Paul F. Schellhammer, MD, a member of the Urology Times editorial council, is professor of urology and program director of the Virginia Prostate Center of the Eastern Virginia Medical School and Sentara Cancer Institute, Norfolk.

Paul F. Schellhammer, MD

Among the excellent papers on the basic science, diagnosis, and treatment of bladder cancer presented at the AUA meeting, a number of important take-home messages emerged on disease recurrence, providing urologists with guidance in how aggressive to be with monitoring and subsequent treatment. 

Patients with two or more recurrences of superficial bladder tumors, with an average of <12 months for recurrence, are at higher risk of developing an upper urinary tract cancer. Patients in lower-risk groups can forgo upper tract imaging.

The specter of upper tract transitional cell carcinoma in patients who have had a diagnosis of bladder cancer has prompted a number of protocols for upper tract monitoring. The most stringent is that of annual intravenous pyelography. However, the risk of upper tract tumors overall is in the range of 4% to 5% in the bladder cancer population. 

Among men undergoing radical cystectomy with TCC of the bladder, urethral tumor recurrence occurs in 7% overall, but those undergoing orthotopic diversion and those without any prostate involvement demonstrate a significantly lower incidence.

The possibility of TCC in the retained urethra after cystectomy has prompted various protocols to identify the risk for this event. 

Although not a contraindication to orthotopic bladder construction, prostatic stromal involvement by tumor increases the risk of urethral occurrences. While patients with orthotopic bladder replacement have an overall lower incidence of urethral cancer than those having ileal conduit diversion, careful questioning about urethral spotting or discomfort warrants urethroscopy. Periodic voided urine for cytology yielding positive results would also warrant urethroscopy. 

For patients with an intact bladder, careful urethroscopy at the time of cystoscopy is a mandatory step in the assessment protocol. For patients with recurrent bladder cancer, specifically carcinoma in situ, biopsy of the prostatic urethra should be considered. 

The fluorescent in situ hybridization (FISH) assay detected all invasive and in-situ TCCs of the bladder in a study of patients followed for TCC.

Cystoscopic evaluation in follow-up of TCC of the bladder remains the gold standard for detection and subsequent treatment of recurrent tumor. However, this is an invasive procedure. For the 500,000-plus patients with a history of TCC that are currently assessed with cystoscopy, a noninvasive urine test that is both sensitive and specific for both low- and high-grade tumors represents one of the holy grails of urothelial cancer management. 

Cytology is very specific, but lacks sensitivity, specifically for low- and intermediate-grade tumors. FISH identifies chromosomal amplifications and deletions that are associated with urothelial neoplasia. 

FISH operating characteristics are more favorable than cytology, specifically with regard to better sensitivities for low- and intermediate-range tumors while maintaining a high specificity. It also provides a lead time before detection of clinical recurrence. This study found that a positive FISH assay, when urine cytology was negative or atypical, predicted subsequent tumor occurrence in 36% of grade I/II Ta TCC; 100% ŽT1 TCC; and 100% carcinoma in situ. However, FISH is one of the most costly urine detection assays. 

Patients undergoing transurethral resection plus one immediate postoperative instillation of chemotherapy show a 39% lower rate of recurrence than patients who receive TUR alone.

TCC of the bladder is notorious for tumor recurrence or "new tumor occurrences." The mechanism is based on both a field disease theory of panurothelial dysplasia or implantation on the traumatized areas of urothelium by tumor cells that have been released into the fluid-filled bladder at the time of resection. Theoretically, implantation can be prevented by the instillation of the chemotherapeutic regimen immediately after the procedure to negate the ability of dislodged tumor cells to adhere, implant, and multiply. 

Numerous clinical trials have shown that patients receiving immediate instillation of chemotherapy after resection reduces the incidence of recurrence when compared with controls not receiving chemotherapeutic instillation. 

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Bladder cancer studies help pinpoint risk of recurrence

The treatment of patients with advanced prostate cancer remains a challenge. Research presented at the 2004 AUA annual meeting did provide valuable insight into such key issues as the role of salvage radiation therapy and the benefit of immediate versus delayed androgen blockade. Five significant take-home points dealing with the treatment of advanced prostate cancer were presented at the meeting. 

Pre-treatment PSA, PSA doubling time, Gleason grade, and seminal vesicle involvement are prognostic variables for estimating the success of salvage radiation therapy. Selected patients with high-grade disease, a short disease-free interval after prostatectomy, and/or rapid PSA doubling times-all poor risk factors-may still achieve a durable response to salvage radiation therapy if treated when PSA is <1.0 ng/mL.

A large, multicenter study of more than 500 patients reported that 3-year PSA progression-free probability was 89% for patients with Gleason 8-10; a history of positive surgical margins; and a PSA doubling time >10 months when radiation was given before the PSA level exceeded 2.0 ng/mL. Progression-free probability was 36% in the same circumstances when the PSA doubling time was £10 months. As with the majority of single-center studies published in the past several years, the PSA level at the time of salvage radiation delivery was an important factor in determining response durability, ie, the lower the PSA at initiation of external beam radiation therapy, the higher the likelihood of benefit. 

Very few solid tumors that fail primary therapy yield to a salvage therapy with this degree of success. In the future, some prognostic indicator may be able to identify those patients with a rising PSA after radical prostatectomy who will absolutely fail salvage radiation, but that prognostic profile is not yet available. 

I consider salvage radiation in all patients with a rising PSA after radical prostatectomy. The only exception is the rare patient whose PSA does not fall to an undetectable level after surgery. 

Re-evaluation of data confirms that patients receiving immediate androgen blockade have superior survival compared with those who have deferred or delayed blockade. Cancer-specific survival at 11.9 years of follow-up is 85% for immediate blockade and 51% for delayed blockade.

The question of early androgen deprivation continues to challenge urologists. Is the timing of androgen deprivation related to a survival benefit? Can one achieve the same survival benefit when androgen deprivation is delivered later in the course of disease at the time of progression and, by doing so, avoid the side-effect profile associated with earlier and more prolonged androgen deprivation therapy? I believe the evidence is accumulating in favor of earlier therapy to provide a survival benefit. 

The Eastern Cooperative Oncology Group (ECOG) EST3886 trial (

 1999; 341:1781) was updated to provide a longer follow-up and address the issue of potential grading imbalance between the two arms of the study. While only 50% of the slides of primary tumor histology could be retrieved, the central histologic re-evaluation of those that were available did not demonstrate an imbalance between the two arms and supported the integrity of the initial analysis. The survival benefit of early androgen deprivation was statistically confirmed. 

A PSA doubling time of less than 10 months is a strong predictor of cause-specific survival after prostatectomy and can be used to define clinical trials for advanced prostate cancer.

Clinical trials studying prostate cancer desperately need a surrogate endpoint to expedite the evaluation of therapeutic options. Prolonged time to objective disease progression and death-the latter being the traditional FDA endpoint of efficacy-necessitates large trials of long duration. 

PSA doubling time in several large database studies has demonstrated a strong correlation with subsequent disease progression and death. The cutpoint of PSA doubling time has varied from 3 months to 12 months depending upon the database analyzed. 

A large Johns Hopkins database demonstrated a PSA doubling time £10 months to be a strong predictor of prostate cancer mortality, thereby identifying patients who require therapy and possibly for use as a surrogate for treatment effect. In June, the FDA held a workshop to investigate the possibility of employing surrogate endpoints. Their decisions and conclusions are awaited. 

I believe the evidence is accumulating in favor of earlier [androgen deprivation] therapy to provide a survival benefit.

Paul F. Schellhammer, MD

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Bladder cancer studies help pinpoint risk of recurrence

Data shed light on salvage RT, immediate hormone Tx