Multicenter trial of the quantitative BTA TRAK assay in the detection of bladder cancer.
Fortunately, 75-85% of newly diagnosed bladder tumors are confined to the bladder mucosa, are not life threatening, and can be treated relatively easily by transurethral resection. The risk of recurrence or new tumor growth in these patients, however, is ~75% (1). Recurrence at the original site may indicate incomplete removal of the initial tumor. New tumor growth at sites other than the original may be the result of carcinogens in the urine affecting different parts of the bladder mucosa at different times or seeding by viable tumor cells, either before or at the time of resection (2). Because of the risk of recurrence, patients must be examined for bladder cancer at frequent intervals, especially during the first few years after treatment (3, 4).
A definitive diagnosis of bladder cancer can be made only by inspection of the interior of the bladder, typically with the aid of a cystoscope, and pathologic examination of a resected tumor or biopsy specimen. However, when bladder tumors are small or flat (carcinoma in situ), they cannot always be visualized reliably by cystoscopy (5, 6). For this reason, many urologists use an adjunctive diagnostic procedure, such as exfoliative cytology. Cytology, however, has several disadvantages, including its reliance for accuracy on the skill of the pathologist, its relative insensitivity to grade I (well-differentiated) tumors, and a lack of standardization of methods (7, 8).
The BTA TRAK[TM] assay, a quantitative enzyme immunoassay for a bladder tumor-associated antigen, is performed on a urine specimen in a clinical laboratory. The antigen measured by the assay is human complement factor H-related protein (hCFHrp),  which is similar in structure and function to human complement factor H (hCFH) (9, 10). In cell culture, hCFHrp has been shown to be produced by several human bladder cancer cell lines but by not healthy epithelial cells (9,10). hCFH plays an important inhibitory role in the control of the alternative complement pathway, and the function of this pathway is the lysis of cells recognized by the host as foreign (9,10). By interacting with complement factor C3 convertase and serving as a cofactor for complement factor I, hCFH inhibits the formation of a membrane attack complex, thereby preventing cell lysis. In vitro, hCFHrp interrupts the complement cascade and protects cells from lysis by complement (9,10). Production of hCFHrp may confer a selective growth advantage to cancer cells in vivo by allowing the cells to evade the host immune system (11).
Here we present the results of a multicenter study comparing the sensitivity of the BTA TRAK assay for bladder cancer with those of voided urine cytology or bladder wash cytology, using cystoscopy or cystoscopy and biopsy as the standard for definitive diagnosis.
Patients and Methods
The study was conducted according to the current (1989) revision of the Declaration of Helsinki. The study protocol was approved by an ethics committee at each of the participating institutions and was conducted in accordance with the laws and regulations of the countries in which it was performed.
Eligible for participation in the study were patients with or without a history of bladder cancer who were suspected of having bladder cancer on the basis of signs, symptoms, or recent intravenous urographic or cystoscopic results and who were scheduled to undergo cystoscopy and cytologic examination. Written or verbal informed consent was obtained from each patient before participation in any study-related activity.
All patients provided a single midstream or catheterized urine or bladder wash specimen the same day as but before their diagnostic workup. A portion of the specimen was frozen at -20[degrees]C and sent to a central laboratory for processing according to the instructions supplied with the BTA TRAK assay kit (Bard Diagnostic Sciences, C.R. Bard, Inc.). The remainder of the sample was sent to the institutions cytology laboratory for processing according to standard procedures. When a bladder wash cytology was performed instead of voided urine cytology, it was done at the time of cystoscopy, and the wash was also sent to the cytology laboratory for processing.
The BTA TRAK assay can be performed on fresh, refrigerated, or previously frozen urine samples. A US study (12) on the stability of the antigen showed that urine specimens can be stored refrigerated for up to 2 weeks without the addition of preservatives or inhibitors and they can be stored frozen at -20 or -80[degrees]C for at least 24-26 weeks with as many as three cycles of thawing and refreezing without deterioration in antigen concentrations.
Urine specimens should be screened for the presence of blood. Because the presence of hematuria is sometimes associated with false-positive BTA TRAK results, it is recommended that upon detection of hematuria by dipstick, that voided urine cytology be performed as well as the BTA TRAK test.
THE BTA TRAK ASSAY
The assay procedure is that of a standard enzyme immunoassay. The assay uses a capture monoclonal antibody (MAb) and an enzyme-labeled reporter MAb that bind specifically to hCFHrp. Patient urine and a diluent are added to microwells coated with capture MAb and allowed to incubate for 1 h at 37[degrees]C. Bladder tumor-associated antigen present in the urine is bound by the capture MAb, and unbound urine components are subsequently removed by washing. The alkaline phosphatase-labeled reporter MAb is then added to the microwells, followed by an additional 1-h incubation at 37[degrees]C. The plate is again washed to remove unbound conjugate, and the bound reporter conjugate is detected by reaction with substrate for 30 min at 37[degrees]C. The amount of antigen is determined by comparing the absorbances in the sample wells with those of calibrators assayed simultaneously (range of quantification, 0-100 kilounits/L). Assay calibrators and controls were calibrated with antigen purified from urine samples of patients with confirmed bladder cancer. The calibration curve used antigen concentrations of 0, 5, 20, 50, and 100 kilounits/L. One unit in the BTA TRAK assay is ~4.7 ng of hCFHrp.
THE BTA TRAK ASSAY DECISION THRESHOLD
Because only symptomatic patients with clinical signs of bladder cancer or patients with known bladder cancer were included in this study, the decision threshold of an earlier clinical evaluation of the BTA TRAK assay was used to select patients with a bladder tumor. In the earlier study (12), the decision threshold, established by an ROC analysis corresponding to 97% specificity, was found to be 14 kilounits/L.
PERFORMANCE CHARACTERISTICS OF THE BTA TRAK ASSAY
The precision of the BTA TRAK assay was determined according to the procedures recommended by the NCCLS (13) by testing two controls and five urine samples in duplicate in each of 20 independent analytical runs (1 analytical run/day) at three different laboratories. The within-run, between-run, and between-site CVs for the low control (9.2 kilounits/L) were 7.1%, 2.4%, and 0.3%, respectively. The CVs for the high control (35.6 kilounits/L) were 6.8%, 2.9%, and 1.2%, respectively (14).
To determine the recovery, urine specimens from four patients with known hCFHrp concentrations were added to a nondiseased urine sample containing endogenous antigen at a concentration of 1.76 kilounits/L, and the resulting antigen concentrations were determined using the BTA TRAK assay. The recoveries for the four patients were 100.0%, 91.4%, 96.0%, and 98.3%.
The results of the BTA TRAK test were not normalized to urinary creatinine. Preliminary results have shown that the association between the creatinine concentration in urine and the BTA TRAK values is not strong. Creatinine does not explain the variability in the BTA TRAK values in the monitoring of a bladder cancer patient, and it does not appear to smooth the values. In the cases of bladder cancer patients, although there is variation in the BTA TRAK values, the values never drop below the threshold of 14 kilounits/L.
Cytology was performed by microscopic examination of a voided urine specimen or bladder washing for exfoliated cells from cancerous bladder epithelium. Bladder washings, when performed, were obtained by irrigating the bladder with physiologic saline solution through a catheter or rigid cystoscope. Cytologic preparations were made by fixing exfoliated cells, placing them on glass slides, and staining them. The cytologic examinations were performed by expert pathologists who adopted common criteria for evaluation and were unaware of the results of the BTA TRAK assay. A positive cytology result was defined as a laboratory report of "positive" for or "highly suggestive" of malignancy. All of the doubtful reports, which involved the need to repeat cytology, such as "suspicious or atypical cells" were not considered positive because they did not provide any definite diagnosis of cancer.
A positive final diagnosis was defined as bladder cancer confirmed by cystoscopy and biopsy. Tumors were graded and staged according to the classification of the International Union Against Cancer (15), in which staging depends on the type of tumor and its extent of penetration into the bladder wall and grading is based on the degree of tumor differentiation. Grade I, II, and III tumors are well, moderately well, and poorly differentiated, respectively. A negative final diagnosis was defined as no bladder cancer ascertained by cystoscopy or cystoscopy and biopsy. If a definitive final diagnosis was not possible (suspicious results), the case was not included in the determination of sensitivity or specificity.
The primary measures of diagnostic efficacy were sensitivity to bladder cancer, defined as the ratio of the number of true-positive results to the number of positive final diagnoses (based on cystoscopy and biopsy), and specificity for bladder cancer, defined as the ratio of the total number of true-negative results to the total number of negative final diagnoses. The number of study participants required to detect a difference of 0.15 or greater between the BTA TRAK assay and cytology sensitivities was computed using the method of Schork and Williams (16). Sensitivities and specificities were calculated using combined data from the six study institutions. The precision of the sensitivity and specificity estimates are shown as exact 95% confidence intervals (CIs). An exact test analogous to the McNemar test was used to compare the overall sensitivities and specificities of the BTA TRAK assay and cytology and the sensitivities for the different tumor grades and stages. Data are presented separately for the two patient types (history of bladder cancer vs no history of bladder cancer) because patients with a history of bladder cancer had received treatment and were being monitored for recurrence.
Urine samples from 220 patients were collected at six institutions in Austria, France, Germany, and Italy. Approximately the same number of patients were obtained from each country; 155 of the patients were men, 65 were women, and 98% were Caucasian. The mean age of the patients was 64.2 years (range, 24-94 years).
COMPARISON OF SENSITIVITIES OF THE BTA TRAK ASSAY AND CYTOLOGY
As is shown in Table 1, of the 100 patients in this study who were diagnosed with bladder cancer by cystoscopy, the overall clinical sensitivity of the BTA TRAK assay was 66% (66 of 100; Fig. 1), whereas that of cytology was 33% (33 of 100; P <0.001). There were no statistically significant differences between the sensitivities in those patients who had a previous history of this disease (n = 51) and those who were newly diagnosed (n = 49) for either cytology or the BTA TRAK assay, nor did the positivities of cytology differ between voided urine samples and lavage fluid samples (not shown).
The sensitivities of the BTA TRAK assay and cytology according to tumor grade and stage are given in Table 2. In terms of sensitivity, the BTA TRAK assay was superior to cytology in the 25 patients with grade I tumors (48% vs 4%; P <0.001) and in the 41 patients with grade II tumors (59% vs 22%; P = 0.001). Similarly, the BTA TRAK assay exhibited a higher sensitivity than cytology in detecting the 55 stage [T.sup.a] tumors (51% vs 15%; P <0.001) and in the 24 stage [T.sub.1] tumors (88% vs 50%; P = 0.011). There were no statistical differences between the BTA TRAK assay and cytology in grade III tumors (n = 34) or in stage [T.sub.2]-[T.sub.4] tumors (n = 16) and [T.sub.is] tumors (n = 5).
[FIGURE 1 OMITTED]
COMPARISON OF THE SPECIFICITIES OF THE BTA TRAK ASSAY AND CYTOLOGY
Seventy-three of the 120 patients whose final diagnosis was negative for bladder cancer had a history of this disease. In addition, 31 were found to have other genitourinary (GU) cancers or GU diseases such as renal calculi and urinary tract infection. The other GU cancers included one prostate cancer, three benign bladder tumors, and one renal cancer. These conditions may cause interference because of the presence of hCFH in the urine and leakage from bleeding because of the disease. Thus, the positive BTA TRAK values in patients with benign disorders and dipstick-positive hematuria would not be surprising.
In contrast to its rather low sensitivity, cytology exhibited excellent specificity in all patient categories. Only one false-positive result was observed in all 120 patients, and that was in a patient with a history of bladder cancer.
The overall specificity of the BTA TRAK assay in these 120 patients was 69% (83 of 120; 95% CI, 60-77%; Fig. 1). As is shown in Table 3, significantly better specificity (P = 0.006) was observed in patients who had no apparent GU disease (76%, 68 of 89; 95% CI, 66-85%) than in the group with GU disease (48%, 15 of 31; 95% CI, 30-67%). In addition, a history of bladder cancer was not related to the observed specificity in either group (Table 3).
Because the group with no previous history of bladder cancer contained a higher percentage of patients with GU disease (47%, 22 of 47) than that with previous bladder cancer (12%, 9 of 73; Table 3), the specificity of the BTA TRAK assay appeared to be better in the latter (80%, with 95% CI, 68-88% vs 53%, with 95% CI, 38-68%).
COMPLEMENTARITY OF THE BTA TRAK ASSAY AND CYTOLOGY
The effects of using both the BTA TRAK and cytology data on sensitivity and specificity are shown in Table 4. Because cytology had an exquisite specificity, calling the overall result positive if either the BTA TRAK assay or cytology were positive yielded a specificity equivalent to that of the BTA TRAK test alone. As anticipated, the use of both assays in this manner produced an apparent increase in sensitivity of the BTA TRAK test alone (71% vs 66%), although this increase was not statistically significant.
As expected, the effect of using cytology as a confirmatory test for the BTA TRAK assay, that is, requiring that both tests be positive to report a positive result, produced a lower overall sensitivity than using cytology alone with a specificity equivalent to that of cytology (Table 4).
Medical science has long sought a reliable tumor marker for bladder cancer. Only recently, however, have researchers discovered markers with practical diagnostic potential. Among them are DNA and genetic anomalies, tumor-suppressor genes, oncogenes, cell receptors, tumor products, tumor proteins, tumor-associated hyaluronic acid, and several tumor-associated antigens, including hCFHrp, defined by MAbs (17,18). The primary goal of this study was to better define the potential roles of the BTA TRAK assay and cytology in the diagnosis and management of bladder cancer. A secondary goal was to serve as a means of comparing the BTA TRAK assay performance in a multicenter European study with the results of a US multicenter clinical trial (12).
In this study, the BTA TRAK assay was significantly more sensitive than cytology for tumor grades I and II (P <0.05) and for stage [T.sup.a] and [T.sub.1] tumors (P <0.05). The fact that the difference in sensitivity between the BTA TRAK assay and cytology in the patients with [T.sub.2]-[T.sub.4] tumors was not statistically significant may be attributable to the small sample size (16 patients). The sensitivity of the BTA TRAK assay in a small group (n = 5) of [T.sub.is] tumors (carcinoma in situ) was 60%, compared with an 80% sensitivity of cytology in the same group. Sensitivities of the BTA TRAK assay in this study were very similar to those reported in a 900-patient US multicenter study (13), both in terms of grade (grade I, 48% vs 53%; grade II, 59% vs 68%; and grade III, 88% vs 85%) as well as in stage ([T.sub.a], 51% vs 59%; [T.sub.1], 88% vs 92%; [T.sub.2]-[T.sub.4],88% vs 88%; and [T.sub.is], 60% vs 67%).
On the other hand, the specificity of cytology (99%) was clearly superior to that of the BTA TRAK assay (69%) in this patient population. It should be noted, however, that the specificity of the BTA TRAK assay reported in this study was artificially lower than generally expected for the following two reasons. First, there were no exclusions made for patients with infections or renal stones as required in the package insert. These conditions may cause interference because of leakage of endogenous hCFH into the urine from the disease process. Thus, the positive BTA TRAK values in the patients with benign urologic disorders would not be surprising. It was shown recently that hCFH is produced in human proximal tubular epithelial cells and human mesangial cells in response to interferon-y, an important mediator of inflammation (19, 21). Second, follow-up information was not available on non-bladder cancer patients who tested positive by the BTA TRAK assay. Sixty-one percent of these patients had a history of bladder cancer, and patients in this group should not necessarily be considered falsely positive. Given the high tumor recurrence rate in patients with a history of bladder cancer, it is likely that many of these positive BTA TRAK tests not confirmed by cystoscopy indicated early detection of subclinical disease.
Thus, in terms of utility, if the primary intent of the physician in using an adjunctive test to cystoscopy is to maximize the detection of cancer while minimizing cost, the BTA TRAK assay could replace cytology in the diagnosis and follow-up of patients with bladder cancer, if infectious GU disease or injury, which reduces specificity, can be ruled out. The BTA TRAK assay appeared to be especially useful in the detection of low-grade tumors because of its greater sensitivity than cytology. Our study population did not include enough patients to draw conclusions regarding the sensitivity of the BTA TRAK assay in patients with carcinoma in situ. Carcinoma in situ generally has a worse prognosis than papillary carcinoma (21). Until the BTA TRAK assay can be further evaluated, we recommend that cytology continue to be used to supplement cystoscopy in patients with a history or suspicion of carcinoma in situ. This approach has the additional advantage that it should detect a few more cancers than the BTA TRAK assay alone, without decreasing the specificity of the BTA TRAK assay.
This work was supported by a grant from Bard Diagnostic Sciences, C.R. Bard, Inc., Redmond, WA.
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LOTHAR THOMAS,  * HERBERT LEYH,  MICHAEL MARBERGER,  EMILIO BOMBARDIERI,  PIERFRANCESCO BASSI  FRANCESCO PAGANO,5 VITO PANSADORO  CORAN. STERNBERG,  LAURENT BOCCON-GIBOD,  VINCENT RAVERY,7 DOMINIQUE LE GULUDEC,  ALAIN MEULEMANS,  PIERRE CONORT,  and LAURA ISHAK 
 Laboratory Medicine, Krankenhaus Nordwest, Stembacher Hold 2, D-60489 Frankfurt, Germany.
 Urology Department, Technical University of Munich, Ismaninger Strasse 22, 81675 Munich, Germany.
 Urology Clinic, University of Vienna, Wjhringer Gtirtel 18-20, Vienna A-1090, Austria.
 Nuclear Medicine Division, National Tumor Institute, Via Venezian 1, I-20133 Milan, Italy.
 Institute of Urology, University of Padova, Via Giustiniani 2, 35128 Padova, Italy.
 Fondazione Vincenzo Pansadoro, Via Aurelia 559, 00165 Rome, Italy.
 Urology Clinic and  Nuclear Medicine, Hopital Bichat, 46 rue Henri Huchard, Paris Cedex 18, France.
 Urology Clinic, Hopital Pitie-Salpetriere, 47-83 bd de Phopital, 75634 Paris Cedex 13, France.
 Clinical Trials, Bion Diagnostic Sciences, 12277 134th Avenue NE, Redmond, WA 98052.
 Nonstandard abbreviations: hCFHrp, human complement factor H-related protein; hCFH, human complement factor H; MAb, monoclonal antibody; CI, confidence interval; and GU, genitourinary.
* Address correspondence to this author at: Krankenhaus Nordwest, Laboratoriumsmedizin, Steinbacher Hold 2, D-60489, Frankfurt, Germany. Fax 49 69 76013647; e-mail firstname.lastname@example.org.
Received July 20, 1998; accepted January 21, 1999.
Table 1. Sensitivity by patient type. Sensitivity Patient type Test n (a) % 95% CI, % No history of BC (b) BTA TRAK 49 76 61-87 Cytology 49 33 19-48 History of BC BTA TRAK 51 57 42-71 Cytology 51 33 21-48 All BTA TRAK 100 66 56-75 Cytology 100 33 24-43 (a) Total number of positive final diagnoses of bladder cancer. (b) BC, bladder cancer. Table 2. Comparison of sensitivity by grade and stage. Test n Sensitivity, % 95% CI, % P Grade I BTA TRAK 25 48 28-69 -0.001 Cytology 25 4 0.1-20 1I BTA TRAK 41 59 42-74 0.001 Cytology 41 22 11-38 III BTA TRAK 34 88 73-97 0.077 Cytology 34 68 50-83 Stage [T.sub.a] BTA TRAK 55 51 37-65 -0.001 Cytology 55 15 7-27 [T.sub.2] - [T.sub.4] BTA TRAK 24 88 68-97 0.011 Cytology 24 50 29-71 T2 -T4 BTA TRAK 16 88 62-98 0.113 Cytology 16 56 30-80 [T.sub.is] BTA TRAK 5 60 15-95 1.00 Cytology 5 80 28-100 Table 3. BTA TRAK assay specificity by patient type and GU disease status. Specificity Patients with GU diseases Patient type n (b) % 95% CI % No history of BC (c) 22 41 21-64 History of BC 9 67 30-93 All 31 48 30-67 Specificity Patients with no GU diseases Patient type n (b) % 95% CI % No history of BC (c) 25 64 43-82 History of BC 64 81 70-90 All 89 76 66-85 (a) Benign or malignant GU disease other than bladder cancer. (b) Total number of negative final diagnoses of bladder cancer. (c) BC, bladder cancer. Table 4. The BTA TRAK assay vs cytology (as complementary tests). Test Sensitivity, % Specificity, % BTA TRAK 66% (66 of 100) (a) 69% (83 of 120) Cytology 33% (33 of 100) 99% (119 of 120) Two tests 71% (71 of 100) 69% (83 of 120) Any one test positive Both tests negative Two tests 28% (28 of 100) 99% (119 of 120) Both tests positive Any one test negative (a) Number of positive results.
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|Title Annotation:||Test Utilization and Outcomes|
|Author:||Thomas, Lothar; Leyh, Herbert; Marberger, Michael; Bombardieri, Emilio; Bassi, Pierfrancesco; Pagano|
|Date:||Apr 1, 1999|
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