AUA 2011

Adoptive immunity may be the next major step forward in cancer treatment. Phase II trials at the National Cancer Institute have shown significant success in mediating the regression of established metastatic cancers, while plans for a phase III trial are currently under review at the Food and Drug Administration.

“We have seen dramatic regressions in patients with melanoma,” said Steven Rosenberg, M.D., Ph.D., Chief of the Surgery Branch at the National Cancer Institute in Bethesda, Maryland. “We’ve seen regressions in patients with sarcomas and lymphomas as well. We are looking at applications of adoptive T cell immunotherapy to the treatment of prostate cancer and kidney cancer. It’s a new way to treat cancer.”

Dr. Rosenberg will discuss the latest developments in adoptive T cell immunotherapy during the annual John K. Lattimer Lecture that concludes today’s opening Plenary Session. Dr. Rosenberg will present his lecture, New Approaches to Cancer Immunotherapy, from 11:40 a.m. – 12:00 p.m. in Hall D of the Walter E. Washington Convention Center.

Researchers are pursuing two approaches to adoptive immunotherapy, Dr. Rosenberg explained. One track uses autologous tumor infiltrating lymphocytes (TILs) that have been selected for antitumor activity. Selected TILs are cultured, expanded and infused back into the patient for treatment. Autologous transfusions are useful primarily in melanomas, the only histological tumor type that readily gives rise to TILs that have demonstrable antitumor activity.

Pilot trials showed objective response rates of 49 percent to 72 percent, Dr. Rosenberg reported. More than a fifth of patients, 22 percent, had complete regression of widespread cancer for up to 82 months.

The second track is an autologous T cell transfer technology that is commonly described as gene therapy. Genes encoding cytokines or antitumor T cell receptors (TCRs) are transduced into normal peripheral lymphocytes. The genetically engineered lymphocytes are cultured and transfused into the patient for treatment.

Antitumor TCRs that recognize the MART-1 and gp100 melanoma/melanocyte antigens, the NY-ESO-1 cancer-testis antigen and the carcinoembryonic antigen have all been identified. Researchers have also used chimeric antibody TCRs against CD19 expressed on B lymphoma cells. Similar cell transfer techniques are being developed to attack prostate and kidney cancers.

Early results are encouraging. A melanoma trial using MART-1 TCR produced an objective response rate of 30 percent. Clinical responses have also been seen in patients with synovial cell sarcoma and melanoma treated with anti-NY-ESO-1 TCR. Patients with B cell lymphoma have shown an objective response to the CD19 chimeric antibody TCR.

“The cellular and molecular mechanisms of precisely how T cells attack and destroy cancers are under active investigation,” Dr. Rosenberg said.

Adoptive immunotherapy is a new area for most clinicians, he noted. The first results from this approach to genetic engineering were published in 2006 from a small trial with just 13 patients. The trial in lymphoma was published in the Journal of Clinical Oncology in November 2010 and the sarcoma trial was published in Blood in March 2011.

“This is all very new,” Dr. Rosenberg said. “It is in aggressive clinical trials but is still highly experimental. It will be at least a couple of years until it moves into more common practice.”

Guidelines for the treatment of children with urinary tract infections and vesicoureteral reflux (VUR) may not be helping urologists when it comes to imaging studies and treatment. That’s because the three organizations that have issued VUR guidelines have looked at the same evidence and come up with different recommendations.

“All three organizations based their guidelines on reviews of the literature. The literature, they all agree is inconclusive, so they have come to different conclusions. Some observers would say they are very different,” said Saul P. Greenfield, M.D., Director of Pediatric Urology at Women’s and Children’s Hospital of Buffalo and Clinical Professor of Urology at the State University of New York at Buffalo School of Medicine & Biomedical Sciences.

Dr. Greenfield will moderate a panel discussion on Conflicting Guidelines for the Treatment of Vesicoureteral Reflux during this morning’s Plenary Session. The panel will meet from 8:45 – 9:10 a.m. in Hall D of the Walter E. Washington Convention Center.

The oldest guidelines were issued in the 1990s by the American Academy of Pediatrics (AAP) and are currently under revision, Dr. Greenfield said. The National Institute for Clinical Excellence (NICE) in the United Kingdom issued its guidelines in 2007 and the AUA issued its own guidelines in 2009.

Each of these groups came at the problem from a slightly different perspective, Dr. Greenfield noted. AAP took a pediatric approach but did include urologists on their guidelines committee. AUA looked at the issue from the urological perspective.

“NICE comes at it from the viewpoint of a group of primary care physicians, urologists and nephrologists,” Dr. Greenfield added. “A big difference is that NICE alone did a cost analysis. Their mandate, if you look at the NICE literature, is to ‘maximize the health gains from limited resources of the National Health Service.’ They are not only interested in outcomes, they are interested in the cost of care.”

That difference in perspective may have influenced the final recommendations, Dr. Greenfield said. The AAP guidelines are in the process of revision but as of this writing, there are similarities between them and the AUA guidelines.

“NICE has recommended a significant departure from current practice in that they suggest much reduced evaluation and imaging of these children,” Dr. Greenfield said. “The Obama Administration has proposed a similar institute, which they call the ‘Comparative Effectiveness Institute.’ The question becomes whose recommendations should you follow? Should the cost to the payer trump the potential benefit to the individual? That’s the quandary here.”

Each of the three panelists participating in today’s discussion will address a different set of guidelines. Julian Hsin-Cheng Wan, M.D., Clinical Associate Professor of Urology at the University of Michigan Health System in Ann Arbor, will discuss AAP’s approach and the pending update. Steven Skoog, M.D., FAAP, Professor of Urology and Director of Pediatric Urologic Surgery at Doembecher Children’s Hospital at Oregon Health & Science University in Portland, will examine the AUA guidelines. Dr. Greenfield will summarize the NICE approach.

“There is no single correct answer,” he cautioned. “These three sets of recommendations don’t agree. They come at the subject from different angles and specialty groups. At the same time, only one of the three has a stated goal to control costs, and this may have influenced their deliberations.”

The growing sophistication of ultrasonography has enhanced the potential for successful fetal interventions in select congenital urological anomalies. It is clear that fetal interventions can be performed successfully, but it is not clear that these interventions yield positive urological outcomes.

“A lot of work and a lot of money have been spent on posterior urethral valves, myelomeningocele and congenital adrenal hyperplasia,” said John W. Brock III, M.D., Director of Pediatric Urology at Monroe Carell Jr. Children’s Hospital, Vanderbilt University, Nashville, Tennessee. “We still don’t have clear answers. The effort is to further define the risk-benefit ratio of the different interventions that are possible.”

Dr. Brock will offer an assessment of fetal interventions for these three conditions during a State-of-the-Art-Lecture from 9:10 – 9:30 a.m. during today’s Plenary Session in Hall D of the Walter E. Washington Convention Center. His lecture is titled Fetal Urologic Intervention Report Card: Valves, Myelomeningocele and Congenital Adrenal Hyperplasia.

The basic problem, Dr. Brock explained, is that while multiple prenatal interventions have been developed and explored, level 1 evidence is sorely lacking. There are a number of nonrandomized retrospective reviews and case series, but little solid data. What data have been collected may, or may not, include urological outcomes.

There are several techniques for decompressing the obstructed fetal bladder, for example, with reported survival rates of 57 percent to 91 percent. But any number of studies show impaired renal function in infants who survive fetal intervention for posterior urethral valves.

“Is it acceptable for us to say that we are improving survivability, yet not improving renal function?” Dr. Brock asked. “In myelomeningocele we have clearly shown a benefit ratio for nonurologic issues such as mental development scores and improved motor function. This is the first fetal intervention for a non-fatal condition with randomized controlled data showing improvement in postnatal status. But we don’t have an answer in terms of long-term urologic care.”

Fetal myelomeningocele closure remains one of the great success stories in prenatal interventions, Dr. Brock continued. Accrual for a National Institutes of Health study comparing fetal and postnatal myelomeningocele closure was halted in December 2010 after an interim analysis showed a highly significant advantage for fetal intervention. But there was no urological outcomes component during the first several years of accrual and no quality urological outcomes data to date. Urological data that are now being collected during patient followup should become available in the future.

Different questions cloud the picture for congenital adrenal hyperplasia. The condition can be treated using dexamethasone to reduce genital virilization. But because treatment must begin well before the need for treatment can be confirmed, 7 of every 8 fetuses treated likely does not need treatment.

“Is it acceptable to say that we may improve the phenotype of the child, knowing that we will treat several children who may not have needed to have been treated?” Dr. Brock asked. “We have been looking at the fetal aspects of urologic care for many years. This report card is intended to let us know how we have actually done along the way and what our realistic expectations for the future might be.”

The World Health Organization published its latest guidelines for semen analysis in April 2010. The new guidelines are part of the WHO Laboratory Manual for the Examination and Processing of Human Semen, 5th ed., and represent a major change over the prior guidelines published in 1999.

“The previous references were based on a combination of expert opinion and consensus,” explained Stanton C. Honig, M.D., Associate Clinical Professor of Urology at the University of Connecticut Health Center in Farmington. “They were not based on any specific data. The new guidelines are based on semen analysis from multiple countries, multiple continents and multiple studies of fathers who have gotten their partners pregnant within 12 months.”

Dr. Honig will moderate a point-counterpoint presentation on the new guidelines from 10:00 – 10:20 a.m. during this morning’s Plenary Session in Hall D of the Walter E. Washington Convention Center. The session is titled Semen Analysis – Is There a Definable Normal Range?

Mark Sigman, M.D., Chief of Urology at Rhode Island Hospital and The Miriam Hospital, and also Chief of Urology at the Warren Alpert Medical School of Brown University in Providence, Rhode Island, will discuss the importance of numbers as well as the limitations inherent in the new guidelines.

Dr. Honig noted that the new guidelines offer evidence-based reference ranges and reference limits for the fertile population, but are tricky to interpret for those who are infertile. There are no absolute values when it comes to semen analysis and pregnancy, and the new ranges can easily be misinterpreted if the basis of how they were reached is not fully understood.

“These guidelines have defined the broad parameters of the men who did get their partners pregnant,” Dr. Honig said. “There is a lot of overlap between couples who are fertile and couples who are infertile. You could have someone with low sperm numbers who got their partner pregnant at 12 months and you could have someone else who has high sperm numbers but didn’t get his partner pregnant until the 13th month.”

One of the major improvements the guidelines make has to do with breaking semen parameters into percentiles. However, it’s easy to misinterpret percentiles for absolute cutoff values, Dr. Honig noted, which is not an appropriate use of individual patient data or the guidelines.

“The guidelines are saying that 95 percent of the people who got pregnant were above that particular value, i.e. 15 million sperm/cc and 32 percent motility,” Dr. Honig explained. “It’s not a cutoff value, but it gives you a sense of what the numbers mean on a broad basis.”

Dolores Lamb, Ph.D., Professor of Urology, and Molecular and Cellular Biology, and Director of the Laboratory for Male Reproductive Research and Testing at Baylor College of Medicine in Houston, Texas, will address a second key issue: semen numbers are a beginning, not a final conclusion. While an individual’s semen count matters, there are multiple factors that can affect a successful pregnancy. Health matters, sperm motility matters and the volume of ejaculate matters. There are other situations when the quality of the sperm can be more important than the quantity of sperm.

“We will also be talking about function tests of the sperm, looking at things like reactive oxygen species and DNA fragmentation and application of clinical proteomics, the protein evaluation of the sperm,” Dr. Honig said.

Changes are under way at the American Board of Urology (ABU), one of which is a survey of urologists and urology patients to examine attitudes and beliefs about the Board. The Board is also preparing the profession for a transformation that will affect all physicians. Maintenance of certification (MOC) is on track to become a key element when the state boards institute maintenance of licensure (MOL).

“MOC will roll into maintenance of licensure,” said Timothy B. Boone, M.D., Ph.D., President of the American Board of Urology. “The two will become synonymous with what it means to keep up with current medical education. It is more than simply CME. It will require peer review, log reviews and examinations. MOC or general medical testing and CME will be required to maintain your state license to practice medicine.”

Dr. Boone will detail the future of MOC and other ABU developments this morning at the opening session of the 2011 AUA Plenary Program. His American Board of Urology Update will be presented from 7:55 – 8:05 a.m. in Hall D of the Walter E. Washington Convention Center.

“We are not picking on diplomats with these changes,” said Dr. Boone, who is Chair of Urology at The Methodist Hospital, Houston, and Professor of Urology at Weil Cornell Medical College of Cornell University, New York. “Most of this is being mandated by the American Board of Medical Specialties. There is a lot of misinformation out there that we would like to address.”

MOC continues on the familiar 10-year schedule with four levels of requirements to be met every two years. MOC does not mean that urologists are expected to know more, but they are expected to demonstrate their current knowledge and proficiency by meeting prespecified benchmarks. The vast majority of practicing urologists in the United States are Board Certified, Dr. Boone noted. And approximately 10 percent of the roughly 10,000 Board Certified urologists in the U.S. have lifetime certificates. Most of these older practitioners are expected to retire within the next five years.

“If you want to know what MOC means in practice, I have a helpful diagram that shows all four levels, what each level requires and in which year of certification it is triggered,” Dr. Boone said.

MOC becomes increasingly important as state medical boards move toward incorporating MOC in medical license renewal. This change comes in response to regulatory pressure from the federal government and the public demanding improvement in the quality of medical care provided in the U.S.

Dr. Boone indicated that there is no firm timetable, but the national federation of state medical licensing authorities has clearly indicated that license renewal will become maintenance of licensure. They expect MOL to be contingent on demonstrating current competency and proficiency as evidenced by MOC.

“The point is that the traditional idea of taking a test when you graduate from residency and you’re qualified for life doesn’t fly today,” he said. “The public is just not accepting it. All physicians, including urologists, are under constant scrutiny for continuing medical education and quality patient care. This is another example of how the Board is working to get ahead of the storm and what may come with maintenance of licensure. This is years down the road — we think. It could come sooner.”

“Urologists who are not Board Certified can expect increasing difficulties in obtaining hospital privileges and other necessities of professional life,” Dr. Boone added.

“I think members will be surprised with much of my presentation,” he said. “Most are not involved at the Board level to see the pressures we face to demonstrate to the public our quality of training and competency to practice. Both have been very lackadaisical for years, but those days are gone. It’s a different ballgame, not only in maintaining certification but in education. This should be on everyone’s radar.”