Effect of Routine Repeat Transurethral Resection for Superficial Bladder Cancer: A Long-term Observational Study

0022-5347/03/1702-0433/0 THE JOURNAL OF UROLOGY® Copyright © 2003 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 170, 433– 437, August 2003 Printed in U.S.A.

DOI: 10.1097/01.ju.0000070437.14275.e0

EFFECT OF ROUTINE REPEAT TRANSURETHRAL RESECTION FOR SUPERFICIAL BLADDER CANCER: A LONG-TERM OBSERVATIONAL STUDY MARC-OLIVER GRIMM,* CHRISTINE STEINHOFF, XENIA SIMON, PHILIPP SPIEGELHALDER, ¨ GELI ROLF ACKERMANN AND THOMAS ALEXANDER VO From the Department of Urology, Heinrich-Heine University (M-OG, CS, XS, PS, RA, TAV), Du¨sseldorf and Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics (CS), Berlin, Germany

ABSTRACT

Purpose: We determined the long-term outcome in patients with superficial bladder cancer (Ta and T1) undergoing routine second transurethral bladder tumor resection (ReTURB) in regard to recurrence and progression. Materials and Methods: We performed an inception cohort study of 124 consecutive patients with superficial bladder cancer undergoing transurethral resection and routine ReTURB (83) between November 1993 and October 1995 at a German university hospital. Immediately after transurethral resection all lesions were documented on a designed bladder map. ReTURB of the scar from initial resection and other suspicious lesions was performed at a mean of 7 weeks. Patients were followed until recurrence or death, or a minimum of 5 years. Results: Residual tumor was found in 33% of all ReTURB cases, including 27% of Ta and 53% of T1 disease, and in 81% at the initial resection site. Five of the 83 patients underwent radical cystectomy due to ReTURB findings. The estimated risk of recurrence after years 1 to 3 was 18%, 29% and 32%, respectively. After 5 years 63% of the patients undergoing ReTURB were still disease-free (mean recurrence-free survival 62 months, median 87). Progression to muscle invasive disease was observed in only 2 patients (3%) after a mean observation of 61 months. Conclusions: These data suggest a favorable outcome regarding recurrence and progression in patients with superficial bladder cancer who undergo ReTURB. ReTURB is suggested at least in those at high risk when bladder preservation is intended. KEY WORDS: bladder, bladder neoplasms, urethra, transurethral resection, outcome, recurrence, progression

Transurethral bladder tumor resection (TURB) is the initial step in the treatment of bladder cancer. Complete tumor resection is mandatory for adequate staging and it serves as definitive therapy, at least for superficial tumors. However, there is growing evidence that TURB is incomplete in a significant number of cases.1⫺4 It may contribute to the high number of recurrences observed in up to 50% to 80% of patients, of which most occur during year 1 after TURB.5 Furthermore, staging error due to incomplete resection might be related to the progression rate of 14% to 53% in superficial tumors.4, 6 – 8 To improve treatment results repeat TURB (ReTURB) 2 to 8 weeks after the initial operation has been recommended.1, 4 Retrospective studies support this approach, describing a frequency of up to 75% tumor detection by ReTURB for Ta and T1 bladder cancers.4 However, the frequency of residual tumor after TURB and the ability of ReTURB to control for complete resection has been widely neglected by the urological community. Although a negative impact of residual tumor after TURB has been anticipated by several groups, ReTURB remains unaccepted since to our knowledge a (favorable) long-term outcome has never been reported. To be considered beneficial to the patient ReTURB should result in prolonged time to recurrence as well as decreased recurrence and eventually a decreased progression rate.5 We evaluated the outcome in a cohort of patients followed for at least 5 years after treatment with routine ReTURB in a prospective study for quality control of TURB for bladder

cancer. We defined the frequency of residual tumor and staging error after TURB prospectively and evaluated the rate of recurrence and progression after ReTURB in a long-term observational study.

PATIENTS AND METHODS

Treatment strategy. Between November 1, 1993 and October 31, 1995 patients undergoing TURB at the department of urology, Heinrich-Heine University were enrolled in a prospective study for quality control by routine ReTURB to define the frequency and location of residual tumor after transurethral resection. In general, resection was performed as a differential transurethral resection with separate sampling of the tumor as well as of the base and the mucosa adjacent to the tumor.9 After TURB the surgeon documented the location of the tumor on a designed bladder map. ReTURB of the scar of the initial resection and other suspicious lesions was performed at a mean of 7 weeks. All patients with histologically confirmed superficial bladder cancer underwent ReTURB except those with small, single focus, low grade papillary tumors (TaGI) and those with poor performance status. If tumor was detected during ReTURB, another ReTURB was recommended given the same exclusion criteria. Tumor stage, grade, focality, volume, concomitant carcinoma in situ, the result of postoperative cytology and adjuvant intravesical instillation (performed at the discretion of the treating urologist) were recorded. Informed consent for the treatment strategy was obtained from each patient. Patient and tumor characteristics. Overall 214 patients

Accepted for publication March 7, 2003. * Corresponding author: Department of Urology, Heinrich-Heine University, Moorenstrasse 5, 40225 Du¨sseldorf, Germany. 433

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REPEAT TRANSURETHRAL RESECTION FOR SUPERFICIAL BLADDER CANCER

(155 men and 59 women) with a mean age of 71 years (range 23 to 98) underwent a total of 257 TURBs during the study period. Table 1 lists the stage and grade of 194 histopathologically confirmed bladder cancers. Multifocal tumors and a solitary lesion were observed in 62% and 38% of the patients, respectively. There were 62% of cases with newly diagnosed bladder cancer, while 15% had a first, 9% had a second and 14% had multiple recurrences. Transitional cell carcinoma represented 94%, squamous cell carcinoma represented 3% and adenocarcinoma represented 1% of tumors. The distribution of tumor characteristics within different subgroups of superficial bladder cancers analyzed (T2 or greater and carcinoma in situ excluded) closely matched the overall study population. Followup. Patients were followed every 3 to 6 months with cystoscopy. All patients undergoing ReTURB were followed until recurrence or death, or a minimum of 5 years. Only 1 patient was lost to followup 12 months after TURB. Mean observation, including all recurrences, was 61 months. The primary end points of this study were the time to histologically confirmed bladder cancer recurrence and time to progression to muscle invasive disease. Actuarial recurrence-free survival rates and estimated times to recurrence reported were considered beginning from the last TURB. Recurrence rates yearly were not considered because treatment after the first recurrence was performed on an individual basis and was not part of the study protocol. Since the protocol did not distinguish between primary and recurrent superficial bladder cancers, recurrent disease during the study period was considered a separate case. Statistical evaluation. All statistical evaluations were performed using commercially available software. Standard statistical procedures were used, such as the Pearson chi-square and Mann-Whitney U tests. Categorical variables with a possible correlation with tumor detection by ReTURB according to standard univariate tests were subjected to logistic regression analysis. The disease free-interval, defined as the time until first recurrence since the last transurethral resection, was evaluated to construct Kaplan-Meier survival curves. Patients who died of other causes or were without recurrence at the last followup were censored. The log rank test was used to stratify patients with respect to prognostic factors, and for comparison between ReTURB and the cohort of patients that did not undergo repeat resection. All reported p values are 2-sided. RESULTS

Overall 214 patients underwent a total of 257 TURBs during the study period. Smooth muscle was obtained in 97.4% of primary transurethral resections. In 63 cases premalignant or nonmalignant findings were observed after TURB, for example dysplastic lesions, chronic cystitis (frequently in patients with a history of bladder cancer and intravesical instillation), bilharziosis or nephogenic adenoma. Bladder cancer was histopathologically confirmed in 194 cases, including carcinoma in situ in 2, Ta in 90, T1 in 34 and muscle invasive (T2 or greater) in 68 (table 1). Figure 1 shows the treatment scheme for the 124 cases of superficial bladder cancer (Ta and T1), which form the basis of this analysis. ReTURB was performed for 63 of 90 Ta tumors and for 20 of 34 T1 tumors. According to the study protocol 12 patients with small unifocal TaG1 tumors and 8

TABLE 1. Distribution of stage and grade of 192 bladder cancers* Stage

No. G1

No. G2

No. G3

Ta 34 50 6 T1 20 14 T2 or greater 8 60 * In 2 additional cases carcinoma in situ (Tis) was the only lesion detected.

FIG. 1. Treatment scheme for 124 cases of superficial bladder cancer. ReTURB was performed in 83 patients at mean of 7 weeks (ReTURB and eventually repeat ReTURB at 8.1 weeks).

with poor performance status did not undergo ReTURB. Of the patients scheduled for ReTURB 20 refused a second intervention. One patient underwent immediate cystectomy due to extensive superficial disease considered to be incurable by TURB (final histology T3a). TURB was considered to be incomplete by the surgeon in 9 of 124 cases (7%). Tumor detection rate by ReTURB after first transurethral resection. Excluding incomplete resection, residual tumor was found in 33% of all ReTURBs, including 27% of Ta and 53% of T1 tumors (table 2). Residual tumor was located at the primary site only in 46% of cases and at another site only in 19%. In 35% of cases the scar after TURB and at least 1 other site were affected, most frequently in T1 tumors. Univariate analysis identified tumor stage (Pearson chisquare p ⫽ 0.04) and grade (p ⬍0.04) as predicting factors for residual tumor. Other factors evaluated include focality or multifocality, carcinoma in situ, tumor volume, postoperative cytology and adjuvant instillation, although none of these factors correlated significantly with tumor detection by ReTURB. Using residual tumor at ReTURB as a dependent variable in a logistic regression model with the variables tumor stage and/or grade the only significant variable identified was tumor grade (Wald statistic p ⬍0.02). Progression in stage or grade was noted in 4 and 2 cases (8%), respectively. Muscle invasive disease was discovered in 3 (4%) of these patients. In an additional case urothelial carcinoma invasive into the prostate gland was detected by ReTURB. Long-term outcome after ReTURB. Of 83 ReTURBs per-

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REPEAT TRANSURETHRAL RESECTION FOR SUPERFICIAL BLADDER CANCER TABLE 2. Tumor stage, grade and frequency of residual tumor on routine ReTURB in 78 cases of superficial bladder cancer* Stage

G1

No. Ta No. T1 No. residual tumor/total No. (%) * Incomplete primary resections excluded.

2/18 2/18 (11)

formed 5 were excluded from followup evaluation. Two of the 3 patients with stage migration to muscle invasive disease underwent cystectomy, while 1 received no immediate further treatment due to advanced age. In addition, the patient with concomitant invasive urothelial cancer of the prostate and one with persistent T1G3 carcinoma detected by repeat ReTURB were treated with radical cystectomy. Tables 3 and 4 show the characteristics of the remaining 78 cases. Except 1 patient who was lost to followup after 12 months all who underwent ReTURB were followed until recurrence or death, or a minimum of 5 years. Recurrence was observed in 30 of the 78 patients (38%) treated with ReTURB at a mean followup of 46 months. Followup of patients without recurrence was 59 months. The estimated risk of recurrence after years 1 to 3 was 18%, 29% and 32%, respectively. After 5 years 63% of patients undergoing ReTURB were still disease-free, equivalent to an actuarial mean recurrence-free survival of 62 months (fig. 2). Stage and grade were predictors of time to recurrence. Only 2 of the 17 patients with a stage T1 tumor had recur-

G2

G3

No. Residual Tumor/Total No. (%)

13/35 4/12 17/47 (36)

1/6 6/7 7/13 (54)

16/59 (27) 10/19 (53) 26/78 (33)

TABLE 4. Tumor characteristics in 78 patients followed after ReTURB Stage Ta: Unifocal Multifocal T1: Unifocal Multifocal Totals

No. G1 (%)

No. G2 (%)

No. G3 (%)

7 (9) 12 (15)

25 (32) 11 (14)

5 (6) 1 (1)

37 (47) 24 (30)

10 (13) 1 (1)

2 (3) 4 (5)

12 (16) 5 (6)

47 (60)

12 (15)

19 (24)

Total No. (%)

78

TABLE 3. Characteristics by treatment group of 114 patients considered for followup analysis No. ReTURB (%)

No. No ReTURB (%)

Total pts 78 36 Age:* Younger than 50 19 (24) 3 (8) 50–59 28 (36) 7 (19) 60–69 23 (30) 15 (42) 70 or Older 8 (10) 11 (31) Gender: Male 64 (82) 25 (69) Female 14 (18) 11 (31) Bladder Ca history:† No (primary) 51 (65) 14 (39) Yes (recurrence) 27 (35) 22 (61) Stage:‡ Ta 61 (78) 25 (69) T1 17 (22) 11 (31) Grade:‡ G1 19 (24) 15 (42) G2 47 (60) 15 (42) G3 12 (16) 6 (16) Additional Ca in situ§ 3 (4) 2 (6) Tumors:‡ Single 49 (63) 23 (64) Multiple 29 (37) 13 (36) Wt (gm):㛳 2 or Less 27 (35) 14 (39) 2–10 44 (57) 21 (58) Greater than 10 6 (8) 1 (3) Tumor stage, grade, weight, number of tumors (single or multiple) and frequency of concomittant carcinoma in situ did not differ significantly between the groups. * Mean age for patients undergoing ReTURB or observation was 67 and 75 years, respectively (t test p ⫽ 0.001). † Mean recurrence-free interval before study entry was 22 months in each group and recurrence within 3 months was noted in 5 and 4 cases of the ReTURB and no ReTUR groups, respectively (Pearson chi-square, p ⬍ 0.01). ‡ According to the study protocol the no ReTURB group included 12 small unifocal TaG1 tumors resulting in a significant higher proportion of TaG1 and unifocal G1 tumors (Pearson chi-square p ⬍ 0.02) as well as a trend of overall more G1 tumors (p ⫽ 0.06) compared to patients undergoing ReTURB. § Adjuvant instillation therapy was administered in a similar proportion of patients in each group (30% and 31%). 㛳 Mean weight of the resected tumor of patients undergoing ReTURB was 4.7 gm compared to 2.4 gm in the no ReTURB group (median 2.0 gm each, not significant).

FIG. 2. Kaplan-Meier recurrence-free survival in patients undergoing ReTURB vs no ReTURB.

rence, resulting in longer disease-free survival than in those with Ta tumors. Seven patients (9%) had stage or grade progression, while progression to muscle invasive disease was observed in 1 patient (1%) only at the first recurrence. Recurrence-free survival of patients undergoing TURB only. ReTURB was not performed in 41 patients, including 12 with small unifocal TaG1 disease, 8 with poor performance status, 1 who underwent immediate cystectomy and 20 who refused ReTURB. Four patients with incomplete initial TURB and 1 with a history of muscle invasive bladder cancer were excluded from followup analysis. Table 3 lists the characteristics of these 36 patients. Overall 19 of the 36 patients (53%) had recurrence. The estimated risk of recurrence after years 1 to 3 was 21%, 57% and 61% compared with 18%, 29% and 32% in the ReTURB group, respectively. The difference in recurrence-free survival between patients undergoing ReTURB versus TURB only was statistically significant (log rank test p ⬍0.03, fig. 2). DISCUSSION

Retrospective studies consistently show a high frequency of residual tumor in 30% to 75% of cases when ReTURB is performed for superficial bladder cancer.1, 4 This retrospective data has been criticized since only a few studies distinguish between incomplete and complete primary TURB, and

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REPEAT TRANSURETHRAL RESECTION FOR SUPERFICIAL BLADDER CANCER

the accumulation of patients at risk, for example with high stage, grade or multifocal disease, undergoing ReTURB has been assumed. In this prospective study, ReTURB was performed routinely except in patients with small, high grade, solitary, mucosa confined tumors (TaG1). Patients with TURBs reported by the surgeon to be incomplete were excluded from analysis. Consistent with previous retrospective data,1⫺4 tumor was detected by ReTURB in about a third of the patients with superficial Ta or T1 bladder cancer. Residual tumor was most frequently located at the site of initial TURB (81%), strongly suggesting incomplete initial surgery. It seems reasonable to assume that the high frequency of residual tumors after intended complete TURB for superficial bladder cancer is responsible for a significant number of recurrences. It is in accordance with molecular biological studies showing that most bladder tumors have common genetic alterations suggesting a single progenitor cell.10, 11 However, the observation of the clonal development of bladder cancer has been mainly attributed to intraluminal seeding, neglecting the possibility of incomplete surgery. Accordingly intravesical immunotherapy and chemotherapy have been extensively studied as adjuvant treatment to prevent bladder cancer recurrence and progression.5, 6 To our knowledge the impact of routine second transurethral resection on the long-term outcome of patients in respect to the recurrence rate, time to recurrence and progression as well as the need for cystectomy has not been investigated up to date. Based on the current literature about 48% and 40% of patients who undergo TURB only are expected to be recurrence-free by 3 and 5 years, respectively.12 In contrast, estimated recurrence-free survival of patients undergoing ReTURB was 62 months (median 87), equivalent to a 3 and 5-year recurrence-free survival rate of 68% and 63%, respectively. Assumption of a favorable impact on the outcome of superficial bladder cancer by ReTURB treatment is further supported by significant prolongation of recurrence-free survival compared with patients undergoing TURB only in this study (fig. 2). This observation must be considered with caution since this study was not randomized and patient characteristics in the group designated TURB only were similar but not balanced compared with the ReTURB group. Indeed, except for patient age and a higher proportion of recurrences the TURB only group included several tumors with comparably favorable prognostic factors, for example a third solitary TaG1 tumors (table 3). Studies addressing recurrence rates after intravesical chemotherapy, focusing mainly on patients at low risk, show worse or at best similar outcomes compared with the cohort undergoing ReTURB in this report.6, 13–16 Notably some instillation protocols included followup cystoscopy after 4 to 6 weeks to ensure complete initial resection, leading to ReTURB in up to 33% of cases.13, 16, 17 However, a correlation of cystoscopic and histological findings of ReTURB showed that 40% of neoplastic lesions are invisible endoscopically in the TURB scar.1 Another major aim in the treatment of superficial bladder cancer is the prevention of disease progression and a decreased need for radical cystectomy.5 The progression rate varies widely in different studies due to patient selection. For example, in a European Organization for Research and Treatment of Cancer Genitourinary Group study 14% of patients mainly at low risk had progression,5, 18, 19 while Cookson et al focused on those at high risk and found a 53% progression rate and a 34% rate of bladder cancer death in the long term.7 In this study progression to muscle invasive disease was observed in only 1 patient (1%) undergoing ReTURB who was followed until the first recurrence. Including later recurrences only 1 additional patient had muscle invasive disease during an observation of 61 months. Tumor

characteristics may explain the low number of patients affected, although the low number at risk was due to better patient selection by ReTURB. Based on ReTURB histological results 5 patients (6%) would have been treated with cystectomy (1 was not eligible). Notably 2 of these patients as well as those who had recurrence with muscle invasive disease during followup had stage Ta G1-G2 disease at initial TURB. ReTURB probably does not prevent progression but it allows early detection of patients at risk and muscle invasive disease that is masked by incomplete resection. It seems reasonable to conclude that ReTURB leads to better stratification since none of the patients at high risk (T1) who were rendered tumor-free by ReTURB had progression to muscle invasive disease. It is further supported by the retrospective study of Brauers et al, in which none of the patients with primary T1G2 to 3 bladder cancer without residual tumor during ReTURB (36%) had progression to muscle invasive disease at 60 months of followup.20 According to these data it may be assumed that cystectomy for stage T1 bladder cancer is often performed too early, neglecting attempts at complete resection.20 However, given the fact of a 50% residual cancer rate after TURB for this high risk disease, ReTURB is suggested when bladder preservation is intended. CONCLUSIONS

The results of this study suggest that a significant proportion of superficial bladder cancer recurrences might be due to incomplete surgery. ReTURB performed 4 to 8 weeks after TURB eradicates this cause of recurrence and provides excellent long-term recurrence-free survival. Furthermore, ReTURB allows better stratification of risk for progression and it may decrease the need for radical cystectomy. Therefore, ReTURB is suggested, at least in patients at high risk, when bladder preservation is intended. The positive long-term outcome in patients undergoing ReTURB in this study must be confirmed in a prospective, randomized trial. REFERENCES

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