- Email: [email protected]
The Effect of Repeat Transurethral Resection on Recurrence and Progression Rates in Patients With T1 Tumors of the Bladder Who Received Intravesical Mitomycin: A Prospective, Randomized Clinical Trial
The Effect of Repeat Transurethral Resection on Recurrence and Progression Rates in Patients With T1 Tumors of the Bladder Who Received Intravesical Mitomycin: A Prospective, Randomized Clinical Trial Rauf Taner Dı˙vrı˙k,* Ümı˙t Yildirim, Ferruh Zorlu and Haluk Özen From the Department of Urology, SB Tepecik Research and Teaching Hospital, I˙zmir (RTD, ÜY, FZ), and the Department of Urology, Hacettepe University, Ankara (HÖ), Turkey
Purpose: We compared the outcomes of repeat transurethral resection plus intravesical mitomycin C with initial transurethral resection of bladder plus intravesical MMC in patients with newly diagnosed pT1 transitional cell carcinoma of the bladder in terms of recurrence, progression and overall survival. Materials and Methods: Of 148 newly diagnosed patients with T1 bladder cancer 142 were prospectively randomized in 2 groups between January 2001 and January 2005. A total of 74 patients underwent second TURB and received adjuvant MMC intravesically (group 1) and 68 patients received adjuvant MMC following the initial TURB (group 2). All repeat TURB operations were performed 2 to 6 weeks following initial TURB. Patients with incomplete resection, Cis or muscle invasive disease were excluded from study. The first dose of mitomycin C (40 mg per week for a total of 8 weeks) was instilled intravesically in all patients during the first 24 hours after the last surgery. Results: Mean followup was 31.5 months (range 6 to 48) with no difference between the 2 groups. The rate of recurrence-free survival was 86.35% (SE 0.4%), 77.67% and 68.72% in group 1, and 47.08%, 42.31% and 37.01% in group 2 for the first, second and third year, respectively (overall 74.32% vs 36.76%, log rank 0.0001). Recurrence was observed in 19 of the 74 (25.68%) patients in group 1 and in 43 of the 68 (63.24%) patients in group 2. Ten of the 19 (52.63%) patients in group 1 and 35 of the 43 (81.39%) patients in group 2 had recurrence within 12 months. Recurrence was observed in 17.6%, 25% and 60% of patients with G1, G2 and G3 tumors, respectively, in group 1. The same rates for group 2 were 25%, 64% and 90%. The RFS rate was significantly worse in the high grade group (G2 and G3) (p ⬍0.001). Progression was observed at 4.05% for group 1 compared to 11.76% for group 2 (log rank 0.0974). OS was 91.89% and 89.71% in group 1 and 2, respectively (log rank 0.732). Conclusions: The high recurrence rate in patients who did not undergo ReTUR is due to a high residual tumor rate following initial TURB. The benefit of ReTUR is especially true for high grade tumors. Since intravesical MMC was present in both groups, this study has shown that intravesical chemotherapy does not compensate for inadequate resection. Progression does not seem to be affected by ReTUR although there was a trend favoring the ReTUR group. We recommend ReTUR for patients with primary high grade T1 disease to achieve better recurrence-free survival. Key Words: bladder neoplasms, reoperation, disease-free survival
ransurethral resection of bladder tumor(s) followed by adjuvant intravesical chemotherapy or immunotherapy is the treatment of choice in patients with superficial TCC of the bladder to delay or prevent tumor recurrence, and possibly to prevent tumor progression. Even with complete resection and intravesical instillation of the most effective agents many of these tumors still may recur. According to the results of our previous report1 and other recent studies2–7 initial TURB may be incomplete in a significant number of cases. Several studies have investigated the rate of complete resection and residual tumors after initial TURB. However, the effect of ReTUR in patients with newly diagnosed pT1 in regard to RFS, PFS and OS were not investigated widely in a prospective, controlled clinical trial.
In this prospective, controlled clinical trial we evaluated outcomes of patients with newly diagnosed pT1 TCC of the bladder treated with initial TURB only plus intravesical MMC vs initial TURB plus ReTUR plus intravesical MMC in terms of recurrence, progression and overall survival.
Submitted for publication April 26, 2005. Nothing to disclose. * Correspondence: 1394 SK. NO:11/13, Alsancak-Izmir, Turkey (telephone: ⫹90 232 4650888; FAX: ⫹90 232 4646050; e-mail: [email protected]).
Editor’s Note: This article is the first of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1970 and 1971.
T
0022-5347/06/1755-1641/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
MATERIALS AND METHODS Of 148 newly diagnosed patients with T1 bladder cancer 142 were prospectively randomized in 2 groups between January 2001 and January 2005. The aim was to resect all of the tumors completely. All of the resections were performed by experienced urologists in our department. A total of 74 pa-
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Vol. 175, 1641-1644, May 2006 Printed in U.S.A. DOI:10.1016/S0022-5347(05)01002-5
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REPEAT TRANSURETHRAL RESECTION OF BLADDER TUMORS TREATED WITH MITOMYCIN TABLE 1. Distribution of patients and tumor characteristics
Mean age (range) Mean mos followup (range) No. sex (%): Men Women No. solitary (%): Less than 3 cm Greater than 3 cm No. multiple (%): Less than 3 cm Greater than 3 cm No. solitary, less than 3 cm (%) No. multiple or greater than 3 cm (%) No. grade (%): 1 2 3 No. grade (%): Low (Grade 1) High (Grade 2 ⫹ 3)
Group 1
Group 2
Overall
p Value
62.5 (37–87) 31.0 (6–48)
64.7 (43–82) 32.1 (19–48)
63.5 (37–83) 31.5 (6–48)
0.194 0.508
67 (90.5) 7 (9.5)
66 (97.1) 2 (2.9)
133 (93.7) 9 (6.3)
0.169
15 (20.3) 25 (33.8)
18 (26.5) 14 (20.6)
33 (23.2) 39 (27.5)
0.157
19 (25.7) 15 (20.3) 15 (20.3) 59 (79.7)
14 (20.6) 22 (32.4) 18 (26.5) 50 (73.5)
33 (23.2) 37 (26.1) 33 (23.2) 109 (76.8)
17 (23.0) 52 (70.3) 5 (6.8)
8 (11.8) 50 (73.5) 10 (14.7)
25 (17.6) 102 (71.8) 15 (10.6)
0.095
17 (23.0) 57 (77.0)
8 (11.8) 60 (88.2)
25 (17.6) 117 (82.4)
0.080
tients underwent repeat TURB and received adjuvant MMC intravesically (group 1), and 68 patients received adjuvant MMC following initial TURB (group 2). All ReTUR operations were performed 2 to 6 weeks following the initial TURB. Patients with incomplete resection, Cis or muscle invasive disease were excluded from study. All patients received the first instillation of 40 mg MMC within 24 hours of the operation. The mean instillation time from the surgery was 2 hours in all patients. After the first instillation, additional 40 mg MMC were given weekly for 7 more weeks. To diagnose a patient with stage T1 disease, muscle tissue free of tumor must be present in the specimen as previously described.1 Urine cytology and followup cystoscopy were performed at 3-month intervals for the first year, biannually for the second year and annually thereafter. Excretory urography was performed yearly. The end points used to assess the efficacy of the treatment of groups were the time to histologically confirmed bladder cancer recurrence (RFS) and to progression to muscle invasive disease and/or presence of Cis. RFS, PFS and OS curves were calculated by the Kaplan-Meier method and compared by the log rank test. Tumors were classified according to the TNM system of the UICC8 and were graded according to WHO classification. Informed consent for the treatment strategy was obtained from each patient.
0.382
a residual tumor directly correlated with the grade of the initial tumor (p ⫽ 0.009).1 The rate of RFS was 86.35% (SE 0.4%), 77.67% and 68.72% in group 1, and 47.08%, 42.31% and 37.01% in group 2 for the first, the second and the third year, respectively (overall 74.32% vs 36.76%, log rank 0.0001). The recurrencefree curves for the 2 groups are shown in figure 1. Recurrence was observed in 19 of the 74 (25.68%) patients in group 1 and in 43 of the 68 (63.24%) patients in group 2. Ten of the 19 (52.63%) patients in group 1 and 35 of the 43 (81.39%) patients in group 2 recurred within 12 months (fig. 2). Median RFS was 27 months (range 6 to 48, mean 26.47) for group 1 compared with 12 months (range 3 to 48, mean 18.97) for group 2. Recurrence was observed 17.6%, 25% and 60% in patients with G1, G2 and G3 tumors, respectively in group 1. The same rates for group 2 were 25%, 64% and 90% (p ⫽ 0.64 for G1, p ⫽ 0.001, OR 5.33, 95% CI 2.27-12.51 for G2 and p ⫽ 0.24 for G3) (table 2). RFS rate was statistically different between 2 groups in terms of the high grade (G2-3) (p ⬍0.001) (table 2). Progression was observed in 3 of the 74 (4.05%) patients for group 1 compared to 8 of the 68 (11.76%) patients for group 2 (log rank 0.0974) (fig. 3). Of these 3 patients 1 had
RESULTS The mean age was 62.5 years (range 37 to 87) and 64.7 years (range 43 to 82) in group 1 and 2, respectively. Mean followup period was 31.5 months (range 6 to 48) without a significant difference between the groups. There were no significant imbalances in regard to demographics and tumor characteristics in the 2 groups (table 1). Since TCC was found to be present in all of the cases who had visible tumor, residual cancer was detected histopathologically in 27 patients (33.8%) in ReTUR group. In 12 of these patients the tumor was detected at the primary site, whereas in 11 patients tumor was detected elsewhere. The remaining 4 patients had residual tumors at the site of the first TURB and in another site. Residual cancers were detected in 5.8%, 38.2% and 62.5% in G1, G2 and G3 tumors, respectively in group 1. The risk of having
FIG. 1. Recurrence-free survival of group 1 vs group 2
REPEAT TRANSURETHRAL RESECTION OF BLADDER TUMORS TREATED WITH MITOMYCIN
FIG. 2. Distribution of patients with recurrence in 6-month period for each group.
cancer while the remaining 2 had no tumor on ReTUR. Of the 8 patients who had progression, 2 had Cis while 6 patients had muscle invasive disease in group 2. All of those patients who had progression to muscle invasive disease during followup underwent radical cystectomy, 3 from group 1 and 6 from group 2. All patients with Cis after ReTUR and/or during followup were treated with intracaviter BCG for a 6-week induction course. Median PFS was 28.5 months (range 6 to 48, mean 30.3) for group 1 compared to 32.0 months (range 6 to 48, mean 31.2) for group 2. Overall survival rate was 91.89% and 89.71% in group 1 and 2, respectively (log rank 0.732, fig. 4). Only 1 of the 6 patients in group 1 died of cancer as 2 of the 7 in group 2. DISCUSSION We have already reported our experience on the need of ReTUR in patients with primary T1 TCC of the bladder.
TABLE 2. Comparison of recurrence rates
FIG. 3. Progression-free survival of each group
Residual tumor rate was found to be 33.8% in 80 patients who underwent ReTUR following the primary diagnosis of T1 disease. Residual tumors were detected more often in high grade tumors compared to well differentiate tumors. While the residual tumor rate was 5.8% in G1 tumors it was 62.5% in patients with G3 tumors (p ⫽ 0.009).1 Thus, we have concluded that it was necessary to perform ReTUR in patients with newly diagnosed, high grade (G2-3), stage T1 bladder cancer for the true staging and complete resection. Grimm et al have investigated the role of ReTUR in a heterogeneous group of patients with superficial bladder cancer.7 They have found that the estimated risk of recurrence after years 1 to 3 was 18%, 29% and 32%, respectively and recurrence was observed in 30 of the 78 patients (38%) treated with ReTUR. In the present study the recurrence rate was 13.65%, 22.33% and 31.28% for group 1 in the first, the second and the third year respectively and overall recurrence was found in 19 of the 74 patients (25.68%) treated with ReTUR plus MMC. We also found the recurrence rate was 52.92%, 57.69% and 62.99% in the first, the second and the third year for group 2, respectively, and overall recurrence was found in 43 of the 68 patients (63.24%) treated
No. Recurrence (%) No
Yes
Totals
14 (82.4) 39 (75.0) 2 (40.0) 55 (74.3)
3 (17.6) 13 (25.0) 3 (60.0) 19 (25.7)
17 (100) 52 (100) 5 (100) 74 (100)
6 (75.0) 18 (36.0) 1 (10.0) 25 (36.8)
2 (25.0) 32 (64.0) 9 (90.0) 43 (63.2)
8 (100) 50 (100) 10 (100) 68 (100)
Histological grading* Group 1: Grade 1 Grade 2 Grade 3 Totals Group 2: Grade 1 Grade 2 Grade 3 Totals
High vs low grade† Group 1: Grade 1 Grade 2–3 Totals Group 2: Grade 1 Grade 2–3 Totals
14 (82.4) 41 (72.0) 55 (74.3)
3 (17.6) 16 (28.0) 19 (25.7)
17 (100) 57 (100) 74 (100)
6 (75.0) 19 (31.7) 25 (36.8)
2 (25.0) 41 (68.3) 43 (63.2)
8 (100) 60 (100) 68 (100)
* For G1 p ⫽ 0.64, for G2 p ⫽ 0.001, OR 5.33, 95% CI 2.27–12.51 and for G3 p ⫽ 0.24. † For high grade disease p ⬍0.001, OR 5.53, 95% CI 2.50–12.23.
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FIG. 4. Overall survival of group 1 vs group 2
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REPEAT TRANSURETHRAL RESECTION OF BLADDER TUMORS TREATED WITH MITOMYCIN
with initial TURB only plus MMC. It is noteworthy that there were significantly more recurrences in group 2 in the first 12 months compared to group 1 (52% vs 81%) (fig. 2). This effect highlights the favorable effect of ReTUR on recurrences. There was only 1 prospective study performed by Grimm et al that could be compared with the current study in terms of the impact of ReTUR on the recurrence and progression of the superficial TCC of the bladder. But in their study, 61 of the 78 patients (78.2%) were pTa tumors and there were 62% of cases with newly diagnosed bladder cancer, while 15% had a first, 9% had a second and 14% had multiple recurrences. Although recurrence and progression rates for Ta and T1 diseases were reported separately in the aforementioned study, meaningful analysis and comparison with the present study is not feasible since the numbers in each group were small. Moreover Grimm et al have not used intravesical therapy as a standard part of their protocol. Although European Association of Urology guidelines published in 2002 recommend intravesical adjuvant BCG for high risk superficial tumors,9 we have used intravesical mitomycin for several reasons. This study was initiated before the publication of the guidelines. Furthermore, although meta-analysis has demonstrated the superiority of BCG compared to mitomycin on recurrence especially in the maintenance group, not all studies produced similar results.10 Finally, since our study group consisted of intermediate and high risk patients with no Cis the results of those aforementioned studies may not be totally applicable. Progression rate was observed in 4.05% (all of the 3 patients progressed to muscle invasive disease) for group 1 compared to 11.76% (6 of the 8 patients progressed to muscle invasive disease, 2 of the 8 patients had Cis) for group 2 (log rank 0.0974) after a mean followup of 31 months in our study. Progression to muscle invasive disease was observed in 2 patients (3%) treated with ReTUR after a mean followup of 61 months in the study performed by Grimm et al. According to tumor grade there was no statistically significant difference between 2 patient groups with G1 bladder tumors in terms of recurrence (p ⫽ 0.64). However, a significant difference of recurrence was found in patients with G2 tumors (p ⫽ 0.001). The absence of statistical significance in G3 tumors may be attributed to the low number of patients in this subgroup. When we compared the recurrence-free survival for the 2 groups in terms of high and low grade, there was a statistically significant difference between the 2 patient groups with high grade (G2-3) tumors (p ⬍0.001). CONCLUSIONS The high recurrence rate in patients without undergoing ReTUR is due to a high residual tumor rate following initial TUR. The significantly shorter recurrence-free period in group 2 also suggests the presence of residual tumors rather than true recurrence. The benefit of ReTUR is especially true for high grade tumors. Since intravesical MMC was present in both groups, this study has shown that intravesical chemotherapy does not compensate for inadequate re-
section. The role for adjuvant intravesical chemotherapy or immunotherapy following ReTUR must be addressed in a separate setting. Progression does not seem to be affected by ReTUR although there was a trend favoring the ReTUR group. The number of events must increase and the followup period must be extended to reach definitive conclusions with regard to progression. We recommend ReTUR for patients with primary high grade T1 disease to achieve better recurrencefree survival.
Abbreviations and Acronyms BCG Cis MMC OS PFS ReTUR RFS TCC TURB
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
bacillus Calmette-Guerin carcinoma in situ mitomycin C overall survival progression-free survival repeat transurethral resection recurrence-free survival transitional cell carcinoma transurethral resection of the bladder
REFERENCES ¨ ., Erog˘lu, A., Zorlu, F. and Özen, H.: Is a 1. Divrik, T., Yıldırım, U second transurethral resection necessary for newly diagnosed pT1 bladder cancer? J Urol, 175: 000, 2006 2. Klän, R., Loy, V. and Huland, H.: Residual tumor discovered in routine second transurethral resection in patients with stage T1 transitional cell carcinoma of the bladder. J Urol, 146: 316, 1991 3. Mersdorf, A., Brauers, A., Wolff, J. M., Schneider, V. and Jakse, G.: 2nd TUR for superficial bladder cancer: a must? J Urol, suppl., 159: 143, abtract 542, 1998 4. Herr, H. W.: The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol, 162: 74, 1999 5. Schips, L., Augustin, H., Zigeuner, R. E., Galle, G., Habermann, H., Trummer, H. et al: Is repeated transurethral resection justified in patients with newly diagnosed superficial bladder cancer? Urology, 59: 220, 2002 6. Dalbagni, G., Herr, H. W. and Reuter, V. E.: Impact of a second transurethral resection on the staging of T1 bladder cancer. Urology, 60: 822, 2002 7. Grimm, M. O., Steinhoff, C., Simon, X., Spiegelhalder, P., Ackermann, R. and Vögeli, T. A.: Effect of routine repeat transurethral resection for superficial bladder cancer a long-term observational study. J Urol, 170: 433, 2003 8. Sobin, L. H. and Wittekind, C. H.: Urinary bladder. In: TNM Classification of Malignant Tumours, 5th edition. International Union Against Cancer (UICC). New York: Wiley-Liss, p. 187, 1997 9. Oosterlinck, W., Lobel, B., Jakse, G., Malmstrom, P., Stockle, M., Sternberg, C. et al: Guidelines on bladder cancer. Eur Urol, 41: 105, 2002 10. Böhle, A., Jocham, D. and Bock, P. R.: Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol, 169: 90, 2003
Purpose: We compared the outcomes of repeat transurethral resection plus intravesical mitomycin C with initial transurethral resection of bladder plus intravesical MMC in patients with newly diagnosed pT1 transitional cell carcinoma of the bladder in terms of recurrence, progression and overall survival. Materials and Methods: Of 148 newly diagnosed patients with T1 bladder cancer 142 were prospectively randomized in 2 groups between January 2001 and January 2005. A total of 74 patients underwent second TURB and received adjuvant MMC intravesically (group 1) and 68 patients received adjuvant MMC following the initial TURB (group 2). All repeat TURB operations were performed 2 to 6 weeks following initial TURB. Patients with incomplete resection, Cis or muscle invasive disease were excluded from study. The first dose of mitomycin C (40 mg per week for a total of 8 weeks) was instilled intravesically in all patients during the first 24 hours after the last surgery. Results: Mean followup was 31.5 months (range 6 to 48) with no difference between the 2 groups. The rate of recurrence-free survival was 86.35% (SE 0.4%), 77.67% and 68.72% in group 1, and 47.08%, 42.31% and 37.01% in group 2 for the first, second and third year, respectively (overall 74.32% vs 36.76%, log rank 0.0001). Recurrence was observed in 19 of the 74 (25.68%) patients in group 1 and in 43 of the 68 (63.24%) patients in group 2. Ten of the 19 (52.63%) patients in group 1 and 35 of the 43 (81.39%) patients in group 2 had recurrence within 12 months. Recurrence was observed in 17.6%, 25% and 60% of patients with G1, G2 and G3 tumors, respectively, in group 1. The same rates for group 2 were 25%, 64% and 90%. The RFS rate was significantly worse in the high grade group (G2 and G3) (p ⬍0.001). Progression was observed at 4.05% for group 1 compared to 11.76% for group 2 (log rank 0.0974). OS was 91.89% and 89.71% in group 1 and 2, respectively (log rank 0.732). Conclusions: The high recurrence rate in patients who did not undergo ReTUR is due to a high residual tumor rate following initial TURB. The benefit of ReTUR is especially true for high grade tumors. Since intravesical MMC was present in both groups, this study has shown that intravesical chemotherapy does not compensate for inadequate resection. Progression does not seem to be affected by ReTUR although there was a trend favoring the ReTUR group. We recommend ReTUR for patients with primary high grade T1 disease to achieve better recurrence-free survival. Key Words: bladder neoplasms, reoperation, disease-free survival
ransurethral resection of bladder tumor(s) followed by adjuvant intravesical chemotherapy or immunotherapy is the treatment of choice in patients with superficial TCC of the bladder to delay or prevent tumor recurrence, and possibly to prevent tumor progression. Even with complete resection and intravesical instillation of the most effective agents many of these tumors still may recur. According to the results of our previous report1 and other recent studies2–7 initial TURB may be incomplete in a significant number of cases. Several studies have investigated the rate of complete resection and residual tumors after initial TURB. However, the effect of ReTUR in patients with newly diagnosed pT1 in regard to RFS, PFS and OS were not investigated widely in a prospective, controlled clinical trial.
In this prospective, controlled clinical trial we evaluated outcomes of patients with newly diagnosed pT1 TCC of the bladder treated with initial TURB only plus intravesical MMC vs initial TURB plus ReTUR plus intravesical MMC in terms of recurrence, progression and overall survival.
Submitted for publication April 26, 2005. Nothing to disclose. * Correspondence: 1394 SK. NO:11/13, Alsancak-Izmir, Turkey (telephone: ⫹90 232 4650888; FAX: ⫹90 232 4646050; e-mail: [email protected]).
Editor’s Note: This article is the first of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1970 and 1971.
T
0022-5347/06/1755-1641/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
MATERIALS AND METHODS Of 148 newly diagnosed patients with T1 bladder cancer 142 were prospectively randomized in 2 groups between January 2001 and January 2005. The aim was to resect all of the tumors completely. All of the resections were performed by experienced urologists in our department. A total of 74 pa-
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Vol. 175, 1641-1644, May 2006 Printed in U.S.A. DOI:10.1016/S0022-5347(05)01002-5
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REPEAT TRANSURETHRAL RESECTION OF BLADDER TUMORS TREATED WITH MITOMYCIN TABLE 1. Distribution of patients and tumor characteristics
Mean age (range) Mean mos followup (range) No. sex (%): Men Women No. solitary (%): Less than 3 cm Greater than 3 cm No. multiple (%): Less than 3 cm Greater than 3 cm No. solitary, less than 3 cm (%) No. multiple or greater than 3 cm (%) No. grade (%): 1 2 3 No. grade (%): Low (Grade 1) High (Grade 2 ⫹ 3)
Group 1
Group 2
Overall
p Value
62.5 (37–87) 31.0 (6–48)
64.7 (43–82) 32.1 (19–48)
63.5 (37–83) 31.5 (6–48)
0.194 0.508
67 (90.5) 7 (9.5)
66 (97.1) 2 (2.9)
133 (93.7) 9 (6.3)
0.169
15 (20.3) 25 (33.8)
18 (26.5) 14 (20.6)
33 (23.2) 39 (27.5)
0.157
19 (25.7) 15 (20.3) 15 (20.3) 59 (79.7)
14 (20.6) 22 (32.4) 18 (26.5) 50 (73.5)
33 (23.2) 37 (26.1) 33 (23.2) 109 (76.8)
17 (23.0) 52 (70.3) 5 (6.8)
8 (11.8) 50 (73.5) 10 (14.7)
25 (17.6) 102 (71.8) 15 (10.6)
0.095
17 (23.0) 57 (77.0)
8 (11.8) 60 (88.2)
25 (17.6) 117 (82.4)
0.080
tients underwent repeat TURB and received adjuvant MMC intravesically (group 1), and 68 patients received adjuvant MMC following initial TURB (group 2). All ReTUR operations were performed 2 to 6 weeks following the initial TURB. Patients with incomplete resection, Cis or muscle invasive disease were excluded from study. All patients received the first instillation of 40 mg MMC within 24 hours of the operation. The mean instillation time from the surgery was 2 hours in all patients. After the first instillation, additional 40 mg MMC were given weekly for 7 more weeks. To diagnose a patient with stage T1 disease, muscle tissue free of tumor must be present in the specimen as previously described.1 Urine cytology and followup cystoscopy were performed at 3-month intervals for the first year, biannually for the second year and annually thereafter. Excretory urography was performed yearly. The end points used to assess the efficacy of the treatment of groups were the time to histologically confirmed bladder cancer recurrence (RFS) and to progression to muscle invasive disease and/or presence of Cis. RFS, PFS and OS curves were calculated by the Kaplan-Meier method and compared by the log rank test. Tumors were classified according to the TNM system of the UICC8 and were graded according to WHO classification. Informed consent for the treatment strategy was obtained from each patient.
0.382
a residual tumor directly correlated with the grade of the initial tumor (p ⫽ 0.009).1 The rate of RFS was 86.35% (SE 0.4%), 77.67% and 68.72% in group 1, and 47.08%, 42.31% and 37.01% in group 2 for the first, the second and the third year, respectively (overall 74.32% vs 36.76%, log rank 0.0001). The recurrencefree curves for the 2 groups are shown in figure 1. Recurrence was observed in 19 of the 74 (25.68%) patients in group 1 and in 43 of the 68 (63.24%) patients in group 2. Ten of the 19 (52.63%) patients in group 1 and 35 of the 43 (81.39%) patients in group 2 recurred within 12 months (fig. 2). Median RFS was 27 months (range 6 to 48, mean 26.47) for group 1 compared with 12 months (range 3 to 48, mean 18.97) for group 2. Recurrence was observed 17.6%, 25% and 60% in patients with G1, G2 and G3 tumors, respectively in group 1. The same rates for group 2 were 25%, 64% and 90% (p ⫽ 0.64 for G1, p ⫽ 0.001, OR 5.33, 95% CI 2.27-12.51 for G2 and p ⫽ 0.24 for G3) (table 2). RFS rate was statistically different between 2 groups in terms of the high grade (G2-3) (p ⬍0.001) (table 2). Progression was observed in 3 of the 74 (4.05%) patients for group 1 compared to 8 of the 68 (11.76%) patients for group 2 (log rank 0.0974) (fig. 3). Of these 3 patients 1 had
RESULTS The mean age was 62.5 years (range 37 to 87) and 64.7 years (range 43 to 82) in group 1 and 2, respectively. Mean followup period was 31.5 months (range 6 to 48) without a significant difference between the groups. There were no significant imbalances in regard to demographics and tumor characteristics in the 2 groups (table 1). Since TCC was found to be present in all of the cases who had visible tumor, residual cancer was detected histopathologically in 27 patients (33.8%) in ReTUR group. In 12 of these patients the tumor was detected at the primary site, whereas in 11 patients tumor was detected elsewhere. The remaining 4 patients had residual tumors at the site of the first TURB and in another site. Residual cancers were detected in 5.8%, 38.2% and 62.5% in G1, G2 and G3 tumors, respectively in group 1. The risk of having
FIG. 1. Recurrence-free survival of group 1 vs group 2
REPEAT TRANSURETHRAL RESECTION OF BLADDER TUMORS TREATED WITH MITOMYCIN
FIG. 2. Distribution of patients with recurrence in 6-month period for each group.
cancer while the remaining 2 had no tumor on ReTUR. Of the 8 patients who had progression, 2 had Cis while 6 patients had muscle invasive disease in group 2. All of those patients who had progression to muscle invasive disease during followup underwent radical cystectomy, 3 from group 1 and 6 from group 2. All patients with Cis after ReTUR and/or during followup were treated with intracaviter BCG for a 6-week induction course. Median PFS was 28.5 months (range 6 to 48, mean 30.3) for group 1 compared to 32.0 months (range 6 to 48, mean 31.2) for group 2. Overall survival rate was 91.89% and 89.71% in group 1 and 2, respectively (log rank 0.732, fig. 4). Only 1 of the 6 patients in group 1 died of cancer as 2 of the 7 in group 2. DISCUSSION We have already reported our experience on the need of ReTUR in patients with primary T1 TCC of the bladder.
TABLE 2. Comparison of recurrence rates
FIG. 3. Progression-free survival of each group
Residual tumor rate was found to be 33.8% in 80 patients who underwent ReTUR following the primary diagnosis of T1 disease. Residual tumors were detected more often in high grade tumors compared to well differentiate tumors. While the residual tumor rate was 5.8% in G1 tumors it was 62.5% in patients with G3 tumors (p ⫽ 0.009).1 Thus, we have concluded that it was necessary to perform ReTUR in patients with newly diagnosed, high grade (G2-3), stage T1 bladder cancer for the true staging and complete resection. Grimm et al have investigated the role of ReTUR in a heterogeneous group of patients with superficial bladder cancer.7 They have found that the estimated risk of recurrence after years 1 to 3 was 18%, 29% and 32%, respectively and recurrence was observed in 30 of the 78 patients (38%) treated with ReTUR. In the present study the recurrence rate was 13.65%, 22.33% and 31.28% for group 1 in the first, the second and the third year respectively and overall recurrence was found in 19 of the 74 patients (25.68%) treated with ReTUR plus MMC. We also found the recurrence rate was 52.92%, 57.69% and 62.99% in the first, the second and the third year for group 2, respectively, and overall recurrence was found in 43 of the 68 patients (63.24%) treated
No. Recurrence (%) No
Yes
Totals
14 (82.4) 39 (75.0) 2 (40.0) 55 (74.3)
3 (17.6) 13 (25.0) 3 (60.0) 19 (25.7)
17 (100) 52 (100) 5 (100) 74 (100)
6 (75.0) 18 (36.0) 1 (10.0) 25 (36.8)
2 (25.0) 32 (64.0) 9 (90.0) 43 (63.2)
8 (100) 50 (100) 10 (100) 68 (100)
Histological grading* Group 1: Grade 1 Grade 2 Grade 3 Totals Group 2: Grade 1 Grade 2 Grade 3 Totals
High vs low grade† Group 1: Grade 1 Grade 2–3 Totals Group 2: Grade 1 Grade 2–3 Totals
14 (82.4) 41 (72.0) 55 (74.3)
3 (17.6) 16 (28.0) 19 (25.7)
17 (100) 57 (100) 74 (100)
6 (75.0) 19 (31.7) 25 (36.8)
2 (25.0) 41 (68.3) 43 (63.2)
8 (100) 60 (100) 68 (100)
* For G1 p ⫽ 0.64, for G2 p ⫽ 0.001, OR 5.33, 95% CI 2.27–12.51 and for G3 p ⫽ 0.24. † For high grade disease p ⬍0.001, OR 5.53, 95% CI 2.50–12.23.
1643
FIG. 4. Overall survival of group 1 vs group 2
1644
REPEAT TRANSURETHRAL RESECTION OF BLADDER TUMORS TREATED WITH MITOMYCIN
with initial TURB only plus MMC. It is noteworthy that there were significantly more recurrences in group 2 in the first 12 months compared to group 1 (52% vs 81%) (fig. 2). This effect highlights the favorable effect of ReTUR on recurrences. There was only 1 prospective study performed by Grimm et al that could be compared with the current study in terms of the impact of ReTUR on the recurrence and progression of the superficial TCC of the bladder. But in their study, 61 of the 78 patients (78.2%) were pTa tumors and there were 62% of cases with newly diagnosed bladder cancer, while 15% had a first, 9% had a second and 14% had multiple recurrences. Although recurrence and progression rates for Ta and T1 diseases were reported separately in the aforementioned study, meaningful analysis and comparison with the present study is not feasible since the numbers in each group were small. Moreover Grimm et al have not used intravesical therapy as a standard part of their protocol. Although European Association of Urology guidelines published in 2002 recommend intravesical adjuvant BCG for high risk superficial tumors,9 we have used intravesical mitomycin for several reasons. This study was initiated before the publication of the guidelines. Furthermore, although meta-analysis has demonstrated the superiority of BCG compared to mitomycin on recurrence especially in the maintenance group, not all studies produced similar results.10 Finally, since our study group consisted of intermediate and high risk patients with no Cis the results of those aforementioned studies may not be totally applicable. Progression rate was observed in 4.05% (all of the 3 patients progressed to muscle invasive disease) for group 1 compared to 11.76% (6 of the 8 patients progressed to muscle invasive disease, 2 of the 8 patients had Cis) for group 2 (log rank 0.0974) after a mean followup of 31 months in our study. Progression to muscle invasive disease was observed in 2 patients (3%) treated with ReTUR after a mean followup of 61 months in the study performed by Grimm et al. According to tumor grade there was no statistically significant difference between 2 patient groups with G1 bladder tumors in terms of recurrence (p ⫽ 0.64). However, a significant difference of recurrence was found in patients with G2 tumors (p ⫽ 0.001). The absence of statistical significance in G3 tumors may be attributed to the low number of patients in this subgroup. When we compared the recurrence-free survival for the 2 groups in terms of high and low grade, there was a statistically significant difference between the 2 patient groups with high grade (G2-3) tumors (p ⬍0.001). CONCLUSIONS The high recurrence rate in patients without undergoing ReTUR is due to a high residual tumor rate following initial TUR. The significantly shorter recurrence-free period in group 2 also suggests the presence of residual tumors rather than true recurrence. The benefit of ReTUR is especially true for high grade tumors. Since intravesical MMC was present in both groups, this study has shown that intravesical chemotherapy does not compensate for inadequate re-
section. The role for adjuvant intravesical chemotherapy or immunotherapy following ReTUR must be addressed in a separate setting. Progression does not seem to be affected by ReTUR although there was a trend favoring the ReTUR group. The number of events must increase and the followup period must be extended to reach definitive conclusions with regard to progression. We recommend ReTUR for patients with primary high grade T1 disease to achieve better recurrencefree survival.
Abbreviations and Acronyms BCG Cis MMC OS PFS ReTUR RFS TCC TURB
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
bacillus Calmette-Guerin carcinoma in situ mitomycin C overall survival progression-free survival repeat transurethral resection recurrence-free survival transitional cell carcinoma transurethral resection of the bladder
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