CURExtra - Monitoring for Bladder Cancer Recurrence

Robert “Jerry” Puffer, a 60-year-old radio broadcaster from Shelby, Montana, suspected something was wrong when he saw blood in his urine one night. After a quick trip to the emergency room, he scheduled an appointment with an urologist. Even before the diagnosis, Puffer says in the back of his mind he knew it was cancer.

I asked him if it was bladder cancer because of my age and the fact that I smoked,” Puffer says. “I got the impression that was what the urologist was expecting.”

Smoking is the No. 1 risk factor for bladder cancer, increasing the risk nearly three-fold. And although men are nearly four times more likely to develop bladder cancer than women, cigarette for cigarette, women have twice the risk from smoking.

Fortunately, Puffer’s vigilance resulted in a stage 1, low-grade diagnosis of papillary bladder cancer that was treated with surgery. Nine months later, Puffer began his trips to the Mayo Clinic in Rochester, Minnesota, where they monitor him for recurrence every three months. “I realize the recurrence rate,” he says. “I am obviously concerned.”

Bladder cancer, the fifth most common cancer in the United States, also has the highest risk of recurrence of all cancers, ranging from 50 to 90 percent depending on stage, grade and number of tumors. And because of this risk, follow-up and therapy over a survivor’s lifetime makes it the most expensive cancer in the United States at $96,000 to $187,000. Because such a high percentage of bladder cancer patients may develop a recurrence, monitoring and early diagnosis are crucial.

Michael O’Donnell, MD, professor and director of urologic oncology at the University of Iowa Carver College of Medicine, says that although bladder cancer has one of the highest recurrence rate, 75 percent of cases are found in an early stages, almost unheard of in solid tumors.

“The reason why we pick up bladder cancer so much earlier is because 75 percent of the cases are marked by blood in the urine, called gross hematuria,” Dr. O’Donnell says. “Patients see that and they become appropriately concerned.” Other symptoms include painful and frequent urination and slowing of urinary stream.

Cytology, the commonly used test for bladder cancer, involves sending a sample of the patient's urine to an off-site laboratory to examine the cells washed from the bladder, a process which can take several days for the patient to receive the results.

Because cytology is not very reliable alone, it is usually combined with cystoscopy, a procedure usually performed under light anesthesia, in which a tube is inserted through the urethra to look inside the bladder. Cystoscopy is the most reliable tool for diagnosing bladder cancer, but it is still somewhat uncomfortable and expensive, which encourages the development of less invasive and less costly alternatives.

“The goal has been to find a way to monitor for recurrence that doesn’t involve sticking a tube in someone’s bladder,” Dr. O’Donnell says. “It would appear logical and natural to develop a test from the urine, because the urine comes from the bladder, and so there should be substances in urine that are reflective of cancer recurrence.”

Currently several urine tests are approved by the Food and Drug Administration for detecting early bladder cancer or for monitoring for recurrence.

NMP22 BladderChek®, approved in 2005 for diagnosis and monitoring, looks for elevated levels of a specific protein in the urine. It uses technology similar to that found in over-the-counter home pregnancy tests.

In contrast to traditional urine cytology, the BladderChek test can be performed quickly in a doctor’s office and is cost effective. Unfortunately, it is not as reliable as cystoscopy, detecting only half of the tumors (sensitivity) and falsely detecting cancer in over half of the cases (specificity). But when BladderChek was combined with cystoscopy, the test increased overall sensitivity to 99 percent when compared with cystoscopy alone (91 percent).

Others diagnostic tests include UroVysion™, which measures chromosomal abnormalities with fluorescent in situ hybridization (FISH); and ImmunoCyt™ Bladder Cancer Monitoring Test, which looks for abnormal proteins on the surface of the same exfoliated cells collected for urine cytology.

No one test is very reliable in detecting cancer and many give patients false-positives in about 50 to 80 percent of cases, meaning more anxiety and more tests for the patient before cancer is ruled out. But to the credit of the approved tests, some have been useful in terms of anticipating a tumor recurrence within the next year.

“With the FISH test, for instance, if you get a positive result and you don’t see a tumor, it doesn’t necessarily mean the test is wrong,” Dr. O’Donnell says. “Sometimes it can predict a tumor recurrence within the next year. And because of that, maybe we check a little more often, we’re more vigilant and we do more tests looking at other places the abnormality may be coming from.”

The problem with all tests is their reduced ability to find recurrent tumors, partly because new tumors discovered during active surveillance tend to be much smaller than those that first bring patients to the urologist’s office, resulting in a 10 to 15 percent drop in sensitivity across the board for almost all of the new tests.

It is not clear whether any currently approved test is superior to any other because there is always a trade-off between sensitivity and specificity. “If you push for the highest sensitivity to not miss any cancers, you get more false positives,” Dr. O’Donnell says. “Likewise, if you push for the greatest degree of confidence (specificity) in knowing that a positive test really signifies cancer, you end up missing many recurrent cancers.”

Newer tests being studied include monitoring microsatellite instability, which are DNA alterations that occur in cancer cells as they begin to proliferate. Another test measures a substance call survivin, which helps prevent cancer cell death. One promising test involves an enzyme called telomerase, a necessary component of immortalization of cancer cells. A recent study in Italy has found that a telomerase urine test detected 90 percent of cancers, with a relatively high specificity (88 percent). However, the study only included newly diagnosed patients with bladder cancer, not patients being monitored for recurrence.

Dan Theodorescu, MD, of the University of Virginia Health Sciences Center, and colleagues have developed a urine test that has high specificity for the detection of bladder cancer.

eliminary data show that by using mass spectrometry (a method of measuring and analyzing protein fragments), the test has higher specificity and fewer false-positives than other urine tests. It is also unique in that it looks for 22 biomarkers for bladder cancer, including an overabundance of a key protein, fibrinopeptide A, which has also been identified in ovarian cancers and gastric cancers.

"One of the problems with current tests is they are not specific,” Dr.Theodorescu says, but pr

Researchers are looking into future studies that will include bladder cancer survivors to help define the best use of such biomarker profiles for detecting the presence of cancer or risk of recurrent cancer. F

urther testing is needed to confirm the results, but the researchers are in preliminary talks with the FDA for product approval.

Since his diagnosis, Puffer has involved himself in the Bladder Cancer WebCafé (www.blcwebcafe.org), a website that provides information and support on bladder cancer, and has educated his listening audience about bladder cancer through his radio show. Because recurrence risk is a life-long reminder to a bladder cancer survivor, Puffer is one of many patients who keep up to date on research in the field.

“A lot of exciting medical things are coming out,” he says. “I think that the next couple of years will be pretty exciting.”