Radical cystectomy for BCG failure: has the timing improved in recent years?

Authors


Mark S. Soloway, Professor and Chairman Department of Urology, University of Miami Miller School of Medicine, P.O. Box 016960 (M814), Miami, Fl 33101, USA.
e-mail: msoloway@med.miami.edu

Abstract

Study Type – Therapy (case series)

Level of Evidence 4

What’s known on the subject? and What does the study add?

High-grade Ta-T1-carcinoma in situ bladder cancer is a heterogeneous group; long-term studies have shown that intravesical BCG therapy can be inadequate in a substantial percentage. Despite concerns about delay in performing RC for patients failing one or more courses of BCG, in our study we have not observed a trend towards a lower pathological stage for patients undergoing RC after BCG.

OBJECTIVE

  • • To analyse if there is a trend in recent years towards performing radical cystectomy (RC) before muscle invasion or extravesical spread after failure of bacille Calmette–Guérin (BCG) for high grade Ta/T1 bladder cancer. Although BCG is indicated for prophylaxis after endoscopic tumour resection there is still a risk of progression.

PATIENTS AND METHODS

  • • A retrospective analysis of our RC database (1992–2008) was performed to identify patients who underwent RC after receiving BCG.
  • • Relevant clinical and pathological data for the patients with clinical stage Ta, T1 and/or Tis at initial transurethral resection of bladder tumour were analysed.
  • • Pathological stage and survival for patients undergoing RC from 2003 to 2007 (group 2) were compared with those for patients operated between 1992 and 2002 (group 1).

RESULTS

  • • A total of 152 patients were included (75 in group 2 and 77 in group 1). Both groups were similar in T-stage before BCG initiation, number of BCG cycles received and time interval to RC.
  • • There was no change in the proportion of patients undergoing RC with ≥pT2 bladder cancer in recent years (P= 0.5).
  • • Fifty-two percent of group 2 and 43% of group 1 had ≥pT2 BC. The 5-year survival was similar.

CONCLUSIONS

  • • Despite concerns about delay in performing RC for patients failing one or more courses of BCG we have not observed a trend towards a lower pathological stage for patients undergoing RC after BCG.
  • • A high proportion of patients have muscle-invasive bladder cancer; more than 10% have lymph node metastasis.
Abbreviations
BC

bladder cancer

TURBT

transurethral resection of bladder tumour

RC

radical cystectomy.

INTRODUCTION

Approximately 70% of patients with newly detected bladder cancer (BC) present with Ta, T1 and/or carcinoma in situ[1]. Transurethral resection of the bladder tumour (TURBT) is the standard initial treatment for Ta and T1 bladder tumours. TURBT establishes the diagnosis and provides important staging information, which is critical for decision-making. The information gained after the initial TUR, and a repeat TUR when indicated, can then be used to assign a risk profile [2,3]. Adjuvant treatment with intravesical BCG is indicated for intermediate-risk and high-risk Ta-T1 BC [4]. The rationale for giving BCG is to treat carcinoma in situ, prevent or delay recurrence, and possibly reduce the risk of progression, with the hope of avoiding cystectomy. BCG is not uniformly effective; nearly 40% of patients fail within the first year [5]. Hence, it is of utmost importance that patients receiving BCG be evaluated carefully and immunotherapy should be abandoned in favour of radical cystectomy (RC) if their disease recurs as high-grade BC having failed BCG. RC is the optimal treatment after BCG failure. The timing of RC is crucial given that the survival after RC is directly related to the pathological stage. If cystectomy is performed before progression to muscle invasion (<pT2) as is the case when BCG is first initiated, the cancer-specific survival is over 90%[6]. Conversely, the 5-year survival declines to below 70% for muscle-invasive BC. It has been reported that patients failing BCG therapy have a poorer prognosis compared with stage-matched primary muscle invasive BC [7].

With increasing data and understanding of the inadequacies of BCG therapy, it might be anticipated that more patients would undergo RC before developing progression. Ours is an academic centre serving a large number of bladder cancer patients referred by community urologists. We analysed our database to see if there is a trend in recent years towards performing RC before muscle invasion or extravesical BC develops. We reviewed our cystectomy database to compare the pathological stage after RC in patients who received BCG across two time periods.

PATIENTS AND METHODS

We performed a retrospective analysis of our institutional review board-approved RC database to identify all patients with urothelial carcinoma who received a minimum of one 6-week course of BCG before RC. We included patients with clinical stage Ta, T1 and/or Tis at their initial TURBT. We excluded patients who received neoadjuvant chemotherapy and those with an incomplete BCG history. Patients who underwent RC between 1992 and 2002 (group 1) were compared with those who had their surgery between 2003 and 2007 (group 2). The patient’s clinical stage before initiation of BCG and the final pathological stage after RC were compared between both time intervals using the 2002 American Joint Cancer Committee TNM staging system. Those patients operated before 2002 and who had T3a according to the old TNM were reassigned T2b in our database. Moreover, the analysis was performed in three stage groups <T2, T2 and >T2. The number of patients with pathological stage <T2 (no muscle invasion) or ≥T2 (muscle invasion) were compared. Total doses of BCG before RC (≤6 or >6) were assessed and compared between time intervals. The category more than six doses of BCG included patients who underwent multiple 6-week courses and/or maintenance therapy. When indicated, patients undergoing TURBT at our institution receive maintenance BCG therapy for 1 year. Preoperative assessment included a history and physical examination, TURBT, CT of the abdomen/pelvis and chest x-ray. An internal review of slides for any TURBT performed outside our centre was routine and the recorded grade and stage were those from our pathologist. In our centre a re-TUR is performed on all high-grade T1 tumours as a routine over the last 3 years. The technique of RC has changed little over the time period of these cases. The use of haemostatic instruments has been incorporated, e.g. vascular stapling devices and the Ligasure. Only recently has the extended pelvic lymph node dissection been a standard part of the procedure. This now includes the common iliac vessels whereas previously it was limited to the external and internal iliac vessels and the region surrounding the obturator vessels and nerve. Postoperatively, patients were evaluated at 2–4 weeks followed by every 3–4 months for 2 years with a complete blood count, comprehensive metabolic panel, chest x-ray and either abdominal CT or ultrasonography. After 2 years the patient was followed semiannually. The Pearson chi-square/Fisher’s exact test were used to compare categorical variables, Student’s t test was used to compare continuous variables and the Kaplan–Meier method was used to analyse survival data. A two-sided P value of ≤0.05 was considered significant.

RESULTS

Between 1992 and 2007, 445 patients underwent RC by a single surgical team. Among them 168 (38%) received intravesical BCG before RC and 152 patients met the inclusion criteria for this analysis. There were 77 patients in group 1 and 75 patients in group 2. The mean age, gender and smoking history were comparable between the groups. There was no significant difference between the groups in tumour stage before initiation of BCG (Table 1). The time interval between initiation of BCG and RC was not significantly different. The proportion of patients receiving BCG for recurrent tumours and those receiving more than six doses of BCG was not significantly different. Following RC, there was no significant difference in final pathological stage between the groups. In group 1, 43% had muscle invasive BC and in group 2 this proportion was 52% (P= 0.5; Table 2). Twenty-six percent of patients in group 1 and 32% of patients in group 2 had extravesical BC (pT3 or pT4 BC). In group 2, 16% had lymph node metastasis (N+) compared with 11% in group 1. Stage-wise comparison of initial and final stage is shown in Table 3. Kaplan–Meier survival analysis showed significantly lower survival estimates for those with T2 or higher pathological stage (Fig. 1). The 5-year disease-specific survival was not significantly different between the groups (Table 2, Fig. 2).

Table 1.  Patient characteristics
CharacteristicsGroup 1 (1993–2002)Group 2 (2003–2007)P value
  • *

    Student’s t-test, all others chi-square/Fisher’s exact test. BCG, bacillus Calmette–Guérin, RC, radical cystectomy.

N7775 
Age (years ±sd)   
 At BCG therapy65.5 ± 1068.5 ± 100.12*
 At radical cystectomy (RC)68 ± 9.570.5 ± 9.50.07*
Male/female64/1355/200.15
Smoking, n (%)   
 Yes48 (62.5)54 (72)0.4
 No20 (26)16 (21) 
 Unknown 9 (11.5) 5 (7) 
T-stage, n (%)   
 Ta26 (34)16 (21.5)0.23
 T134 (44)40 (53.5) 
 Carcinoma in situ17 (22)19 (25) 
BCG initiation to RC (months)   
 Mean time interval ±sd23 ± 2721 ± 250.72*
 Median time interval 1110 
BCG given for:, n (%)   
 Primary tumour46 (60)54 (72)0.12
 Recurrent tumour31 (40)21 (28) 
Number of doses, n (%)   
 Single 6-week42 (54.5)38 (50.5)0.9
 Maintenance 8 (10.5)12 (16) 
 Repeated 6-week27 (35)25 (33.5) 
Table 2.  Comparison of pathological stage at radical cystectomy and survival
CharacteristicsGroup 1Group 2P value
<T2, n (%)44 (57)36 (48)0.5
T2, n (%)13 (17)15 (20) 
>T2, n (%)20 (26)24 (32) 
N+, n (%) 8 (11)12 (16)0.1
5-year disease-specific survival60 ± 668 ± 80.2 (log-rank)
(Events)3615 
Table 3.  Comparison of initial and final pathological stages
 Initial stageFinal pathological stage, n (%)
<T2T2>T2
Group 1Ta17 (65) 1 (4) 8 (31)
T115 (44) 8 (23.5) 11 (32.5)
CIS12 (70.5) 4 (23.5) 1 (6)
Group 2Ta10 (62) 1 (6.5) 5 (31.5)
T114 (35)11 (27.5)15 (37.5)
CIS12 (63) 3 (16) 4 (21)
Figure 1.

Disease-specific survival by final pathological stage.

Figure 2.

Disease-specific survival by group (log-rank P = 0.2).

DISCUSSION

High-grade Ta-T1-carcinoma in situ BC is a heterogeneous group and it is being increasingly realized that there is a significant variation in the response and the risk of progression after BCG therapy [8]. Up to one-third of patients with high-grade T1 urothelial carcinoma initially treated with BCG die of bladder cancer [9,10]. In a review of patients who underwent RC after failing BCG for high-grade Ta or T1 BC, Nieder et al.[11] reported that 19% died of bladder cancer. Herr [12] reported 15-year outcome data for patients with high-grade T1 showing that 52% of patients progressed to muscle invasion and 31% died of their disease. Cookson et al.[9] reported 15-year results in 84 patients with high-risk non-muscle-invasive bladder cancer treated with TUR ± BCG. Disease progressed in 53% of patients, 36% underwent cystectomy and 34% died of bladder cancer. Multiple retrospective reviews suggest that up to one-third of patients with high-risk Ta-T1 BC who receive BCG will require RC and one-third will die of metastatic disease [10,13]. These long-term studies indicate that high-grade Ta-T1 urothelial carcinoma of the bladder is associated with significant mortality and TUR with intravesical therapy is inadequate in a substantial percentage of patients. Our results also show that a significant proportion of these patients develop muscle invasion and extravesical BC. Furthermore, in our series more than 10% of patients who were initially diagnosed with non-muscle-invasive BC and received BCG had lymph node metastases at RC. Hence it is imperative that failure of BCG is recognized early and that RC is performed promptly. More importantly, we report that the pathological outcome has not changed in the past few years, underscoring the need for widespread awareness and caution in continuing a bladder-preserving strategy once high-grade BC persists or recurs.

With 15-year follow-up, Herr and Sogani [6] reported that patients who underwent early RC had better survival than those who delayed surgery, 92 vs 56%, respectively. The challenge is to identify the potentially lethal tumours before development of ≥T2 disease without over-treating a significant number of patients. Most patients and urologists accept the risk of progression with an initial diagnosis of Ta-T1 BC and initiate treatment with intravesical therapy usually with one or two courses of BCG before considering RC. Long-term studies suggest that approximately one-third of patients treated with BCG for high-grade urothelial cancer are cured [10]. A 6-week induction course of BCG followed by maintenance therapy is the suggested initial treatment for patients with high-risk Ta-T1 BC. Although only 16% of patients completed full 3-year maintenance in the Southwest Oncology Group trial, reduced BCG dosing and changes in treatment schedules may allow patients to better tolerate treatment [14]. In the current analysis, nearly 35% of patients in both groups had more than six BCG doses, indicating that the use of repeat courses of BCG has not significantly changed over time. In a recent review, Herr [15] concluded that the available evidence does not support liberal use of maintenance BCG. The disease-specific survival in our study group is similar to a recently published article with similar study population who received BCG and later underwent RC [16].

In a recently reported study: age, history of recurrence, high-grade, T1 stage, and recurrence at first cystoscopy were independent predictors of progression in patients treated with BCG [17]. There are no validated markers available to predict response to BCG. In the absence of reliable clinical tests to predict response to intravesical BCG, in our opinion the persistence or recurrence of high-grade urothelial cancer after one 6-week course of BCG warrants consideration of abandoning a bladder preservation strategy. The urologist must take into consideration the patient’s age and comorbidity along with the clinical stage and grade of the persistent or new tumour. This retrospective review emphasizes the lack of precision in staging and the reluctance of physicians and their patients to proceed promptly to RC without delay.

Our study has several limitations. It is retrospective single-centre study with relatively small study population. Furthermore, ours is a referral centre and the initial TUR and intravesical BCG therapy were usually initiated by a referring urologist and therefore the extent and type of therapies varied. Many patients did not undergo a re-TUR before BCG and many were referred for RC when progression had already occurred. Another limitation is that we could not account for those patients who failed BCG and did not undergo RC, as this is predominantly a referral population. Finally as this is a cystectomy series we do not report on patients who received BCG and did not recur or were cured with intravesical therapy. However, our data show that the pathological outcome and timing have remained unchanged over time and they underscore the need for early detection of BCG failure leading to RC at a time when the survival is not compromised.

A high percentage of patients who undergo RC for Ta, T1 and carcinoma in situ after receiving BCG have pT2 or higher BC. Over the past 15 years, we did not find a trend towards early surgery at a lower pathological stage in patients undergoing RC after BCG. It is hoped that an initial re-TUR for high-grade T1 tumours, ‘early’ RC if there is not a complete response to BCG, and careful surveillance will lead to a higher survival in the next decade. Intense monitoring of patients receiving BCG and optimal timing of RC are essential to improve survival.

ACKNOWLEDGEMENTS

We are grateful to Miller school’s “Center for Urologic Research Education and Diseases” (CURED) and Vincent A. Rodriguez.

CONFLICT OF INTEREST

None declared.

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