is the next most commonly used therapy for localized prostate cancer after prostatectomy and radiation therapy (11), its use is comparatively infrequent, and it is not recommended as primary therapy (75, 76) because of evidence suggesting ineffectiveness (32), as well as an association with important adverse events, such as coronary heart disease, myocardial infarction, diabetes, and fractures, when given for more advanced prostate cancer (77-79).

Our study has some limitations. We excluded non–English-language articles, which could result in language bias, although we identified no non–English-language studies that would have met inclusion criteria. We included cohort studies of treatments, which are more susceptible to bias and confounding than well-conducted randomized trials. However, confounding by indication may be less of an issue in studies that evaluate harms (80), and analyses stratified by study design did not suggest differential estimates. If patients are selected for a specific prostate cancer treatment, in part because of a lower perceived risk for harms, the likely effect on observational studies would be to underestimate risks. For mortality outcomes, which may be more susceptible to confounding by indication, we included only studies that performed statistical adjustment. Finally, studies did not distinguish well between active surveillance and watchful waiting. Active surveillance might be associated with more harms (due to repeat biopsies or subsequent interventions) compared with watchful waiting, and studies with well-described active surveillance interventions that are consistent with current definitions for this therapy are needed (14).

In summary, PSA-based screening is associated with detection of more prostate cancers; small to no reduction in prostate cancer–specific mortality after about 10 years; and harms related to false-positive test results, subsequent evaluation, and therapy, including overdiagnosis and overtreatment. If screening is effective, optimal screening intervals and PSA thresholds remain uncertain. The ERSPC trial evaluated longer screening intervals (2 to 7 years) and in some centers lower PSA thresholds (2.5 to 4.0 mcg/L) as compared with typical U.S. practice (7). When available, results from the Prostate Cancer Intervention Versus Observation Trial, which compared prostatectomy with watchful waiting for screening-detected cancer, may help clarify which patients would benefit from prostatectomy or other active treatments, potentially reducing harms from unnecessary treatment (81).

Inflammation Marker may Guide Prognosis for Prostate Cancer

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1) Current methods often fail to separate lethal from non-lethal cancers. 2) Levels of prostatic intraepithelial neoplasia (PIN) identify lethal cancers. 3) Men with PIN were 89 percent more likely to die of prostate cancer.


Current methods of prostate cancer detection, like the prostate-specific antigen (PSA) test, often fail to identify which cancers will prove fatal and which cancers will remain benign until a patient dies of other causes.

“We are in need of better markers that distinguish between aggressive and indolent disease in this population,” said Jennifer R. Rider, Sc.D., an instructor in medicine at the Brigham and Women’s Hospital, Harvard Medical School in Boston, Mass.

In a study published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research, Rider and colleagues suggested that levels of prostatic intraepithelial neoplasia (PIN) could allow for a more precise prognosis.

The researchers evaluated men with localized prostate cancer diagnosed following a surgical procedure to treat benign prostatic hyperplasia. Of these men, 228 died of prostate cancer and 387 were diagnosed with prostate cancer, but were still alive after 10 years. Those with PIN were 89 percent more likely to die of prostate cancer.
Even after accounting for age, Gleason score, year of diagnosis, inflammation and type of focal atrophy present, PIN still managed to independently predict the lethality of a given tumor. There was also a suggestion that the degree of chronic inflammation adjacent to the tumor could predict lethal outcome.

“Identifying features surrounding the tumor that can predict prognosis, such as the presence of PIN or inflammation, can improve our understanding of the biology of aggressive prostate cancer and help to guide clinical decision-making,” said Rider.

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Shorter radiation course for prostate cancer is effective in long-term follow-up

A shorter course of radiation treatment that delivers higher doses of radiation per day in fewer days (hypofractionation) is as effective in decreasing intermediate to high-risk prostate cancer from returning as conventional radiation therapy at five years after treatment, according to a randomized trial presented at the plenary session, October 3, 2011, at the 53rdAnnual Meeting of the American Society for Radiation Oncology (ASTRO).

"This long-term study confirms that hypofractionated radiation that shortens treatment by about two and a half weeks is a practical approach to effectively controlling prostate cancer, as compared to the more standard treatment for men with intermediate to high-risk prostate cancer," Alan Pollack, MD, chairman of radiation oncology at the University of Miami Miller School of Medicine in Miami, said.

The strategy to compress treatment schedules using hypofractionation is based on years of studies indicating that there could be a radiobiologic advantage to this approach. Prior research has indicated that tumor cells would be killed to a greater degree with hypofractionation than the potentially damaging effects on the surrounding normal tissues, namely the rectum, penile structures affecting erections and bladder. Another newer approach to hypofractionation incorporated into this trial is the use of intensity modulated radiotherapy (IMRT), which further limits dose to the normal tissues. IMRT has proven value in limiting side effects in the treatment of prostate cancer with external beam radiotherapy.

The study involved 303 men with intermediate to high-risk prostate cancer who were randomized to receive either hypofractionated IMRT or conventionally fractionated IMRT between 2002 and 2006. The high risk patients also received a form of hormone therapy for two years. The patients were followed for over five years to find out if their cancer returned by monitoring prostate specific antigen (PSA), a blood test and established indicator of prostate cancer recurrence when increasing levels are seen.

Dr. Pollack said, "we are still learning how best to apply hypofractionation and the results in this trial show that the technique is very effective."

The hypofractionation approach used was given in a shorter period of time with higher doses per day and was expected to be equivalent to four extra treatments using conventional fractionation. While the hypofractionation treatment was hypothesized to be superior, the same tumor control rates were observed. The conventionally fractionated patients had better outcomes than expected. The benefit of the hypofractionation method used was that comparable results were achieved in two and a half fewer weeks of treatment.

In terms of side effects, the rates were relatively low for both methods. There were identical long-term rates of bowel/rectal reactions and the frequency of unsatisfactory erections. There was, however, significantly higher bladder control in the conventionally fractionated patients.

"Late urinary symptoms were higher with hypofractionation but were low overall, particularly when the incidence of persistent urinary symptoms (<10 percent at five years) was analyzed, rather than just as an isolated event," Dr. Pollack said. "Hypofractionation is rapidly gaining momentum for many types of cancers. The results presented here bring us much closer to effectively treating prostate cancer in a shorter period of time, with acceptable side effects."

New analysis indicates that risk of bladder cancer from smoking greater than previously reported

CHICAGO – An analysis of data that includes nearly 500,000 individuals indicates that the risk of bladder cancer among smokers is higher than reported from previous population data, and that the risk for women smokers is comparable with that of men, according to a study in the August 17 issue of JAMA.

More than 350,000 individuals are diagnosed with bladder cancer per year worldwide, including more than 70,000 per year in the United States. Tobacco smoking is the best established risk factor for bladder cancer in both men and women, with previous studies indicating that current cigarette smoking triples bladder cancer risk relative to never smoking, according to background information in the article. "However, the composition of cigarettes has changed during the past 50 years, leading to a reduction in tar and nicotine concentrations in cigarette smoke, but also to an apparent increase in the concentration of specific carcinogens, including beta-napthylamine, a known bladder carcinogen …," the authors write. They add that changing smoking prevalence and cigarette composition warrant revisiting risk estimates for smoking and bladder cancer.

Neal D. Freedman, Ph.D., M.P.H., of the National Cancer Institute, Department of Health and Human Services, Rockville, Md., and colleagues conducted a study to examine the association between tobacco smoking and bladder cancer using data from men (n = 281,394) and women (n = 186,134) in the National Institutes of Health-AARP (NIH-AARP) Diet and Health Study, who completed a lifestyle questionnaire and were followed up between October 1995 and December 2006. Previous studies of smoking and incident bladder cancer were identified by systematic review of the available literature.

During the course of follow-up, 3,896 men and 627 women were newly diagnosed with bladder cancer. Cigarette smoking was a significant risk factor for bladder cancer in both sexes. Relative to never smokers, former and current smokers had increased risk of bladder cancer in both men and women. Analysis of the data indicated that former smokers had a 2.2 times increased risk of bladder cancer and that for current smokers, the risk was about 4 times higher, relative to never smokers. "In contrast, the summary risk estimate for current smoking in 7 previous studies (initiated between 1963 and 1987) was 2.94," the authors write.

Ever smoking explained a similar proportion of bladder cancer in both sexes, with population attributable risks of 50 percent in men and 52 percent in women.

The researchers write that factors that may have strengthened the cigarette smoking-bladder cancer association include changes in the constituents of cigarette smoke (such as increased concentrations of beta-napthylamine), and increased awareness of bladder cancer risk in smokers, which may prompt earlier diagnostic workup.

"These results support the hypothesis that the risk of bladder cancer associated with cigarette smoking has increased with time in the United States, perhaps a reflection of changing cigarette composition. Prevention efforts should continue to focus on reducing the prevalence of cigarette smoking."

NEW TREATMENT OPTION FOR ADVANCED PROSTATE CANCER

Prostate cancer that has become resistant to hormone treatment and that does not respond to radiation or chemotherapy requires new methods of treatment. By attacking stem cell-like cells in prostate cancer, researchers at Lund University are working on a project to develop a new treatment option.

A successful interdisciplinary project is underway between two research groups, in which senior researcher Rebecka Hellsten and Professor Anders Bjartell at the Faculty of Medicine’s division for Urological Cancer Research, Skåne University Hospital in Malmö, and Professor Olov Sterner and Assistant Professor Martin Johansson at the Lund University division of Organic Chemistry recently published their latest research findings in the scientific online journal PLoS ONE.

“Prostatic tumours are thought to consist only of about 0.1 per cent cancer stem cells, but if you are not successful in eradicating that tumour cell population, there is a risk of subsequent uncontrolled growth of the tumour. The cancer stem cells are often unresponsive to both hormonal treatment and to chemotherapy, so it is essential to develop a direct treatment towards all types of cancer cells”, says Anders Bjartell.

Exploring the tumour biology of prostate cancer, the research group have now observed that the protein STAT3 is active in the stem cell-like cells. In their previous studies, they have proven that the natural compound galiellalactone affects STAT3 and has inhibitory effects on the growth of prostate cancer.

Through the development of new specific STAT3-inhibitors with galiellalactone as a model, the researchers hope to develop targeted therapies that attack the stem cell-like cancer cells in prostate cancer and prevent the tumour from growing and spreading.

Men Have Overly Optimistic Expectations About Recovery from Prostate Cancer Surgery

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Nearly half of men undergoing surgery for prostate cancer expect better recovery from the side effects of the surgery than they actually attain one year after the operation, a University of Michigan Comprehensive Cancer Center study finds.
In addition, prior to surgery, a small proportion of men had expected to have better urinary continence and sexual functions a year after the surgery than they had before it – the exact opposite of what typically happens.

“This is a belief that does not reflect preoperative counseling which, on the contrary, alerts men to urinary and sexual problems after surgery,” says study author Daniela Wittmann, M.S.W, sexual health coordinator at the U-M prostate cancer survivorship program.

The study, published in the August issue of the Journal of Urology, surveyed 152 men undergoing radical prostatectomy, an operation to remove the prostate. All of the men filled out questionnaires before surgery, after receiving preoperative counseling. The questions asked the men about their expectations of urinary, bowel, hormonal and sexual function a year after the surgery.

The study showed that for the most part, men’s expectations of hormonal and bowel function matched what happened one year after surgery. But, when it came to urinary incontinence only 36 percent of the men’s expectations corresponded to what happened one year post-surgery.

In addition, only 40 percent of men found what they expected for sexual function to be true one year post-surgery.

Also, 46 percent of the men found worse than expected outcomes in urinary incontinence and 44 percent of men found worse than expected outcomes in sexual function one year after surgery.

"When we provide preoperative education, we can only inform men in terms of overall statistics. We can't predict for the individual,” explains Wittmann. “This may mean that, if in doubt, people tend toward being hopeful and optimistic, perhaps overly optimistic.”

The researchers suggest that it is important to provide men with tools for urinary and sexual recovery after surgery and with support that will lead to the best possible outcome.

Patients who undergo surgery for prostate cancer at U-M participate in the prostate cancer survivorship program. The program includes partners as well. It is designed to provide men with excellent surgical care along with tailored, couples-oriented support both before and after surgery to help ease recovery from the side-effects of surgery.
“Although preoperative education is very important and should be explicit about the general expectations regarding outcomes, we also need to help men and their partners with the recovery process after surgery in order to help them regain their intimate lives,” says Wittmann.

Improved radical surgery techniques provide positive outcomes for bladder cancer patients

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Bladder cancer patients who have radical surgery at university hospitals can benefit from excellent local control of the disease, acceptable clinical outcomes and low death rates, according to research in the August issue of the urology journal BJUI.

Researchers studied 2,287 patients who had radical cystectomy surgery, where the bladder is removed, together with nearby tissue and organs as required. The surgery was performed at eight Canadian academic centres between 1998 and 2008.

The study found that there were three independent factors, apart from pathological stage at surgery, that influenced survival rates. Patients who smoked had lower survival rates, while patients who had pelvic lymphadenectomy - lymph nodes removed from the pelvic area - had higher survival rates, as did patients who received adjuvant chemotherapy, which aims to destroy microscopic cancer cells left after surgery.

However, the researchers found that neoadjuvant chemotherapy - which is often recommended prior to surgery to improve outcomes - tends to be under utilised for bladder cancer in Canada.

"Recent advances in combined radiation with chemotherapy have challenged the role of radical cystectomy (RC) with pelvic lymphadenectomy, which is used to treat muscle invasive and refractory non-muscle invasive bladder cancer" says co-author Dr Wassim Kassouf, from McGill University Health Centre, Quebec, Canada.

"These bladder-preservation strategies are potentially attractive in terms of health-related quality of life and cancer outcomes, but they only tend to work in highly selected patients.

"Advances in RC surgery have improved surgical care and techniques and reduced complications and mortality rates. The aim of our study was to evaluate a contemporary series of patients with bladder cancer to assess the clinical outcomes and identify any variables that affected their long-term health."

Key findings of the study included:

- 79% of the patients were male, the median age was 68 and the average follow-up of live patients was just over 29 months. 66% reported a family history of tobacco smoking.
- More than three-quarters of the patients had high-grade tumours. Pathological specimen examination revealed no evidence of cancer in 7% of patients, muscle invasive disease in 73% and positive nodal involvement in 25%.
- Adjuvant chemotherapy was offered to 19% of patients and neoadjuvant chemotherapy to just over 3%.
- All patients had previously undergone transurethral resection of bladder tumours and the median time from this to RC surgery was 49 days. This is similar to waiting times reported in international studies conducted in Sweden (49 days), the USA (42 days) and Germany (54 days).
- The 30, 60 and 90-day death rates were 1.3%, 2.6% and 3.2% respectively. Cancer returned in 33% of patients within a median of 10 months. Local recurrence rates were 6% in the overall group and 4% in the organ-confirmed node-negative group.
- The five-year overall, recurrence-free and cancer-specific survival rates were 57%, 48% and 67% respectively.

Multivariate analysis showed that lower pathological stage, negative surgical margins, receipt of adjuvant chemotherapy, performance of pelvic lymphadenectomy and an absence of smoking were associated with prolonged disease-specific and overall survival.

"Our study shows that very good results can be achieved when RC is performed at academic centres within a universal healthcare system and that it remains an effective clinical option for treating patients with bladder cancer" says Dr Kassouf.

Hormone therapy may be hazardous for men with heart conditions

Adding hormone therapy to radiation therapy has been proven in randomized clinical trials to improve overall survival for men with intermediate- and high-risk prostate cancer. However, adding hormone therapy may reduce overall survival in men with pre-existing heart conditions, even if they have high-risk prostate cancer according to a new study just published online in advance of print in the International Journal of Radiation Oncology•Biology•Physics, the official scientific journal of ASTRO.

From 1991 to 2006, 14,594 men with prostate cancer were treated with brachytherapy-based radiation therapy. Of these, 1,378 (9.4 percent) had a history of congestive heart failure or myocardial infarction. Among these men with heart conditions, 22.6 percent received supplemental external beam radiation therapy and 42.9 percent received four months of androgen deprivation therapy to reduce testosterone in their bodies, which can help the cancer grow.

For the entire group of men with a history of heart problems, adding hormone therapy led to a significant increase in overall mortality. For men with pre-existing heart conditions and high-risk prostate cancer, researchers found that by 5 years, 31.8 percent of the men who received hormones had died compared to 19.5 percent of the men who did not receive hormone therapy.

"We found that for men with localized prostate cancer and a history of heart problems, treatment with hormones plus radiation was associated with a higher all-cause mortality than treatment with radiation alone, even for patients with high-risk malignant disease," Paul L. Nguyen, M.D., lead author of the study and a radiation oncologist at the Dana-Farber/Brigham and Women's Cancer Center in Boston, said. "Despite Phase III data supporting hormone therapy use for men with high-risk disease, the subgroup of men with a history of heart disease may be harmed by hormone therapy."

He added, "Future research is necessary to understand the mechanisms of this effect. In the meantime, I encourage men with prostate cancer and a history of heart disease to talk to their doctor about the benefits and risks of hormone therapy."

Nearly all patients with high-grade bladder cancer do not receive guideline-recommended care

A study at UCLA's Jonsson Comprehensive Cancer Center found that nearly all patients with high-grade, non-invasive bladder cancer are not receiving the guideline-recommended care that would best protect them from recurrence, a finding that researchers characterized as alarming.

In fact, out of the 4,545 bladder cancer patients included in the study, only one received the comprehensive care recommended by the American Urology Association and the National Comprehensive Cancer Network.

Receiving the recommended comprehensive care for high-grade bladder cancer is critical because it can significantly minimize the likelihood that patients will die from their cancer, said Dr. Karim Chamie, a postdoctoral fellow in urologic oncology and health services research and lead author of the study.

"We were surprised by the findings in this study, particularly in an era when many suggest that doctors over-treat patients and do too much in the name of practicing defensive medicine," Chamie said. "This study suggests quite the contrary, that we don't do enough for patients with bladder cancer. If this was a report card on bladder cancer care in America, I'd say we're earning a failing grade."

The study is published July 11, 2011 in the early online edition of CANCER, a peer-reviewed journal of the American Cancer Society.

The study then investigated the cause of poor compliance. What they found was that non-compliance knew no boundaries and that patient-level factors such as age, race, ethnicity or socioeconomic status had very little impact. Instead, non-compliance with guideline-recommended care was primarily attributed to urologists. The patients in the study were elderly, but capable of withstanding these simple measures.

"It wasn't their age, race, ZIP code or how wealthy they were. It all came down to who their doctor was," Chamie said

Dr. Mark S. Litwin, professor of urology and public health and senior author of the study, said it's not clear why physicians are not routinely following established guidelines for care.

"It is puzzling, because strong evidence supports those guidelines," Litwin said. "But this is a wake-up call to all physicians caring for patients with bladder cancer. We know definitively what constitutes high-quality care. Now we just need to make sure it happens."

Patients with primary high-grade bladder cancer, which has not yet invaded the muscle of the bladder, have a 50 to 70 percent chance of their cancer coming back in the bladder following treatment. They also have a 30 to 50 percent chance of the cancer becoming more aggressive and invading into the muscle, where it is much harder to treat. Once the cancer invades the muscle, the bladder and surrounding organs must be removed and both the quality and the quantity of the patient's life are significantly impacted, Chamie said.

Chamie said that, at diagnosis, about 75 percent of bladder patients have disease that has not invaded the muscle. So treating those patients with the guideline-recommended care to help minimize recurrences and prevent invasion of the tumor into the muscle could help a large number of patients.

The recommended medical guidelines call for injecting a cancer-killing drug directly into the bladder to minimize recurrence and progression. They also recommend an intense follow-up schedule, including the repeated use of a scope to evaluate the bladder from the inside, a procedure called cystoscopy, and a urine test that is similar to a pap smear every three months to check for abnormal cells.

Only one patient in the study, which analyzed date from Surveillance, Epidemiology and End Results (SEER)-Medicare linked database, was given the recommended care. The study also found that nearly half of urologists treating these patients had not performed at least one cystoscopy, one urine test, and one infusion of the cancer-killing drug into the bladder.

To rectify the situation, Chamie and Litwin suggest a quality-improvement initiative and or changes to physician reimbursements. To complicate matters, despite the poor compliance rate, bladder cancer is the most expensive malignancy to treat on a per-patient level. While improving compliance with changes to physician reimbursement or a quality improvement initiative will increase healthcare costs in the short term, preventing recurrences or progression of the cancer likely will cut costs in the long term.

"We have to improve compliance and there are two ways to do that: Modify our reimbursement schedules to provide incentives to doctors to follow the guidelines, or go out and interact and educate the community urologists - who are delivering the vast majority of bladder cancer care - on the importance of providing compliant care," Chamie said. "Unlike some patients diagnosed with bladder cancer after having it spread to other sites when it's too late to treat effectively, or those with low-grade tumors that are not likely to ever be aggressive, this is a potentially curable cohort of patients. If we don't do a good enough job treating these cancers, we're going to lose these patients."

MAKE BLADDER CANCER CELLS MORE SUSCEPTIBLE TO CHEMOTHERAPY

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Improving efficacy of drugs would boost post-surgery survivorship


Researchers at the UC Davis Cancer Center have discovered a way of sensitizing muscle-invasive bladder cancer cells so that they succumb to the toxic effects of chemotherapy. The finding adds to mounting evidence that tiny strands of RNA — called microRNA — play key roles in some of the deadliest types of cancer.
In the current study, published online June 28 in International Journal of Cancer, researchers boosted the production of a microRNA found in bladder cancer cell lines — encoded for by the gene miR-34a — and found that this resulted in more of the cells being killed by cisplatin, a chemotherapy drug used to treat many types of cancer.


Ralph deVere White
"When we took the bladder cancer cell lines and activated miR-34a, they were more responsive to chemotherapy," said Ralph deVere White, UC Davis Cancer Center director and professor of urology.

The study establishes, for the first time, a link between sensitivity of bladder cancer cells to chemotherapy and the expression of miR-34a. It suggests that miR-34a may be used as a predictor of response to chemotherapy, as well as a target for new drugs.

Currently, about 50 percent of patients with advanced bladder cancer will survive five years after diagnosis. Although clinical trials have demonstrated that chemotherapy before surgery can improve survival rates, it is rarely used because fewer than 50 percent of patients will respond favorably. Without knowing which patients will improve as a result of chemotherapy, physicians are generally reluctant to use a treatment that can cause their patients to suffer significant side effects.

"So, now we have to prove that it works to predict chemotherapy response in patients," deVere White said. To that end, UC Davis has entered into a partnership with Israel-based Rosetta Genomics to develop a microRNA profile for muscle-invasive bladder cancer that may be used to predict response to chemotherapy.

As part of the current study, deVere White and his colleagues studied 27 patients and found that many who expressed lower levels of miR-34a subsequently did not respond to the combined chemotherapy-surgery treatment. Because the finding was not statistically significant, however, further work in this area is needed.

The team also studied tumor samples taken from eight of the patients who did not respond to chemotherapy. They compared the expression of miR-34a before and after chemotherapy.

"We wanted to see, if you looked at the patient's tissue before chemotherapy, were there differentially expressed microRNAs in the patients who responded to the drugs versus those that didn't respond," deVere White explained.

The team found that expression of miR-34a increased after treatment in only two of the eight cases, suggesting that gene expression levels remained low during treatment and confirming the link between low gene expression and failure to respond to treatment.

"The combined data indicate that the elevation of miR-34a expression levels prior to chemotherapy would be of benefit to muscle-invasive bladder cancer patients, particularly in a setting of low mi-R-34a expression," the authors write.

Since their discovery in 1993, microRNAs have been found to be involved in a number of types of cancer, heart disease and diseases of the nervous system. In 2007, deVere White was part of a team that identified miR-125b, a gene that encodes for a microRNA that jump starts prostate cancer cell growth midway through the disease process, eventually causing it to become fatal.

The microRNA studied here was also recently found to play a role in medulloblastoma, an aggressive type of brain cancer. MicroRNAs, which are usually 22 to 33 nucleotides in length, are known as post-transcriptional regulators. That means they work by turning genes on or off during the part of the protein synthesis process that involves making a strand of RNA from a DNA template. The human genome encodes for an estimated 1,000 microRNAs.

According to the authors, future studies involving miR-34a will focus on testing its ability to increase sensitivity to chemotherapy and analysis of miR-34a expression in patients with muscle-invasive bladder cancer. With the currently low chemotherapy success rate and poor five-year survival rate for patients with this disease, "such studies are clearly warranted," the authors write.

"If we can prove what is causing chemotherapy resistance in patients with muscle-invasive bladder cancer, American ingenuity will come up with ways to overcome it," predicted deVere White.