FLUORESCENCE ENDOSCOPY WITH 5-AMINOLEVULINIC ACID REDUCES EARLY RECURRENCE RATE IN SUPERFICIAL BLADDER CANCER

0022-5347/01/1654-1121/0 THE JOURNAL OF UROLOGY® Copyright © 2001 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 165, 1121–1123, April 2001 Printed in U.S.A.

FLUORESCENCE ENDOSCOPY WITH 5-AMINOLEVULINIC ACID REDUCES EARLY RECURRENCE RATE IN SUPERFICIAL BLADDER CANCER CLAUS R. RIEDL, DMITRI DANILTCHENKO, FRANK KOENIG, REINER SIMAK, STEFAN A. LOENING AND H. PFLUEGER From the Department of Urology and Ludwig Boltzmann Institute of Andrology, Municipal Hospital Lainz, Vienna, Austria, and Department of Urology, Charite´ Medical School, Humboldt-University, Berlin, Germany

ABSTRACT

Purpose: Several investigators have demonstrated an approximately 20% higher tumor detection rate by 5-aminolevulinic acid (ALA) fluorescence endoscopy compared to standard white light cystoscopy, and suggested a reduction in tumor recurrences when fluorescence endoscopy was performed as standard procedure during transurethral resection. We test this hypothesis. Materials and Methods: In a prospective randomized multicenter study 102 patients underwent transurethral resection of bladder tumor(s) either with white light or ALA fluorescence assisted endoscopy. A second look transurethral resection with ALA fluorescence endoscopy was performed 6 weeks after the initial operation. Results: At second look transurethral resection tumor was detected in 20 of 51 patients (39%) in the white light group and in 8 of 51 (16%) in the ALA fluorescence endoscopy group. This difference was statistically significant (p ⫽ 0.005). Conclusions: ALA fluorescence endoscopy is an innocuous and inexpensive diagnostic procedure that significantly improves bladder tumor detection rates compared to standard white light endoscopy. In our controlled study ALA fluorescence endoscopy reduced the residual tumor detection rate at second look transurethral resection by 59%. KEY WORDS: aminolevulinic acid, fluorescence, endoscopy, bladder neoplasms

Tumor recurrence is a main problem of superficial bladder cancer, with rates of up to 70% within 5 years,1 depending on stage and grade of the primary tumor(s). Recurrent tumors have a great impact on patient morbidity and on medical care systems that pay the costs of reoperations. The high rate of early recurrences (up to 60% within 3 months) reported by several authors2–5 leads to suspicion that a significant percentage of so-called tumor recurrences are persistent tumors overlooked at initial resection. A method that improves endoscopic tumor detection would be beneficial, especially for multilocular disease and tiny satellite tumors, and should reduce the rate of early recurrences. Since the first reports on the use of 5-aminolevulinic acid (ALA) for detection of bladder cancer by Kriegmair et al in 1996,6 several authors have shown that ALA fluorescence assisted endoscopy increases tumor detection rates by 20% to 25% compared to standard cystoscopy.7–11 However, these results were not obtained in randomized studies and did not include followup and recurrence rates. We designed a 2 center, prospective randomized trial that compared the early recurrence rates on second look transurethral resection in patients after standard white light versus ALA fluorescence assisted endoscopic resection.

sisted endoscopy. Each center had an individual randomization code formulated before initiation of the study. Since suspicion of bladder tumor was the only inclusion criterion, no stratification as to tumor stage, grade or demographic data was performed. Preparation for fluorescence endoscopy has been described previously.9 Briefly, 1.5 gm. ALA in 50 cc sodium bicarbonate 1.4% to adjust pH to 6.5 were instilled into the empty bladder 1 to 4 hours before endoscopy. A high power white light source with a bandpass filter (380 to 450 nm.) for violet-blue light was used to induce red fluorescence. For endoscopic examination of the bladder specially designed 30-degree optical lenses were used with an integrated light cable to maximize illumination, and a yellow filter to reduce the blue background light and thereby optimize discrimination between normal blue urothelium and red fluorescing areas (figs. 1 and 2). In both patient groups all visible tumor or suspicious lesions were resected. Patients with greater than T1 lesions on histological examination were excluded from further evalua-

MATERIALS AND METHODS

From August 1998 to January 2000 patients with suspected bladder tumor on prior cystoscopy, ultrasound or cytology and with no history of surgical or medical therapy for bladder cancer during the preceding 6 months gave informed consent and were enrolled in the study. All patients were randomized to undergo primary transurethral resection either with conventional white light or ALA fluorescence asAccepted for publication November 10, 2000.

FIG. 1. Carcinoma in situ visualized with ALA fluorescence (A) and white light (B) endoscopy. 1121

1122

FLUORESCENCE ENDOSCOPY FOR SUPERFICIAL BLADDER CANCER TABLE 2. Primary characteristics of tumor recurrence found at second look transurethral resection

FIG. 2. Tiny papillary tumors visualized with white light (A) are larger and better delineated with ALA fluorescence endoscopy (B).

tion and underwent cystectomy. All other patients underwent ALA fluorescence assisted second look transurethral resection 6 weeks after the initial resection. During this operation the former tumor site as well as all newly diagnosed lesions were resected and sent for histological evaluation. None of the randomized patients received adjuvant intravesical therapy throughout the study. Statistical analysis of recurrence rates was performed by Fisher’s exact test with p ⬍0.05 considered statistically significant. RESULTS

Of the 115 patients (56 from 1 center and 59 from the other center) initially randomized for the study 13 were excluded after primary transurethral resection because of muscle invasive bladder cancer on microscopic examination. There were 51 cases treated with white light (group 1) and 51 treated with ALA fluorescence (group 2) with comparable demographic and tumor characteristics (table 1). Mean patient age was 67 years (range 19 to 86). Patients were equally distributed between both centers with no statistically significant difference in any variable. At second look transurethral resection tumor was detected in 28 of 102 patients (27.4%), including 20 (39%) in group 1 and 8 (16%) in group 2. The difference between both groups was statistically significant (p ⫽ 0.005). Orthotopic tumors were found in 16 patients, heterotopic tumors in 13 and heterotopic and orthotopic recurrence in 1 (table 2). A statistically significant difference in recurrence rates was noted for primary Ta (p ⫽ 0.05) and T1 (p ⫽ 0.01) tumors, and G2 (p ⫽ 0.008) and multilocular (p ⫽ 0.008) tumors but not for G1 (p ⫽ 0.43), G3 (p ⫽ 0.37) and single (p ⫽ 0.12) tumors. In 1 group 1 patient no tumor was found on microscopic examination of the primarily resected tissue. However, multilocular pTaG2 tumor was found and histologically confirmed at the second fluorescence assisted resection. Tumor progression occurred in 2 patients who subsequently underwent cystectomy. No negative side effects from ALA instillation occurred.

TABLE 1. Patients characteristics Total pts. Center 1 pts. Center 2 pts. Men Women Tumor type: TaG1 TaG2 TaG3 T1G1 T1G2 T1G3 Solitary Multilocular Concomitant Ca in situ

No. Group 1

No. Group 2

51 25 26 37 14

51 26 25 36 15

7 30 3 0 9 2 31 20 1

7 29 4 2 6 3 19 32 0

% Recurrence rate (No./total No.) No. orthotopic No. heterotopic % Primary stage (No./total No.): Ta T1 % Primary grade (No./total No.): G1 G2 G3 % Primary solitary tumor (No./ total No.) % Primary multilocular tumor (No./total No.) % Center 1 (No./total No.) % Center 2 (No./total No.)

Group p 1

Group 2 (ALA)

p Values

39 (20/51) 10 10

16 (8/51) 6 2

0.005 0.1 ⬍0.05

33 (13/39) 58 (7/12)

18 (7/40) 9 (1/11)

⬍0.05 ⬍0.05

14 (1/7) 41 (16/39) 60 (3/5) 32 (10/31)

0 (0/9) 14 (5/35) 43 (3/7) 16 (3/19)

0.4 ⬍0.05 0.3 0.1

50 (10/20)

16 (5/32)

⬍0.05

36 (9/25) 42 (11/26)

8 (2/26) 24 (6/25)

0.01 0.04

DISCUSSION

The reported rate of tumors found at second look resection is 30% to 40% for all superficial bladder tumors,2–5 and with an increasing percentage of T1, G3 and multilocular tumors it may be as high as 60%. Thus, routine second look transurethral resection 4 to 6 weeks after the initial operation has been advocated by many investigators to remove residual tumors.4, 5, 12 When the potential for about 20% additional tumor detection by ALA fluorescence endoscopy is considered, the early recurrence rate of superficial bladder cancer might be lowered to 10% to 20%. In accordance with this hypothesis, we demonstrated an early recurrence rate of 39% for an unselect group of patients with superficial bladder cancer treated with a conventional technique, whereas the recurrence rate was significantly decreased to 16% in the ALA group. Thus, using ALA the overall recurrence rate of superficial bladder carcinoma was reduced by 59%. Primary tumor stages were comparable in both groups, with the only difference being a higher percentage of (unfavorable) multifocal tumors in the ALA group. The statistically significant difference in recurrence rates was demonstrable for most tumor subgroups (Ta/1, G2, multifocal) but not for G1 and G3 tumors, most probably due to the small number of patients in these subgroups, or single tumors. To our knowledge, there has been only 1 other randomized study comparing white light and fluorescence transurethral resection in patients with superficial bladder cancer.13 The authors found a 59.4% early recurrence rate in the white light group compared to 38.5% in the ALA group, with the second look resection performed 10 to 14 days after the initial procedure under white light. The difference was statistically significant but interpretation is difficult, as the almost 60% recurrence rate in the white light group, which included 80% of the randomized cases in the low/moderate risk groups, was high. Similarly, the almost 40% recurrence rate in the ALA group is difficult to explain, as followup endoscopy was performed under white light and, thus, should have been less informative than the fluorescence procedure. In addition, there was a 39% dropout rate of randomized patients, which significantly interfered with statistical analysis of the results. The 59% reduction in early recurrence rate in our study could have great impact on the morbidity of patients with superficial bladder cancer. Even if this is not a life threatening disease in most cases because progression infrequently occurs, institution of ALA fluorescence endoscopy may spare every second patient a reoperation within 6 weeks after transurethral resection. Despite the excellent visibility of even the tiniest tumors, which may be also difficult to detect for the examining pathologist, 16% of tumors remain undetected in the ALA group at second look transurethral resection. Possible reasons for

FLUORESCENCE ENDOSCOPY FOR SUPERFICIAL BLADDER CANCER

nondetection of tumors with ALA have been discussed previously when the sensitivity of this procedure was reported to be about 95%.6, 9, 14 Incorporated in the intracellular heme synthesis cycle, ALA is metabolized to protoporphyrine IX, which is a potent photosensitizer.6, 15 Protoporphyrine IX selectively accumulates in malignant and dysplastic urothelial cells, and administration of blue light leads to its red fluorescence. Short instillation times, well differentiated tumors with incipient cell dedifferentiation and only minor metabolic changes or photobleaching may be responsible for tumors missed on fluorescence endoscopy. However, this undetection may apply only to heterotopic tumors. In our series 6 of 8 early recurrences (75%) in the ALA fluorescence endoscopy group were orthotopic tumors. Since tumor resection was performed using a standardized method with separate resection of tumor margins, incomplete resection of the primary lesion is improbable. At this point, the etiology of early recurrences has to be discussed. In addition to a small number of true recurrences that are not present or detectable at primary transurethral resection, most of the tumors found at second look resection are residual and overlooked at the initial operation. True recurrences and residual tumors are more likely to be heterotopic. In addition, it is likely that tumors are implanted at the site of resection from tumor cells resected at the initial procedure. Free-floating, brightly fluorescing resected tumor clumps are frequently observed during ALA transurethral resection, which suggests that implantation may be the origin of orthotopic tumor recurrence in a significant percentage of cases. The results of our study and of the aforementioned investigations refer to optimal indications for the institution of fluorescence endoscopy and to suggestions for the operative and postoperative management of superficial bladder cancer. Fluorescence endoscopy is recommended for all multifocal tumors, carcinoma in situ and positive cytology/negative endoscopy cases, second look resection of all T1 and G3 tumors, and transurethral resection in cases treated with extensive prior endoscopic surgery or instillation therapy, which are difficult to investigate endoscopically. Filbeck et al reported that for optimal evaluation fluorescence assisted second look transurethral resection should not be performed earlier than 6 weeks after the initial operation,16 which was the interval we used. The high rate of orthotopic recurrences in the ALA group, possibly due to tumor implantation, is a strong argument for perioperative mitomycin C instillation therapy.17 Only 2 (4%) heterotopic recurrences were found in the ALA group. If these are regarded as true recurrences/new tumors, any tumor found at second look endoscopy after primary ALA transurethral resection might be an ominous sign of bladder cancer at high risk for recurrence and mandate immediate recurrence prophylaxis, preferably with bacillus CalmetteGuerin.18, 19 No side effects due to intravesical administration of ALA for fluorescence endoscopy have been reported.7–10, 20 With total costs of about $20,000 for fluorescence endoscopy equipment, which can also be used for standard endoscopy and, thus, may replace standard light sources and cystoscopes, and individual costs of about $60 per ALA instillation, fluorescence endoscopy is an innocuous and inexpensive diagnostic procedure that is significantly superior to conventional white light endoscopy. It should be added to standard evaluation methods of superficial bladder cancer based on the aforementioned indications. Dr. Robert L. Stephen critically reviewed the study design and data, and provided invaluable assistance with manuscript editing.

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