By Gary Wolfe
The predominant techniques traditionally used by urologists to screen patients for early-stage or recurrent bladder cancer have been flexible cystoscopy, voided urine cytology, and upper tract evaluation by methods such as IVP and ultrasound. These methods are relatively time-consuming and sometimes deliver less-than-optimal accuracy unless used in combination with each other.
Matritech’s NMP22 BladderChek test
Moreover, cytoscopy, the traditional “gold-standard” of tests to identify bladder cancer is a costly, invasive, and traumatic procedure for patients to endure. By contrast, the non-invasive approaches (urine cytology and upper tract imaging) afford results of variable quality, as they depend on human visual acuity and interpretive skills, both subjective factors.
Complementing the more traditional tests, physicians and clinics also have a choice of rapid, non-invasive POC bladder cancer assays, which yield results in minimal time.
In this article, we discuss two such assays: the NMP22 BladderChek test from Matritech, Inc. of Newton, Mass. (distributed in North America by Cytogen Corporation of Princeton, N.J.); and the BTA stat test from Polymedco, Inc. of Cortlandt Manor, N.Y. (manufactured by Polymedco’s subsidiary Alidex, and distributed in North America by Mentor Corporation of Santa Barbara, Calif.).
Matritech NMP22 BladderChek test
Matritech’s NMP22 BladderChek test is an easily performed, point-of-care, in vitro diagnostic assay for bladder cancer (Transitional Cell Carcinoma [TCC]). The CLIA-waived test enables a physician to quickly detect the presence of NMP22, a nuclear matrix protein, which is released into the urine by urothelial cells.
Says John Quigley, vice president of sales and marketing for Matritech, “NMPs are found in the nuclei of cells where they contribute to nuclear structure and regulate important cell functions. When present in the urine at significantly elevated levels (typically 20 to 80 times higher than normal concentrations), NMP22 has been shown to be a dependable indicator of the presence of bladder cancer.”
This test is an FDA-approved rapid assay screening test that physicians can use in their offices to help diagnose patients with bladder cancer. Quigley notes, “It is only the second tumor marker approved by the FDA for screening patients with cancer, the other being the Prostate Specific Antigen (PSA) test for prostate cancer.”
“The NMP22 BladderChek Test is as easy-to-perform as a pregnancy test and specificity is reported to be 85 percent,” says Quigley. The patient provides a voided urine specimen, then the physician places four drops of the urine on the one-time-use, disposable test cassette and waits 30 minutes. Appearance of a purple line within the prescribed time indicates the probable presence of a bladder cancer. Hence, by using this test, a physician can provide patients with answers while they are in the office, facilitating patient management decisions.
Advantages magnified when combined with other tests
According to Quigley, “The NMP22 BladderChek test, when used in combination with cytoscopy, enables physicians to detect 89 percent of invasive cancers. Cytoscopy alone has been shown to detect 56 percent of all invasive bladder cancers. And the NMP22 test alone can detect about 60 percent. Moreover, in clinical trials conducted on 1,331 persons at 22 sites in 9 U.S. states for submission to the FDA, the test has been demonstrated to detect three times more early-stage bladder tumors and twice as many life-threatening, high-grade tumors as cytology.”
The qualitative NMP22 BladderChek Test is a derivative of Matritech’s quantitative NMP22 laboratory assay, which received FDA approval in 1996 for diagnosing patients experiencing the first onset of bladder cancer and for monitoring the recurrence of the disease in previously diagnosed patients. The use of the NMP22 assay in monitoring protocols enables urologists to accurately predict residual or recurrent bladder cancer as soon as five days after transuretheral resection of a bladder tumor.
The earlier version of the NMP22 test has been used in the U.S. in a semiautomated Microtiter configuration. Says Quigley, “There is a 93 percent concordance between the BladderChek and Microtiter versions.” He adds that a fully-automated laboratory version of the test, based on a DPC Immulite system, is currently being employed outside the U.S., but regulatory approval by the FDA for use in the U.S. is anticipated in the near term.
There are limitations to the test in case of urinary tract trauma. According to Quigley, “Any trauma to the urinary tract or the presence of stents, either of which can cause an inordinate amount of NMP22 to be released into the urine, can cause some interference with the test in a small percentage of patients. However, there is no interference from common therapeutic medications.”
Polymedco BTA stat test
Polymedco’s BTA stat test is a simple, non-invasive in vitro urine assay that is used to monitor for recurrent bladder cancer. It qualitatively measures the presence of human complement factor H-related protein (hCFHrp), an antigen produced by the tumor cells to protect themselves from the body’s natural defenses and related to human complement factor H (hCFH). Company literature notes that, “In cell culture, hCFHrp was shown to be produced by several human bladder cancer cell lines but not by normal epithelial cell lines.”
Polymedco’s BTA stat test
Mike Sanfilippo, MS, ASCP-SC, technical operations director for Polymedco and also a clinical biochemist explains, “The protein spills into the urine and can be detected earlier than other types of diagnostic or investigative assays, such as imaging and cytology. The more tumor cells present, the greater the amount of this protein that will be produced. Hence, there is a direct correlation between the amount of the protein and the extent of the disease.”
The quantitative laboratory counterpart to the BTA stat test is Polymedco’s BTA trak test, a laboratory assay that reveals the exact concentration of hCFHrp. Sanfilippo notes the correlation between the two tests is very close: 67 percent for BTA stat and 72 percent for BTA trak.
“In 1999,” he adds, “the BTA stat test received an award for innovation and progress from the Medical Device and Diagnostic Industry Journal.”
Currently over 40 peer-reviewed clinical papers have been published, showing the benefit of the BTA stat test. Sanfilippo says, “The test has been shown in clinical studies to have a sensitivity as high as 90.1 percent for detecting primary tumors and has an overall sensitivity of 83 percent. Virtually no false negatives make it an excellent rule-out test.”
Sanfilippo says, “Other research presented in 2001 has shown the utility of the BTA stat test for detecting upper tract TCC, the most common form of bladder cancer, which is almost impossible to detect by imaging or cystoscopy. Overall sensitivity in this application was 82 percent.”
FDA clearance for the BTA stat test as was first granted in 1997. At that time, the test was classified as CLIA moderate complexity. The test was later granted CLIA-waived status for the test.
To perform the test, the patient voids urine into a cup. Then the patient, physician, or technician uses a pipette provided in the test kit to put five drops into the disposable sample well. If after exactly five minutes, a red line appears, the test is considered a positive indicator for the presence of bladder cancer. However, the manufacturer does caution against using readings if the five-minute test time is exceeded.
Urine sample integrity an advantage
Another advantage of the BTA stat test cited by Sanfilippo involves urine sample integrity. He says, “The hCFHrp antigen detected by the test remains stable at room temperature for 48 hours, for seven days if refrigerated, and for one year if frozen.” This means the BTA stat test can be performed with a high degree of confidence, despite the variability in the ways that urine samples may be collected, stored, and transported.
There are some precautions and potential interferences with BTA stat as well. Sanfilippo advises that “factors such as trying to use grossly hemolyzed urine samples or samples taken after trauma to the urinary tract due to surgery, cytoscopy, bladder washing, and the like may adversely affect the results obtained by the BTA stat test.”
Gary Wolfe is a freelance writer based in Franklin, Mass.
