Three years ago, I was approached by the folks at 

 to gauge my interest in a publication that catered to the independent urology community, specifically those practitioners and groups that were actively managing genitourinary malignancies. The company’s sales force recognized that a plethora of new therapies had been approved in the area of metastatic castration-resistant prostate cancer (mCRPC), with more in many phases of clinical trial. The pharmaceutical companies involved in the development of these new agents provided a target-rich environment for potential sponsors and educational offerings. The challenge was how to engage and involve urologists in an area where historically very few had interest or experience. Everyone needs a good challenge now and then, right?

Today, as we start our fourth year of this publication, I believe we are making progress with that educational hurdle. Many groups are taking the initiative to start their own advanced prostate/therapeutic centers, folding in all the disciplines needed to manage these difficult patients. The American Urological Association has embraced the importance of our involvement. They are supporting postgraduate courses at the annual meeting, as well as throughout the year, to help urologists establish advanced therapeutic centers of excellence. There are more and more physicians in communities across the United States who have a better grasp and understanding of the agents approved and are now willing to take on the management of this challenging population. Nurse champions/navigators are in place to hopefully identify these potential patients in order to institute therapies when appropriate and avoid delay before the patients are symptomatic—our classic downfall in the past. The goal should always be better patient care, and more important, maintaining quality of life in the process. Remember (to steal a line from Eric Klein): Don’t confuse the ability to treat with patient benefit!

Yes, we are making strides in managing the mCRPC patient so that global adoption among independent urology groups takes place. The importance of this adoption needs to be viewed in the context of the role of the urologist in prostate cancer in general. As we continue to move down the road of payment reform, it is incumbent upon us to be the lead physicians in diagnosis and management of the disease, both localized and advanced.

		Move beyond PSA to determine who needs a first biopsy.

		Develop better technology when prostate biopsy is indicated.

		Adopt better risk stratification tools for optimal patient management.

		Be more cognizant of the nuances of disease progression once androgen deprivation therapy is instituted and identify the at-risk patient who will benefit from earlier treatment.

		Have a working knowledge of all the therapies available for the correctly-indexed patient whose disease is metastatic.

		Be willing and prepared to deal with potentially non- urologic issues (pain, end-of-life care) that traditionally has not always been within our domain or our comfort zone of practice

Our willingness to address all these issues and lead the efforts to find the solutions will serve our specialty well. It is still unclear to many if the Accountable Care Organization (ACO) model will be the ultimate winner in the primary care market. Regardless, management of elevated PSAs (or the next testing equivalent) and prostate cancer should default to the urology world, just like always. I hope to see that trend continue.

Articles

Management of elevated PSAs, or the next testing equivalent, and prostate cancer should default to the urology world, just like always. 

The Challenge: Involving Urologists in Cancer Care

It seems like the feature stories and meetings coverage this month singularly revolve around prostate cancer. That’s not by accident—prostate cancer is garnering interest in a lot more areas than just clinical studies.

In our feature story, “BMS, Bavarian Nordic Forge $1 Billion Prostvac Deal,” Associate Editor Tony Hagen covers the manufacturing and distribution arrangement between Bristol-Myers Squibb and Bavarian Nordic for the immunotherapy Prostvac. Prostvac is a pox viral vaccine expressing prostate-specific antigen. The agent has shown efficacy as both a monotherapy and in combination with other therapies.

Under terms of the deal, Bavarian Nordic will receive an initial payment of $60 million and the potential for up to $975 million in milestone and upfront payments. BMS receives exclusive rights to license and commercialize the immunotherapy, which is in phase III development for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).

In a slightly more personal take, we profile the persistence and tenacity of Thomas Neville, PhD, an analyst formerly with the US Department of Energy. After a positive prostate cancer diagnosis in 2002, Neville embarked on a journey to understand the results of his biopsy and to determine the best course of action. Initially, he discovered great variability associated with treatment—some evidence supported radical prostatectomy, some supported radiation, and some supported active surveillance.

Trying to make sense of the treatment possibilities led him to propose the idea of “smart screening,” that is, using dynamic analysis of PSA results to make an informed decision, which could be adopted by other patients. Instead of relying on a single PSA test to make a decision on the course of treatment, Neville proposed combining PSA analysis patterns culled from Veterans Affairs data sets with many other factors, such as age, race, family history, digital rectal exam result, and prostate volume. His exercise in data analysis gives a fuller, comprehensive picture about prostate cancer that can lead to decreased morbidity, reduced biopsies, and savings in healthcare costs.

Meetings coverage in this issue focuses on the 2015 Genitourinary Cancers Symposium and the 8th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies. The GU conference resulted in more than 640 abstracts submitted by researchers worldwide and focused on the theme, “Integrating Biology Into Patient-Centric Care.” The data that caused the largest stir at the meeting were results from the phase III ASSURE trial, the first study to evaluate the efficacy of multi-targeted VEGF inhibitors in the adjuvant setting for patients with locally advanced renal cell carcinoma (RCC) at high risk of recurrence.

Standard therapy in patients with resected nonmetastatic disease is close observation, with scans performed at regular intervals. The ASSURE trial was carried out to determine if either of these VEGF inhibitors could provide benefit for patients with resected primary disease in the adjuvant setting. Patients were randomized in a 1:1:1 ratio to receive one of the two VEGF inhibitors or placebo for one year.

The results demonstrated that neither sorafenib nor sunitinib offered benefits above and beyond those of placebo in the adjuvant setting. Overall survival was shown to be similar among all 3 arms, reported Naomi B. Haas, MD, associate professor, Abramson Cancer Center of the University of Pennsylvania.

At the IPCC conference, Leonard Gomella, MD, kicked off the meeting by elucidating the PSA screening debate, boiling down the decision whether to screen to “using common sense, shared decision making, and choosing the right patients to screen.” Comprehensive presentations of the latest studies involving immunotherapies in bladder and renal cancer kept oncologists, urologists, and other clinicians up-to-date on this emerging treatment regimen.

It seems like the feature stories and meetings coverage this month singularly revolve around prostate cancer.

Prostate Cancer Coverage Extends Beyond Clinical Studies

The data took years to acquire and months to prepare, and the actual analysis took weeks and sometimes months for the largest datasets. The progression of PSA levels correlated so strongly with the danger from prostate cancer that it virtually jumped off the screen.

Now, a new phase begins for Thomas Neville, PhD, a Yale and Stanford-trained engineer and economist who worked in energy and helped build an international industrial combustion engineering company before a prostate cancer diagnosis drew him into medical research.

“When I first got involved with prostate cancer research, the results were so strong that I assumed they would have an immediate impact on screening practices,” Neville said. “I was naïvely optimistic, but that’s probably a good thing because it kept me going.”

Neville started down his current path in 2002, when his doctor called to say that a prostate biopsy had tested positive for cancer.

His doctor suggested several options, but Neville lacked the expertise to compare them, so he did what any well-educated individual would do: He reviewed the existing research.

Neville’s initial investigation provided far less certainty than he’d expected. Some evidence supported radical prostatectomy. Some supported radiation. Some supported active surveillance. Different experts further muddied the water with conflicting recommendations.

Still, Neville collected all the evidence he found and synthesized it as best he could, noting areas of consensus and evaluating the relative strengths of conflicting studies. He posted his findings online, updating his material as he went along. His latest material on prostate cancer can be found at ProstateSmart.info.

By the time Neville chose to undergo a radical prostatectomy, his work had reached a surprising number of grateful readers, readers who inspired Neville to supplement the treatment information with similar information about screening. Eventually, the lack of persuasive answers to relatively basic questions about screening inspired Neville to undertake new research.

With his wife Kelly, he also decided to turn his avocation into a business, and they founded a start-up company called Soar BioDynamics, Inc., near their home in North Lake Tahoe.

The observation that cancer tends to increase production of a protein called prostate-specific antigen (PSA) has made blood tests the primary way of finding the disease in asymptomatic men for the past 20 years. Indeed, during much of that time, many medical organizations recommended yearly PSA tests for men, starting at age 50.

Normal PSA levels vary considerably among men, but doctors have traditionally regarded PSA levels above 4.0 ng/mL with enough suspicion to consider performing a biopsy and making a definitive diagnosis.

Recent research, however, has challenged this reliance on PSA testing in a number of different ways. Studies have demonstrated that some prostate cancer victims have PSA levels below 4.0 ng/mL, while many cancer-free men have much higher concentrations of PSA in their blood. Other studies have found that early prostate cancer detection often does more harm than good. Men frequently overreact and choose to fight indolent tumors with treatments that can potentially result in serious side effects such as impotence and incontinence.

Such findings have led some experts to recommend against widespread yearly PSA testing, but it led Neville (and others) to ask a question: If doctors used data from many years’ of PSA tests rather than considering one test in isolation, could they detect cancer more reliably and gain some insight into its likely speed of progression?

Neville realized that he’d be regarded as a crazy dilettante unless he could attract some established collaborators, so he reached out to many of the experts who were doing related research.

“I was extremely fortunate to have had superb physicians care for me during my time as a patient, and we have stayed in touch. They are also top researchers. Peter Carroll is now associate dean of the School of Medicine and chief of Urology at UCSF, and Eric Klein is now chairman of the Glickman Urological and Kidney Institute at Cleveland Clinic,” Neville said. “But a lot of it is just knocking on doors and saying, ‘Hi. I’m Tom Neville.’ Sometimes folks slam the door in my face, but sometimes they let me in and I end up with a new resource.”

Few people take on a new field as complicated as medical research after they become eligible for AARP membership, but Neville has demonstrated a wide range of talents over the course his life.

During his time at Yale University, Neville performed well enough as captain on the football field to be drafted by the Baltimore Colts and well enough in the classroom to graduate first in his Engineering and Applied Science class and be selected as a Rhodes Scholar. He chose Oxford over Baltimore and, in addition to earning a degree in economics and politics, learned rugby quickly enough to make the university’s top squad within months of his arrival, playing twice in the annual Oxford-Cambridge match.

Neville returned to the US in 1973 to attend Stanford University just as the first oil embargo was getting underway, and it attracted his interest. While at Stanford, he landed a summer job as an energy policy analyst at a precursor to the US Department of Energy, where he later worked as a policy office director upon the department’s creation in 1979. At Stanford, he worked on energy policy, studied with pioneers of Bayesian decision-making under uncertainty, and earned a PhD in economics and finance, awarded in 1979.

Over the next three decades, Neville’s career took him around the energy sector and then into industrial combustion engineering. By the time he received his prostate cancer diagnosis, he was the chief technology officer and co-owner of North American Manufacturing Co., a privately held firm that sold ultra-low-emission combustion systems to customers in heavy industry around the world.

Neville and his partners sold their firm to the Fives Group in 2008, and he began working full-time to further the ongoing revolution in prostate cancer care.

That revolution has seen prostate cancer mortality fall more than 40% in the past 25 years. The American Cancer Society says the 5-year survival rate is now close to 100%, and the 15-year survival rate is 94%.

Those numbers reflect a long series of innovations: breakthroughs such as nerve-sparing radical prostatectomy, high-â€¨energy radiation treatment and, perhaps, the PSA test.

There is, however, plenty of room for further improvement. Prostate cancer still kills nearly 30,000 American men each year.

Neville’s initial question about the potential value of dynamic analysis of multiple PSA tests arose from pioneering work done by Ballentine Carter, MD, professor of Urologic Oncology at Johns Hopkins University and now director of the Division of Adult Urology, and Chris Morrell, PhD, professor of Statistics at Loyola University in Maryland.

Carter spent nearly 2 decades investigating possible strategies for extracting valuable data from changes in PSA levels, including initial work with records from the Baltimore Longitudinal Study of Aging. But Neville figured that additional analy-â€¨tical techniques, like those employed by Morrell to find hidden relationships in many different fields, might work to extract value from a man’s PSA values over time.

Many research projects by Neville and colleagues showed significant correlations between PSA progression and patient health. For example, Neville worked with a team from the University of Innsbruck to follow 817 Austrian men with elevated PSA levels and at least 5 PSA test results in a 4-year period. Analysis of subsequent biopsies and prostatectomies showed that a man whose cancer PSA increased 50% per year had a 35% chance of having an aggressive tumor, while a man whose PSA increased 5% per year had a 12% chance of having an aggressive tumor.

Neville’s Innsbruck colleagues presented the study at the American Urology Association’s annual meeting in 2010. But he sensed that the analysis would be far more compelling if it could be substantiated on a very large data set.

Neville, therefore, set his sights on a data pool that would satisfy even the most skeptical reviewer, the one maintained by the US Department of Veterans Affairs with 33 million PSA test values for 14 million men.

“I knew the VA shared its data with medical researchers because I’d seen a lot of studies that used it, so I figured it would be pretty easy for us to get access,” Neville said. “It ended up taking 4 years, which I thought was an eternity, but researchers have come up to me since then and asked how we moved so fast.”

Even once the data was obtained, work proceeded slowly at first, because the sheer amount of data the VA maintains on each veteran’s medical records made it important to systematically separate relevant material from the rest and get it into properly structured fields.

Neville describes some of the project’s fundamental insights:

When doctors have access to several years of PSA values for each man, the VA data indicate that sophisticated analysis of PSA growth above a no-cancer baseline provides better predictive power about the presence of cancer and the aggressiveness of that cancer than any single PSA test can provide. The time patterns are valuable in helping to determine both the probability of finding cancer and the deadliness of that cancer. Neville commented, “If you take these powerful dynamic screening results and add to them some of the other valuable tools that are available, there should be way of devising a system of “smart screening” that can bring enormous value to clinical decision-making.”

When screening analysis considers both dynamic analysis of PSA patterns and many other factors, such as age, race, family history, digital rectal exam result and prostate volume, the VA data suggests that screening can become much more effective than relying on a single PSA test. Indeed, Neville and his colleagues estimate that, if such “smart screening” became the norm, it could reduce prostate cancer deaths by 40% while also reducing biopsies by 65% and treatment by 50% while saving $5 billion per year in US medical costs.

He goes on to explain that so many good outcomes are possible because of the divergence in screening in the US — some men are not screened or they are under-screened, and other men are over-screened. The VA results suggest that many prostate cancer deaths are associated with men who were not screened or screened inadequately and diagnosed at high PSA levels, and many biopsies and subsequent diagnoses and treatment are associated with different men who were biopsied prematurely at low risk.

Neville and his urologist colleagues presented three posters at the most recent AUA meeting along with a press briefing and will present additional confirmatory findings on another significant data set at the upcoming AUA meeting in May. He and his colleagues are preparing journal articles on a range of new findings.

He hopes that the work on dynamic screening and “smart screening” will lead to a revolution in screening practices. But, as he says, “I’ve learned that changes in clinical practice don’t happen quickly or easily, so it’s important to stay at it, one step at a time — especially when what’s at stake is the chance to improve the health and well-being of 100 million men around the world. For now, that’s enough to keep me going.”

A new phase begins for Thomas Neville, PhD, a Yale and Stanford-trained engineer and economist who worked in energy before a prostate cancer diagnosis drew him into medical research.


Thomas Neville's Dynamic Analysis of Multiple PSA Results Leads to Better Reliability, Insights

Older, single white males with advanced bladder cancer have the highest suicide risk among those with other cancers of the male genitals and urinary system, researchers report. When compared with the general population, overall suicide risk was 2.7 times higher for bladder cancer patients, rates were 1.86 times higher in kidney cancer patients, 1.27 times higher in prostate cancer, 1.23 times higher in testicular cancer, and 0.96 times higher in penile cancers.

“The older, white, single male is already at higher risk in the general society for suicide; add on the fact that he has advanced bladder cancer, and this is a high-risk patient,” said Zachary Klaassen, MD, a urology resident at the Medical College of Georgia at Georgia Regents University, the study’s corresponding author. “But this has taught me that we have to look for warning signs in all these patients.”

Researchers reviewed the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program, or SEER, database from 1988-2010 to find 1.2 million people with genitourinary cancer, examining variables such as age, sex, race, as well as disease and treatment aggressiveness.

They found that bladder cancer patients across the board, whether or not they had surgery or advanced disease, had a higher suicide risk than patients with other genitourinary cancers. Older patients with bladder, prostate, and testis cancer were generally at an increased risk. When looking specifically at the black population, those with bladder cancer also had the highest suicide rates; however, those with bladder, prostate, and kidney cancer had much lower suicide rates than whites in the group. Prostate cancer patients had an increased suicide risk over time, with the highest rate 15 years or more after their diagnosis.

The review identified suicide in these patients as a public health dilemma that needs physician awareness, particularly in patients who are older, male, and have aggressive disease.

“It’s a tough situation. We have to talk more with our patients about how they are feeling even if it’s uncomfortable for us,” said Martha K. Terris, MD, chief of the section of Urology, chief of Urology at the Charlie Norwood Veterans Affairs Medical Center, and the study’s senior author.

The clinicians recognized the challenging road faced by many of these patients during recovery. Those with bladder cancer, for example, often have surgery to both remove their diseased bladder and divert urine to a collection bag at their side. Recovery from this major procedure takes about 3 months; interferes initially with bowel function; can result in ongoing problems such as leakage and infection; and patients need long term, close follow up for signs of metastasis, so it’s also a very expensive cancer to treat.

The average age of diagnosis of bladder cancer is 73, and about nine out of 10 patients with bladder cancer are over age 55, according to the American Cancer Society. Bladder cancer is more common in men and smokers, with about 74,000 new cases annually in this country and more than a half million survivors. Suicide is the 10th leading cause of death in the United States; cancer is number two, according to the Centers for Disease Control and Prevention. 

Older, single white males with advanced bladder cancer have the highest suicide risk among those with other cancers of the male genitals and urinary system, researchers report.

Advanced Bladder Cancer Increases Suicide Risk, Study Says

A United States Preventive Services Task Force (USPSTF) recommendation against the use of prostate specific antigen (PSA) testing needs to be updated, said Gary Kirsh, MD, president of the Large Urology Group Practice Association (LUGPA)—a professional association representing more than 20% of the nation’s practicing urologists. The task force gave the screening test a grade of D, meaning that there is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.

“This was a travesty,” said Kirsh, in an interview with 

. “Their interpretation of the literature with regard to PSA testing is hotly disputed by many experts in the field,” he said. “In the era of PSA testing, we have seen a 40% reduction in prostate cancer mortality in the United States.”

Kirsh contends that when the recommendation was first issued in 2011, the task force failed to take into account evolving trends in the thinking of urologists regarding the PSA testing and prostate cancer treatment. In years past, when a patient had an elevated PSA level, it might automatically have resulted in a prostate biopsy. A positive cancer result from a biopsy may have led to immediate surgical or radiation treatment.

“But the practice of medicine has evolved,” Kirsh said. “Now, if a patient has an elevated PSA, we look for a trend, or we can consider other mitigating factors that influence the decision to have a biopsy. If the cancer has a low or very low risk, many patients are going on active surveillance protocols. The recommendation does not recognize the current treatment paradigm. But not performing a PSA could lead to prostate cancer being identified at later, more aggressive, stages.”

Now, legislation proposed by Representatives Marsh Blackburn (R-TN) and Bobby L. Rush (D-IL) has galvanized 3 of the nation’s largest urology associations to support their bill to reform the way the USPSTF reviews and makes recommendations for clinical preventive services to primary care physicians. The USPSTF Transparency and Accountability Act of 2015, HR 1151, would reform the task force by requiring a balanced and relevant representation of medical personnel, requiring members to disclose conflicts of interest, and requiring consultation with those who treat the specific disease in question. The other groups in support of the legislation are the American Association of Clinical Urologists (AACU) and the American Urological Association (AUA).

The failure of the current system is underscored by recent data demonstrating the deleterious impact of the USPSTF recommendation against PSA screening. Researchers found that between 2011 and 2013, in the immediate wake of the USPSTF recommendation, there was a 6% increase in the diagnosis of intermediate or higher risk prostate cancer in men and concluded that many more deaths could result from this disease.

They made no determination whether a decline in PSA screening was the cause.

The recommendation has also affected policy, said Kirsh. “Some commercial payers are denying coverage for PSA testing. It’s going to affect patient outcomes in the long run.”

Other changes proposed in the legislation include publishing a draft research plan to guide the systemic evidence review process; considering findings and research by federal agencies and departments; and making the evidence review available for public comment. Currently, the only research plan that is available for public comment on the USPSTF web site has to do with healthful diet and physical activity for cardiovascular disease prevention.

“I am concerned that decisions are being made without proper input from the specialists who treat these diseases,” representative Blackburn said in a statement. “Our legislation would require common sense coordination among relevant agencies and stakeholders while protecting the doctor-patient relationship.”

“This bill will bring the appropriate specialists and stakeholders to the table, and add clarity to the process of making recommendations on the preventative services that should be available to the American people, said representative Rush.

The task force is made up of 16 volunteer members who are experts in prevention, evidence-based medicine, and primary care. Their fields of practice and expertise include behavioral health, family medicine, geriatrics, internal medicine, pediatrics, obstetrics and gynecology, and nursing. Task force members are appointed by the director of the Agency of Healthcare Research and Quality (AHRQ) to serve 4-year terms.

			Hall MD, Schultheiss TE, Farino G, et al. Increase in higher risk prostate cancer cases following new screening recommendation by the US Preventive Services Task Force (USPSTF). 2015 Genitourinary Cancers Symposium. 

 2015;33 (suppl 7). Abstract number: 143. Available here: http://meetinglibrary.asco.org/content/140836-159.

			US Preventive Services Task Force. Opportunity for comment. Available here: http://www.uspreventiveservicestaskforce.org/Page/Name/us-preventive-services-task-force-opportunities-for-public-comment. Accessed March 10, 2015.

A United States Preventive Services Task Force recommendation against the use of prostate specific antigen testing needs to be updated, said Gary Kirsh, MD, president of the Large Urology Group Practice Association.

April 2015 | Special Issues

The Challenge: Involving Urologists in Cancer Care

Prostate Cancer Coverage Extends Beyond Clinical Studies

Thomas Neville's Dynamic Analysis of Multiple PSA Results Leads to Better Reliability, Insights

Advanced Bladder Cancer Increases Suicide Risk, Study Says

Task Force PSA Recommendation Needs Updating, LUGPA President Says