BBI Contributing Editor

CHICAGO, Illinois The annual gathering of the American Urological Association (AUA; Baltimore, Maryland), held here in late April at the sprawling McCormick Place convention center, embraced several important topics that are significant to urologists and their predominantly male patients.

Benign prostatic hyperplasia, more commonly known by its acronym BPH, is one of the mainstays of urology, accounting for a significant share of office visits, prescriptions written and surgical procedures. From 12 million to 15 million American men suffer from symptomatic BPH, a condition that increases with aging and is characterized by an enlargement of the prostate gland. This results in several annoying lower urinary tract symptoms, including frequent urination, difficulty in voiding and urgency that affect the quality of life by interfering with normal daily activities and sleep patterns.

It is estimated that about 15% to 20% of BPH sufferers seek some kind of treatment in any given year.

The AUA's most recently published BPH clinical practice guidelines recommend watchful waiting as the treatment of choice for mildly symptomatic patients. For patients with moderate-to-severe symptoms, the AUA counsels the use of either medical management, minimally invasive or surgical therapies. Since their introduction nearly a decade ago, drugs have become the first line of defense for most mild-to-moderate BPH cases. About 1.5 million American men are currently being treated with medical management.

Before the availability of pharmaceutical therapies, about 400,000 TURP (transurethral resection of the prostate) surgeries were performed. This procedure, which is invasive and carries risks such as incontinence, has been the gold standard for BPH for several decades. Over the past decade, the popularity of TURP has steadily declined, with an estimated 140,000 to 150,000 performed annually. Medical management and less-invasive surgeries have clearly been gobbling up market share.

The latter category now accounts for about 40,000 to 50,000 procedures annually. This group includes a potpourri of procedures, such as transurethral needle ablation (TUNA), transurethral microwave thermotherapy (TUMT), interstitial laser coagulation (ILC) and high-frequency ultrasound (HIFU). The first two procedures are endorsed by the AUA and are recognized as safe and effective. However, they suffer from shortcomings such as the need for catheterization post-procedure to prevent urinary retention and a several-day delay in symptomatic relief.

In late 2001, Laserscope (San Jose, California) introduced a higher-powered potassium titanyl phosphate (KTP) laser that emits a green light laser. The key to its efficacy in BPH is that its 532 nm wavelength is selectively absorbed by hemoglobin with shallow penetration. Its thermal energy is confined to a small volume of prostatic tissue, which is rapidly vaporized with minimal charring or coagulation. The procedure is called PVP, an acronym for photo-selective vaporization of the prostate.

Prior to this year's AUA meeting, there were several peer-reviewed, favorable reports on the PVP procedure, but these trials were either limited to one site or were not long enough to establish long-term safety and efficacy. However, the 2003 meeting saw the presentation of two significant papers addressing these issues.

The first, "Photoselective Vaporization of the Prostate: Five-Year Experience with High Power KTP Laser," delivered by Reza Malek, MD, professor of urology at the Mayo Clinic (Rochester, Minnesota), concluded that PVP is easy and safe to perform, produces rapid and effective relief from obstructive BPH. Most importantly, the benefits were sustained for five years.

The second study, "Laser Vaporization of the Prostate for the Treatment of Benign Prostatic Hyperplasia: The First Multi-Center Prospective Trial," delivered by Alexis Te, MD, assistant professor of urology at Columbia University (New York), also concluded that PVP is safe, effective and provides rapid symptomatic relief from BPH. This study included procedures performed at six centers and had a 12-month follow-up period.

At the Laserscope exhibit at this year's AUA gathering, several physicians reported on their positive experiences with the system, whose brand name was recently changed to the GreenLight PV.

Typical of the sentiments of these urologists was Jeffrey Lapeyrolerie, MD, of Cleveland Urology Associates (Garfield Heights, Ohio), who has treated 150 patients since early 2002, many referred by friends or via the Internet. He said that he was "extremely skeptical" before using this laser but has become convinced because 95% of his patients are "extremely satisfied." The biggest benefit he sees is a very low rate of post-op bleeding and other complications and that nearly three-quarters of his patients do not require a catheter for post-op voiding. This latter benefit is important to patients who are eager to return to normal activities as quickly as possible.

Dr. Mahmood Hai, MD, from the Oakwood Hospital (Wayne, Michigan), echoed Lapeyrolerie's ebullience, saying that this procedure is a "great advance in BPH therapy." He said he has treated more than 300 patients since he began using the technique and noted that his family life had improved because he no longer receives middle-of-the-night phone calls from patients who could not void their urine. He said that fewer than half his patients require post-procedural catheterization.

A third urologist, Amos Lash, MD, in private practice in Huntington Beach, California, has treated about 40 cases since he began PVP in late 2002 and has nearly eliminated all TURP procedures in favor of this technique. Noting that the physician reimbursement rate is somewhat lower than for other BPH surgeries, he said that patient satisfaction is so high that PVP "will survive on its own merits." Lash has access to the laser from a mobile medical device provider PRI (Glendale, California), whose CEO Lou Buther told The BBI Newsletter that he expects PVP will ultimately become the standard of care for BPH surgery.

Buther's enthusiasm was supported by David Kaminski, marketing manager of ForTec Medical (Streetsboro, Ohio), which also provides medical lasers on a mobile rental basis. In 2002, Fortec's lasers accounted for over half of the total PVP procedures performed in the U.S. He told BBI that he is a fan of PVP because it provides "the same results as TURP but allows the patient a much more rapid return to normal activities." ForTec has been involved with other less-invasive BPH surgical technologies and, as far as patient outcome, Kaminski said, "this is the best procedure we've seen."

Different effects of TUNA, TURP

A British study presented during the AUA meeting said that two common treatment options for BPH have markedly different effects on patient sexual function. The study of 152 men with enlarged prostates compared TUNA therapy, a minimally invasive treatment from Medtronic (Minneapolis, Minnesota), with TURP, the standard surgical treatment. Half (76) of the men involved in the study received TUNA therapy; the other half underwent TURP procedures. According to the researchers, none of the men who received TUNA therapy experienced ejaculatory dysfunction, compared to 57% of those treated with TURP. Those treated with TUNA therapy also had fewer complications and reduced recovery time.

Dr. Jaspal Virdi, a urologist with Princess Alexandra Hospital NHS Trust (Harlow, UK), the senior consultant for the study, said, "When the goal is to preserve sexual function in men being treated for enlarged prostate, using targeted, low-level radiofrequency energy with TUNA therapy is preferred over the old surgical standard, TURP."

In addition, none of the men treated with TUNA required blood transfusions, vs. eight (10.5%) of those who underwent TURP. Those who received TUNA therapy were out of the hospital approximately two days earlier than those treated with TURP.

TUNA therapy involves delivery of low-level radio frequency energy directly into the prostate to destroy excess tissue and improve the symptoms of BPH, such as the frequent or sudden need to urinate; a weak, variable or dribbling stream; difficulty beginning urination; the need to strain or push to initiate urination; pain or burning during urination; and the sensation that the bladder is not completely empty after urination. Medtronic said in a statement, "These symptoms reduce quality of life by causing interrupted sleep, discomfort, inconvenience and embarrassment."

According to the AUA, 50% of men older than 50 years of age and 80% of those older than 80 years of age experience symptoms of the condition.

Medtronic received FDA clearance for the TUNA therapy in 1996 for the treatment of symptoms of BPH in men over the age of 50 with prostate sizes between 20 cc and 50 cc. It received the CE mark in 1994.

Study touts BladderCheck, cystoscopy combo

Physicians presented clinical findings at the AUA meeting that the diagnosis of bladder cancer can be improved by combining cystoscopy with the NMP22 BladderChek test from Matritech (Newton, Massachusetts). The NMP22 BladderCheck test is an in-office urine test that works much like a home pregnancy test. It was approved in March, conditional upon FDA clearance of manufacturing procedures. That final clearance was reported by the company just prior to AUA. It previously was FDA-cleared for monitoring patients previously diagnosed with bladder cancer.

The technology identifies proteins that are highly over-expressed in bladder cancer patients. Matritech's scientists discovered that high levels of the nuclear matrix protein NMP22 in urine frequently indicated the presence of cancer. NMPs are found in the nuclei of cells where they contribute to nuclear structure and regulate important cell functions. NMP22 is elevated in bladder cancer cells 20- to 80-fold and is released into the urine of bladder cancer patients. Four drops of urine are placed on the device in the physician's office and results are obtained during the patient visit.

The research, presented by Kevin Tomera, MD, studied 248 patients with risk factors for urothelial cancer. Cystoscopy is the insertion of a flexible tube-like instrument into the bladder, through the urethra, to visually inspect the inside of the bladder. When cystoscopy was combined with the NMP22 BladderChek test, 94% of the cancers were correctly identified. "Cystoscopy has long been the gold standard for bladder cancer diagnosis; however, at times cancers are missed," Tomera said. "Often it is because the tumor is very small, obscured by blood or flat against the bladder wall and difficult to see. By combining cystoscopy with the NMP22 BladderChek test, which is not affected by these issues, we have an excellent and accurate combination. This is good news for the diagnosis and management of bladder cancer."

The NMP22 BladderChek test is available internationally and distributed to urologists by Cytogen (Princeton, New Jersey), an oncology-focused biopharmaceutical company.

Tomera's research also studied the accuracy of cytology, a laboratory-based urine test. Cytology correctly identified only 18% of the individuals with bladder cancer, missing 15 patients with the disease. Cystoscopy combined with cytology did not improve the detection rate of bladder cancer.

According to the American Cancer Society (Atlanta, Georgia), 41,500 new cases of bladder cancer are diagnosed in men each year, a rate comparable to the incidence of colon cancer. If diagnosed in its early stages, the five-year bladder cancer survival rate exceeds 90%. About 12,400 people in the U.S. died of bladder cancer in 2001. Many of these died because the disease was not caught in its earliest stages. If the cancer reaches an advanced stage, the five-year survival rate can be less than 10%.

Elsewhere at AUA

Cellegy Pharmaceuticals (South San Francisco, California) reported on a paper presented by Jeremy Heaton, MD, a scientific advisor to Cellegy Canada, titled, "Evidence for the Use of Low-Dose Nitric Oxide in the Treatment of Rising PSA associated with Biochemical Failure following Radical Prostatectomy." This preliminary study suggests that low-dose nitric oxide donor treatment can potentially reduce rising prostate-specific antigen (PSA) levels in patients experiencing biochemical failure following radical prostatectomy.

None of the patients tested experienced drug-related adverse events. The treatment may be able to slow the progression of metastic markers that typically occur in at least 25% of patients following radical prostatectomy. This work follows up other clinical studies, published in the Journal of the National Cancer Institute and the Journal of Biological Chemistry, which established that low doses of nitric oxide releasing agents can reverse the upregulation of a metastic phenotype in a hypoxic (low oxygen) environment.

Cellegy said it believes this therapeutic approach "may provide a valuable adjunctive clinical tool in the management of prostate cancer." The company, which has certain intellectual property rights covering use of nitric oxide mimetics in the treatment and prevention of abnormal cell phenotypes, plans to advance this program and validate these preliminary results by conducting further studies.

Two new studies demonstrating the safety and effectiveness of cryoablation for treating renal (kidney) cancer were presented at the meeting, according to Endocare (Irvine, California), a developer of such technology. A total of 99 patients took part in the two studies that were conducted at several U.S. hospitals. In a long-term follow-up study of 76 patients treated by cryoablation for small renal cancers (median tumor size was 2.5 cm), the results showed that 93% of the patients showed complete radiographic resolution of their lesion with a disease-specific survival rate of 100%. The median hospital stay was two days and none of the patients developed delayed hemorrhage, urinary leaks or renal toxicity. The median length of follow-up on the patients, who ranged in age from 33 to 91 years old, was 17 months with 45% of the patients having been followed for more than 25 months and 10 patients for longer than 40 months.

The other study of 23 patients with 25 renal tumors (ranging in size from 1.5 cm to 10 cm) focused on the use of cryoablation for assisting in partial nephrectomy. The study investigators concluded that cryoablation is an effective alternative for assisting in partial nephrectomy and facilitating the excision of localized renal masses. No intraoperative complications occurred and the cryoablation was considered successful in all patients. Mean follow-up was 18 months and no recurrences were detected.

Four studies demonstrating the efficacy of Endocare's cryoablation system for the treatment of prostate cancer also were presented. Collectively, the studies showed that cryoablation is particularly effective for treating low-risk, primary care cases, as well as recurrent prostate cancer that occurs after failed radiation therapy. The studies also demonstrated that these patients tolerate the minimally invasive procedure very well and it helps preserve their quality of life, the company said. The four studies involving a total of 547 patients were co-authored by a combined total of 31 leading physicians at major clinical centers throughout the U.S. and Canada.

Clinical data for Urologix' (Minneapolis, Minnesota) recently FDA-approved Cooled ThermoCath treatment catheter were presented at the meeting. The catheter is used in conjunction with the Urologix Targis microwave generator. The company said the Cooled ThermoCath incorporates design features to enhance the treatment of benign prostatic hyperplasia (BPH) and will strengthen Cooled ThermoTherapy/TUMT as a leading minimally invasive treatment for BPH. Cooled ThermoCath incorporates catheter cooling technology designed to improve the heat exchange coupled with improved catheter conformance to the urethral tissue. Early results from clinical studies indicate rapid necrosis formation and outcomes achieved in 28.5 minutes.