Multicenter evaluation of the prognostic value of pT0 stage after radical cystectomy due to urothelial carcinoma of the bladder

Authors


  • M.M. and P.J.B.: equal study contribution

Hans-Martin Fritsche, Department of Urology, University of Regensburg, Caritas St. Josef Medical Center, Landshuter Str. 65, 93053 Regensburg, Germany. e-mail: hans-martin.fritsche@klinik.uni-regensburg.de

Abstract

Study Type – Therapy (case series)

Level of Evidence 4

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

Only little and often contradictory data exist pertaining to the frequency and prognosis of patients with stage pT0 after radical cystectomy (RC). Furthermore there is discussion about the role of a radical transurethral resection of the urinary bladder (TURB) for complete tumour eradication.

Within a RC population with clinical tumour stages cTa–cT2, cN0, cM0 and no neoadjuvant chemotherapy or radiotherapy, ≈6% had pathological stage pT0 with a 5-year cancer-specific survival (CSS) rate of 87%. Clinical tumour stage (advantage for non-invasive stages) and TURB time frame (advantage for more recent surgery) were independent predictors for stage pT0. A radical TURB is, assumedly, not the cause of this improved survival rate, but rather it is that individual tumour characteristics allow for complete tumour eradication through the TURB procedure. Concluding, a TURB with R0 resection is, as such, only a sign of a better tumour prognosis.

OBJECTIVE

• To evaluate the characteristics and long-term outcome of patients with pT0 stage after radical cystectomy (RC) for urothelial carcinoma of the urinary bladder (UCB).

PATIENTS AND METHODS

• Clinical and pathological records of 2403 patients treated with RC for UCB were collected in a multi-institutional database.

• The patients met the following criteria: clinical tumour stage cTa–cT2, cN0, cM0, no neoadjuvant chemotherapy or radiotherapy.

• Overall (OS) and cancer-specific survival rates (CSS) were calculated for the various clinical tumour stages in relation to their corresponding pathological tumour stage in the RC sample.

• Further to this, a multivariable prediction model was developed based onthe available clinical data to estimate the probability of tumour stage pT0.

RESULTS

• The mean follow-up was 53 months and 132 patients (5.5%) were stage pT0.

• Patients withstage cT2–pT0 had a 5-year CSS of 87% vs 69% for cT2–pT2 (P= 0.012) and 57% for cT2–pT+ (P < 0.001).

• In a multivariable Cox-model, stage pT0 led to a significant reduction of cancer-specific mortality (hazard ratio0.27; 95% confidence interval 0.12–0.61).

• A logistical regression model identified clinical tumour stage (advantage for non-invasive stages) and transurethral resection of the urinary bladder (TURB) time frame (advantage for more recent surgery) as independent predictors for stage pT0.

CONCLUSIONS

• In muscle-invasive clinical tumour stages, patients with pathological tumour stage pT0 form a subgroup showing a significantly better CSS.

• A radical TURB is, assumedly, not causative of this improved survival rate, but rather it is that individual tumour characteristics allow for complete tumour eradication through the TURB procedure.

• A TURB with R0 resection is, as such, only a sign of a better tumour prognosis.

Abbreviations
RC

radical cystectomy

UCB

urothelial carcinoma of the urinary bladder

TURB

transurethral resection of the urinary bladder

OS

overall survival

CSS

cancer-specific survival

Tis

carcinoma in situ

HR

hazard ratio

INTRODUCTION

With an incidence of 66 000 cases per year, urothelial carcinoma of the bladder (UCB) is the most common urogenital neoplasm affecting both genders in Europe [1]. The radical cystectomy (RC) is an effective standard treatment in non-metastatic muscle-invasive tumour stages and aggressive high-risk carcinoma without muscle-invasion [2]. That notwithstanding, around one third of all patients treated with RC still die from their carcinoma.

RC is typically preceded by transurethral resection of the urinary bladder (TURB). About10% of the patients in current RC studies exhibit no residual tumour cells (pT0) in the definitive histological analysis of their RC sample. As yet, only little and often contradictory data exists pertaining to the prognosis of these patients [2–11]. The goal of the present cross-institutional study was to evaluate the prognosis of tumour stage pT0 in a large and homogenous RC series of patients not having undergone neoadjuvant treatment.

PATIENTS AND METHODS

The clinical and pathological details of 2556 consecutive patients treated with RC for UCB in eight urology clinics (six university hospitals and twomaximum medical care hospitals) over a period of 20 years (1989–2008) were collated in a multi-institutional database. In all of the clinics involved, the indication to perform RC was based on the respective guideline recommendations in place at the time of the relevant procedure. Patients having undergone neoadjuvant systematic chemotherapy or intravesical instillation therapy between TURB and RC (55 patients), patients with tumour stage ≥ T3 (80) and patients with firm CT-provided indicators of lymphatic and/or haematogenous metastasis (cN+ and/or cM+; 18) were all systematically excluded, thus leaving a study group of 2403 patients withtumour stages Ta–T2N0M0.

All histopathological reports were produced according the 6th Edition of the TNM classification system [12]. For RC procedures before 2002, the TNM classification was adapted for the study group. Where difficulties in classification arose, the original histopathological report was accepted. The documented characteristics of the study group are shown in Table 1.

Table 1.  Clinical and histopathological characteristics of the complete study group, and patients stratified to pT0/pT+
CriteriaStudy group (n= 2403)pT0 (n= 132)pT+ (n= 2271) P
Mean age, years  65.7 65.5  65.70.875
Gender, n (%)   0.824
 M1912 (79.6)104 (78.8)1808 (79.6) 
 F 491 (20.4) 28 (21.2) 463 (20.4) 
Time frame of TURB, n (%)   <0.001
 1989–1996 548 (22.8) 26 (19.7) 522 (23.0) 
 1997–2002 906 (37.7) 29 (22.0) 877 (38.6) 
 2003–2008 949 (39.5) 77 (58.3) 872 (38.4) 
cT-stage, TURB, n (%)   0.072
 Ta  66 (2.7)  5 (3.9)  61 (2.7) 
 Tis  87 (3.6)  9 (6.8)  78 (3.4) 
 T1 607 (25.3) 39 (29.5) 568 (25.0) 
 T21643 (68.4) 79 (59.8)1564 (68.9) 
Grading, TURB, n (%)   0.932
 G1 103 (4.3)  6 (4.5)  97 (4.3) 
 G2 633 (26.3) 33 (25.0) 600 (26.4) 
 G31667 (69.4) 93 (70.5)1574 (69.3) 
Assoc. Tis, TURB, n (%) 746 (31.0) 38 (28.8) 708 (31.2)0.629
pT-stage, RC, n (%)   <0.001
 pT0 132 (5.5)132 (100) 
 pTa  77 (3.2)  77 (3.4) 
 pTis 104 (4.3) 104 (4.6) 
 pT1 389 (16.2) 389 (17.1) 
 pT2a 463 (19.3) 463 (20.4) 
 pT2b 194 (8.1) 194 (8.5) 
 pT3a 538 (22.4) 538 (23.7) 
 pT3b 258 (10.7) 258 (11.4) 
 pT4a 214 (8.9) 214 (9.4) 
 pT4b  34 (1.4)  34 (1.5) 
pN, RC, n (%)   <0.001
 pN01792 (74.6)123 (93.2)1669 (73.5) 
 pN+  611 (25.4)  9 (6.8) 602 (26.5) 
Grading, RC, n (%)   <0.001
 G0 132 (5.5)132 (100) 
 G1  76 (3.2)  76 (3.3) 
 G2 610 (25.4) 610 (26.9) 
 G31585 (66.0)1585 (69.8) 
Assoc. Tis, RC, n (%) 747 (31.1)  0 747 (32.9)<0.001
Adj. Chemotherapy, n (%) 328 (13.6)  5 (3.8) 323 (14.2)<0.001

The mean (range) follow-up for patients still alive at the end of the study was 53 (2–240) months. The extent of preoperative tumour stage determination, the histopathological processing of TURB and RC specimens as well as the type of follow-up treatment were defined according to standardized (yet individual) clinic-internal protocols.

A comparative analysis was carried out according to combinations derivable from the clinical and pathological tumour stages: cTa/carcinoma in situ (Tis)–pT0 vs cTa/Tis–pTa/pTis, cT1–pT0 vs cT1–pT1, cT2–pT0 vs cT2–pT2. In a second comparative analysis, the possible combinations of the clinical and pathological tumour stages were modified: cTa/Tis–pT0 vs cTa/Tis–pT+, cT1–pT0 vs cT1–pT+, cT2–pT0 vs cT2–pT+.

Overall (OS) and cancer-specific survival (CSS) rates were calculated using the Kaplan–Meier method, with group differences being shown by a log-rank test. A multivariable regression model was developed with the goal of identifying the factors amongst Tstage, grading, age, sex, year of TURB and associated Tis that would facilitate an independent prediction of the pT0 tumour stage. For all statistical tests, P≤ 0.05 was considered to indicate statistical significance.

RESULTS

Table 1 shows the clinical and pathological characteristics for the entire study group (2403 patients), the subgroup in pathological tumour stage pT0 (132, 5.5%) and those patients with carcinoma present in their RC sample (2271). In all, 25.4% of the study group (611) had positive lymph nodes (6.8% with pT0 vs 26.5% with pT+, P < 0.001). In all, 13.6% of the study group (328) received adjuvant chemotherapy.

The 5-year OS and CSS of patients with stage pT0 were 75% and 92%, respectively. In patients with pT0pN0 the 5-year OS and CSS rates were 79% and 96%, respectively. Equally, cT2–pT0 patients (79) had a 5-yearOS and CSS of 69% and 87%, respectively (Table 2). CSS in stage cT2–pT0 was significantly better than in stage cT2–pT2 (P= 0.009, Fig. 1) and also in stage cT2–pT+ (P < 0.001, Fig. 2). That said there was no benefit in OS or CSS through attaining pathological tumour stage pT0, when muscle invasion was not present in the TURB (cTa/Tis as well as cT1, Table 2).

Table 2.  Univariate analysis of OS and CSS stratified to corresponding combination of clinical and pathological tumour stage
Tumour Stage n 5-yearsurvival, %HR (95% CI; P)
OS    
 cTa/Tis–pT0  14 89 1
 cTa/Tis–pTa/pTis  63 84 1.84 (0.24–14.44; 0.560)
 cTa/Tis–pT+ 139 64 5.56 (0.77–40.32; 0.090)
 cT1–pT0  39 82 1
 cT1–pT1 289 68 1.56 (0.76–3.23; 0.228)
 cT1–pT+ 568 62 1.83 (0.90–3.71; 0.094)
 cT2–pT0  79 69 1
 cT2–pT2 547 60 1.46 (0.92–2.30; 0.110)
 cT2–pT+1564 47 2.16 (1.38–3.37; 0.001)
CSS    
 cTa/Tis–pT0  14100 1
 cTa/Tis–pTa/pTis  63 9726.30 (0–3433.80; 0.696)
 cTa/Tis–pT+ 139 8424.14 (0.07–8205.65; 0.284)
 cT1–pT0  39100 1
 cT1–pT1 289 86 4.14 (0.56–30.73; 0.164)
 cT1–pT+ 568 77 6.86 (0.96–49.27; 0.056)
 cT2–pT0  79 87 1
 cT2–pT2 547 69 2.64 (1.23–5.64; 0.012)
 cT2–pT+1564 57 4.20 (2.00–8.85; <0.001)
Figure 1.

Kaplan–Meiercurve of CSS after RC in patients with clinical muscle-invasive tumour stage cT2, stratified to corresponding pTstage pT0 vs pT2.

Figure 2.

Kaplan–Meiercurve of CSS after RC in patients with clinical muscle-invasive tumour stage cT2, stratified to corresponding pTstage pT0 vs pT+.

In a multivariable Cox-model, age, pTstage and pNstatus had an independent effect on OS (allP < 0.001; Table 3). The CSS was equally affected by these three factors (all P < 0.001), as well as by patient sex (P= 0.019; disadvantage for females; Table 4). In a second Cox-model, pT0stage was included in the analysis alongside age, sex, clinical tumour stage, pNstatus, RCgrading and evidence of associated Tis. Stage pT0 was significantly associated with an increased OS (hazard ratio [HR] 0.62; P= 9.050; Table 3) and increased CSS (HR 0.27; P= 0.001; Table 4) compared with specimens showing residual carcinoma.

Table 3.  Multivariate Cox-regression analysis predicting OS (model 1 including pTstage, model 2 including pT0stage)
VariableStandard deviationHR95% CI P
Model 1     
 Age (continous)0.0031.021.01–1.03<0.001
 Gender (male vs female)0.0761.030.89–1.200.680
 cT-stage, TURB (four stages)0.0520.960.87–1.060.417
 pT-stage, RC (10 stages)0.0191.271.23–1.32<0.001
 pN, RC (pN0 vs pN+)0.0701.611.41–1.85<0.001
 Grading, RC (G0, G1, G2, G3)0.0520.920.83–1.020.113
 Assoc. Tis, RC (no vs yes)0.0740.990.85–1.140.843
Model 2     
 Age (continous)0.0031.021.02–1.03<0.001
 Gender (male vs female)0.0761.020.88–1.190.764
 cT-stage, TURB (four stages)0.0531.201.08–1.330.001
 pT0-stage, RC (pT+ vs pT0)0.2460.620.38–1.000.050
 pN, RC (pN0 vs pN+)0.0672.111.85–2.40<0.001
 Grading, RC (G0, G1, G2, G3)0.0601.100.97–1.230.130
 Assoc. Tis, RC (no vs yes)0.0730.810.70–0.940.004
Table 4.  Multivariate Cox-regression analysis predicting tumour-specific survival (model 1 including pTstage, model 2 including pT0stage)
VariableStandard deviationHR95% CI P
Model 1     
 Age (continous)0.0041.021.01–1.03<0.001
 Gender (male vs female)0.0911.241.04–1.480.019
 cT-Stage, TURB (four stages)0.0741.060.92–1.230.434
 pT-Stage, RC (10 stages)0.0251.411.34–1.48<0.001
 pN, RC (pN0 vs pN+)0.0841.941.65–2.29<0.001
 Grading, RC (G0, G1, G2, G3)0.0710.900.79–1.040.146
 Assoc. Tis, RC (no vs yes)0.0921.070.89–1.280.466
Model 2     
 Age (continous)0.0041.021.01–1.03<0.001
 Gender (male vs female)0.0911.221.02–1.460.028
 cT-Stage, TURB (four stages)0.0781.471.26–1.72<0.001
 pT0-Stadium, RC (pT+ vs pT0)0.4070.270.12–0.610.001
 pN, RC (pN0 vs pN+)0.0812.772.36–3.25<0.001
 Grading, RC (G0, G1, G2, G3)0.0751.050.91–1.220.492
 Assoc. Tis, RC (no vs yes)0.0910.840.70–1.010.058

A logistical regression model identified clinical tumour stage (P= 0.011, advantage for non-invasive stages) and TURB time frame (P= 0.001; advantage for more recent procedures) as independent predictors for pathological tumour stage pT0. Age, sex, grading and associated Tis in the TURB did not have a significant influence (Table 5).

Table 5.  Binary logistic regression-model for prediction of pT0 tumour stage
VariableOdds ratio (95% CI)Standarddeviation P
Age (<50, 50–59, 60–69, 70–79, >80 years)0.95 (0.79–1.13)0.090.542
Gender (male, female)1.01 (0.66–1.56)0.220.962
cT-Stage, TURB (Ta, Tis, T1, T2)0.74 (0.59–0.94)0.110.011
Grading, TURB (G1, G2, G3)1.00 (0.72–1.38)0.160.974
Assoc. Tis, TURB (no, yes)0.76 (0.51–1.15)0.210.198
Time frame, TURB (1989–96, 1997–2002,  2003–2008)1.54 (1.20–1.98)0.130.001
Reference0.080.69<0.001

DISCUSSION

In published reports pT0stageis found in 5.1–20.1% of cases [2–11]. The interpretation of this type of data is rendered difficult by virtue of the fact that data series are often not homogenous for the level of treatment already undergone by patients [5,6,8,9,11]. If the levels of treatment patients had received were to be standardized, as was the case in a recent study by Sonpavde et al.[13], the proportion of patients with pT0 histology couldincrease up to 30% or more. In a prospective randomized multi-institutional study by Grossman et al.[14] the proportion of patients with pT0 was 38% for those having undergone neoadjuvant chemotherapy, compared with15% of patients only having had a RC. Equally, we can postulate that more patients in stage pT0 are to be found in clinics where a larger proportion of patients have no evidence of clinical muscle invasion in a TURB. In the presentRC series, slightly more than two thirds of the patients had muscle invasion at the time of their TURB. The rather low rate of 5.5% pT0 found compared with published rates can be explained by the fact that patients with pN+ were included in the present analysis. The exclusion of more than a quarter of patients (611) would lead to a significant and confusing bias.

WHAT CAN BE CONCLUDED FROM THE PRESENTRESULTS AND ALL AVAILABLE DATA RELATING TO THE PROGNOSIS OF PATIENTS WITH PT0 HISTOLOGY?

According to a cross-institutionally developed nomogram containing the records of >9000 patients who have undergone RC, patients in stage pT0 showed a better CSS than patients in other stages [15]. According published reports, only four studies have been carried out in which the prognostic value of tumour stage pT0 has been evaluated taking into account the clinical tumour stage [4,5,7,10]. But the findings of these studies are contradictory and comparisons between the length of patient survival in subjects with identical tumour stages and tumour presence are mainly missing [6,8,9,11].

In 1994, Thrasher et al.[5] published a RC dataset of 433 patients, of which 66 (15.2%) were tumour stage pT0. Rendering the interpretation of the results more difficult, a third of the latter 66 patients (22) had undergone neoadjuvant radiotherapy. Evaluating their data, the authors reported that no CSS advantage could be established for patients in stage pT0 when compared with patients of the same clinical stage and confirmed pathological stage [5]. Volkmer et al.[10]confirmed these results in clinical stages without muscle invasion and additionally in stage cT2b (albeit only with 11 patients). However,in their single-centre RC series (900 patients without neoadjuvant treatment), they reporteda significantly better CSS for patients in stage cT2a (196) for whom total tumour eradication (pT0) was successful, compared with patients with residual traces of carcinoma in their RCsample. The observation that no patients in pathological tumour stage pT0 pN0 had a local relapse in thatRC series was also an important result for the postoperative care of patients after RC [10]. In a recent publication with a sample of 197 RCpatients not having undergone neoadjuvant treatment, Cho et al.[7] also reported that patients in stage cT2 with following stage pT0 had a significantly better CSS comparedwithpatients in stage pT2. Finally Tilki et al.[4]reported on characteristics and outcome of 228 patients with pT0 stage: the medianfollow-up was 48.2 months, 17 (7.5%) had lymph node metastasis, disease recurred in 14 (6.7%) patients with lymph node-negative disease. The 5- and 10-year CSS rates were 93% and 92%, respectively. The 5- and 10-year OS rates were 84% and 66%, respectively. In particular the CSS of the last study is confirmed by the presentresults using our multi-institutional RC series.

DO THE RESULTS OF THE PRESENT MULTICENTRE STUDY ENABLE US TO DRAW GENERAL CONCLUSIONS DESPITE THEIR INHERENT LIMITATIONS AND DO THESE CONCLUSIONS CONTRIBUTE TO INTERNATIONAL RESEARCH TO DATE?

We think the present results are important in providing better information on individual risk profiles of patients with pT0 tumour stage and in the determination of their prognostic values. The presentstudy uses data collected over a span of two decades, the large time frame seeing changes in staging methods and where applicable, the development and improvement of operative procedures. Thus, coupled with the lack of a central pathological review and the various different hospital-specific protocols for diagnosis, treatment and after-care treatment of the patients involved, were the limiting factors of the presentstudy. That said, precisely these potential weaknesses make the presentresults applicable to wider urological practice compared with results generated from studies in single, highly specialized centres with high case numbers.

Apart from local stage many other factors determine the oncological outcomes and should be considered in recommending treatment.Information about tumour size, about the exact degree of muscle invasion in the TURB, as to the estimation of the degree of radicalization of the TURB by the operating surgeon, about the length of time between TURB and RC procedures and about the multifocality of bladder tumours were, respectively, only available for 62%, 44%, 41%, 54% and 39% of patients, and as such, these factors were not included in the present analysis. Furthermore, lymphovascular invasion was not routinely specified in TURB specimen in many centres.The integration of these factors would have enabled us to develop further insight into this topic; however, due to the retrospective and multi-institutional approach used in the present study this was not possible to implement. Future work on this topic should investigate and establish the significance of the aforementioned factors in the prediction of pathological tumour stage pT0.

SHOULD A T0 RESECTION IN TURB ALWAYS BE AT LEAST TRIED?

This conclusion cannot be drawn based on the presented results. The significance of a ‘radical’ TURB for prognosis improvement in cases of muscle-invasive UCB could only be determined through a prospective randomized study in which tumour-individual characteristics are balanced between the groups (radical TURB vs staging TURB). Until such results are obtained, all we can derive from the presentresults is that the significance of an early RC is high. Patients with the potentially lethal muscle-invasive UCB should undergo a RC immediately after diagnosis. The improved survival rate for those patients with muscle-invasive tumours undergoing RC is not due to a R0resection in itself; rather that it is by virtue of the fact that a R0resection is at all possible. The tumour-specific characterization of these patients predominantly follows the pattern pT2a, a monofocal carcinoma with a small tumour diameter and no associated Tis. If these prognosis relevant patterns emerge in the TURB, then a surgeon is more likely (and indeed, would see him or herself prompted to a higher degree) to be able to achieve a R0 resection. Additionally, it should be mentioned, that there are attempts tostratifyrisk of progression in patients afterneoadjuvant chemotherapy when clinical R0 disease is discovered (i.e. the selective bladder preservation against radical excision (SPARE) trial [16]). But the present study does not support those who may favour radiotherapy rather than surgery in such cases, as neoadjuvant chemotherapy was an exclusion criterion and the study only provides data on pathological stage T0, not on clinical stage T0. Finally, we cannot conclude that a radical TURB alone (where applicable with documented R0 status in a follow-up resection) provides for a similarly good prognosis. Even in a study with a bladder-sparing approach for T1G3tumours and cases with complete tumour eradication, up to 60% of patients relapse within the first 5 years after treatment [17]. Indeed, invasive carcinoma can appear to have been satisfyingly treated in the short term after a R0 resection, nevertheless, the long term brings with it higher relapse and progression risks. The difficulty with primarily conservative treatment standards is due to the fact that UCB is a panurothelial disease of polyclonal origin.

In conclusion, in the presentlarge, multi-institutional RC series of patients without neoadjuvant treatment, a clinical muscle-invasive UCB with downstaging to stage pT0 had a greater CSS compared with stage-equivalent tumours (pT2). A radical TURB is, assumedly, not causative of this improved survival rate, but rather it is that individual tumour characteristics, such as small tumour size, unifocality and occurrence of stage T2a, allow for complete tumour eradication through the TURB procedure. A TURB with R0 resection is, as such, only a sign of a better tumour prognosis.

ACKNOWLEDGEMENTS

We thank Patrick Goldsworthy for his excellent assistance.

CONFLICT OF INTEREST

None declared.

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