Delaying Radical Cystectomy for Muscle Invasive Bladder Cancer Results in Worse Pathological Stage

0022-5347/03/1704-1085/0 THE JOURNAL OF UROLOGY® Copyright © 2003 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 170, 1085–1087, October 2003 Printed in U.S.A.

DOI: 10.1097/01.ju.0000086828.26001.ca

Original Articles DELAYING RADICAL CYSTECTOMY FOR MUSCLE INVASIVE BLADDER CANCER RESULTS IN WORSE PATHOLOGICAL STAGE SAM S. CHANG,* J. MATTHEW HASSAN, MICHAEL S. COOKSON, NANCY WELLS AND JOSEPH A. SMITH, JR. From the Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee

ABSTRACT

Purpose: While radical cystectomy remains the treatment of choice for invasive transitional cell carcinoma, the importance of its timing has been increasingly scrutinized. We determined whether the interval between diagnosis of muscle invasion and definitive radical cystectomy influenced pathological staging outcome. Materials and Methods: Of the 303 patients who underwent radical cystectomy from January 1998 to December 2001, 153 were diagnosed with muscle invasive transitional cell carcinoma at transurethral resection. Charts were reviewed for pathological stage, demographics and time between diagnosis of muscle invasion and radical cystectomy. Results: Mean patient age was 67.2 years (range 35 to 88) with the majority (121 of 153, 79%) being male. At the time of cystectomy, 68 of 153 (44%) patients had organ confined disease (pT2B or lower), while node positive disease was found in 58 of 153 patients (38%). Mean time from transurethral resection diagnosis of muscle invasive disease until cystectomy was 63 days (range 8 to 473). A statistically significant correlation existed between time of diagnosis and cystectomy, and final pathological stage. Specifically, those patients with an interval greater than 90 days were more likely to have pT3 or higher, nonorgan confined disease compared to those patients undergoing cystectomy before 90 days (81% versus 52%, p ⫽ 0.01). Furthermore, those patients with organ confined disease had a significantly shorter mean time between diagnosis and cystectomy of 47.5 days versus 75.1 days for nonorgan confined disease (t test p ⫽ 0.02). Conclusions: In patients with muscle invasion at diagnosis, a delay in surgery is associated with more advanced pathological stage, especially when the delay is longer than 90 days. While appropriate time should be given for consideration of options and pretreatment evaluation, undue delay may compromise cancer control. KEY WORDS: carcinoma, transitional cell; survival, cystectomy

In the United States bladder cancer remains a significant cancer with an incidence of more than 54,000 cases each year, and it is the second most common urological malignancy.1 Approximately 20% of patients are found to harbor invasive disease at the time of presentation. Radical cystectomy remains the treatment of choice for muscle invasive transitional cell cancer, but it is a major operative procedure with potential for significant, serious complications.2–5 However, improvements in surgical technique and perioperative care have led to decreased mortality and morbidity rates.6, 7 Despite these improvements patients often do not immediately proceed to radical cystectomy for reasons such as completion of a metastatic evaluation, preoperative medical preparation, patient comorbidities, patient wishes, physician scheduling delays, seeking multiple opinions, and neoadjuvant therapies like radiation and/or chemotherapy, among others. Once the diagnosis of muscle invasive disease is made, proceeding with radical cystectomy expeditiously would seem to be in the patient’s best interest.

Recent data have demonstrated the significant impact that delaying cystectomy has on patients with noninvasive disease.8 We determined whether the time between diagnosis of muscle invasive transitional cell carcinoma by transurethral resection (TUR) and radical cystectomy had a significant impact on the nature and stage of the tumor. Specifically we examined whether an increased duration between diagnosis and radical cystectomy resulted in worse pathological stage. MATERIALS AND METHODS

Of the 303 patients who underwent radical cystectomy from January 1998 to December 2001, 153 were diagnosed with muscle invasive transitional cell carcinoma at TUR. Patient charts were reviewed for pathological stage, demographics and time between diagnosis of muscle invasion at TUR and radical cystectomy. Data were analyzed using SPSS (SPSS, Inc., Chicago, Illinois). Frequency distributions and measures of central tendency were examined to determine distribution of data. Chisquare was used for categorical variables and Student’s t test was used for continuous variables. Initially demographic and clinical variables were compared between the subsample (those patients with muscle invasive bladder cancer diag-

Accepted for publication April 11, 2003. * Corresponding author: Department of Urologic Surgery, Vanderbilt University Medical Center, A-1302 Medical Center North, Nashville, Tennessee 37232-2765 (telephone: 615-322-2142; FAX: 615322-8990; e-mail: [email protected]). 1085

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NEGATIVE IMPACT OF DELAYING RADICAL CYSTECTOMY DISCUSSION

TABLE 1. Demographic characteristics Variable Median pt age (range) No. male (%) No. female (%) No. pathological stage (%): pT0 pT1 pT2 pT3 pT4 No. lymph node status (%): Neg Pos

Pts With Muscle Invasive Ca at TUR

Pt Cohort

69 (35–88) 122 (78.0) 33 (21.3)

66 (32–86) 231 (76.1) 72 (23.8)

0 0 68 66 21 95 58

(43.9) (42.6) (13.5)

20 86 84 75 29

(6.8) (29.3) (28.6) (25.5) (9.9)

(62.1) (37.9)

262 51

(83.7) (16.3)

nosed by TUR) with followup data and the total patient sample. Differences in demographic and clinical variables by tumor stage (pT2 vs pT3/4) were examined. A number of standard cut points (eg 30 days, 50 days, etc) were examined to determine the number of days of delay that might predict low (pT2) and high (pT3/4) stage cancer. This evaluation was also performed for patients with node negative versus node positive disease. Once a cut point was identified patients were collapsed into low and high delay groups, and differences in stage, demographics and clinical variables were examined using the chi-square and t tests. Level of significance was set at p ⱕ0.05. RESULTS

Mean patient age was 67.2 years (range 35 to 88) with the majority, 121 of 153 (79%), being male. At the time of cystectomy, 68 of 153 (44%) patients had organ confined disease (pT2B or lower), while node positive disease was found in 58 of 153 patients (38%). Patients with muscle invasive disease at TUR had a more advanced pathological stage, and a greater proportion had positive nodes than the full cohort of patients who had undergone cystectomy (table 1). Mean time from TUR diagnosis of muscle invasive disease until radical cystectomy for all patients was 63 days (range 8 to 473, median 42). Those patients with organ confined disease at radical cystectomy had a mean interval from diagnosis by transurethral bladder tumor resection until cystectomy of 47.5 versus 75.1 days for patients whose cystectomy specimen had nonorgan confined disease (t test p ⫽ 0.02). On examination of nodal status those patients with node negative disease underwent cystectomy sooner than those with node positive disease (56 versus 75 days, respectively), but this difference was not statistically significant (p ⫽ 0.10). Time from diagnosis until cystectomy was collapsed into 5 categories, a delay of less than 30 days, 31 to 60, 61 to 90, 91 to 120, and more than 120 days (table 2). Although no linear correlation was found between delay and pathological stage, there was a significant statistical threshold value. Those patients with more than a 90-day interval were more likely to have pT3 or higher nonorgan confined disease compared to those patients undergoing cystectomy before 90 days (81% versus 52%, chi-square analysis p ⫽ 0.01, see figure). Age and gender did not correlate with pathological stage (p ⫽ 0.48 and 0.49, respectively).

Patients diagnosed with muscle invasive bladder cancer are a diverse population who require careful evaluation and staging before determining the best treatment option. However, our series demonstrates that delaying definitive therapy in the form of radical cystectomy results in advanced disease. After evaluating all patients who underwent radical cystectomy at our institution, delay from the time of diagnosing muscle invasive bladder cancer until radical cystectomy resulted in a worse pathological stage, especially when the delay was greater than 90 days (p ⫽ 0.01). Those patients with organ confined disease at the time of radical cystectomy had a mean interval time from diagnosis by transurethral bladder tumor resection until cystectomy of 47.5 versus 75.1 days for patients whose cystectomy specimen had nonorgan confined disease (t test p ⫽ 0.02). More than 80% of patients whose radical cystectomy was delayed more than 90 days from the time of TUR diagnosis of muscle invasive disease had advanced, nonorgan confined disease. Similarly, the majority of patients who had cystectomy after 90 days had node positive disease. Our findings paralleled a review from Memorial Sloan-Kettering Cancer Center, where the median time from diagnosis until cystectomy was 67 days, and patient outcome was better when radical cystectomy was performed within 3 months of diagnosis.9 Although we focused on those patients with a clear indication for radical cystectomy, the importance of avoiding a delay in the performance of radical cystectomy in patients may also apply to those with nonmuscle invasive disease. Herr and Sogani demonstrated the importance of time duration in the treatment of nonmuscle invasive disease. Significant differences were seen in survival if cystectomy was delayed more than 2 years in patients with recurrent and progressive superficial bladder cancer. Of 55 patients with recurrent muscle invasive bladder disease, 41% and 18% survived when cystectomy was performed within and after 2 years, respectively.8 In our series more than 60% of patients had pT3 or higher or node positive disease at the time of cystectomy. In patients who present with muscle invasive disease, cancer progression is unquestionably associated with decreased survival. Completion of a thorough preoperative assessment is mandatory in these patients, but delay for nonessential reasons is likely to result in worse disease. The rationale for delaying cystectomy because the patient is too sick is becoming increasingly difficult to defend. Although the morbidity of the procedure is often perceived as prohibitive, this perception has decreased. Multiple studies have demonstrated that complication rates have decreased during the last 20 years.10 –12 Our data and those of others have demonstrated the safety and effectiveness of this procedure even in elderly patients with significant comorbidities.10, 13 Other reasons for delay can be patient driven, such as seeking other medical opinions and patient preference, and these cannot be significantly altered. This retrospective series does not provide the definitive safe time between diagnosis of muscle invasive disease and radical cystectomy, nor does it attempt to do so. Selection bias and clinical understaging may have had an impact on

TABLE 2. Timing of cystectomy and pathological stage Days From TUR Diagnosis to Cystectomy 0–30 31–60 61–90 91–120 More than 120 * Percent within time category.

No. Pts (%)

Median Pt Age (range)

No. pT3 or Higher (%)

No. Pos Nodes (%)

43 (28.1) 65 (42.5) 26 (17) 6 (3.9) 13 (8.5)

64 (40–84) 72 (35–88) 67.5 (39–87) 71.5 (59–76) 71 (58–79)

24 (55.8)* 34 (52.3) 12 (46.2) 4 (66.7) 11 (84.6)

15 (36.6)* 25 (38.5) 8 (30.8) 1 (16.7) 9 (69.2)

NEGATIVE IMPACT OF DELAYING RADICAL CYSTECTOMY

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time should be given for consideration of options and pretreatment evaluation, an undue delay may compromise cancer control. REFERENCES

Negative impact of increasing length of time from TUR diagnosis of muscle invasive cancer until radical cystectomy on pathological stage.

this outcome as well. Furthermore, we did not assess all preoperative risk factors that could influence pathological stage. Additionally, time from onset of symptoms until diagnosis and treatment of muscle invasive disease may impact pathological stage and, in fact, may be the most predictive of outcome.14 Undoubtedly pathological stage at cystectomy is influenced by many factors and we are not advocating that any time period (ie 90 days) represents a safe period before disease progression. Instead we believe that this series confirms, albeit in a nonrandom manner, the inherently logical principle that the longer a malignant disease process has to progress, the more likely the malignancy will no longer be organ confined. Thus we advocate an expeditious evaluation and performance of cystectomy in patients who present with muscle invasive bladder cancer. CONCLUSIONS

In patients with muscle invasive bladder cancer, a delay in surgery negatively impacts pathological stage, especially when the delay is longer than 90 days. While appropriate

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