Pathology-based risk stratification of muscle-invasive bladder cancer patients undergoing cystectomy for persistent disease after induction chemoradiotherapy in bladder-sparing approaches

Authors


Fumitaka Koga, Department of Urology, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. e-mail: f-koga.uro@tmd.ac.jp

Abstract

Study Type – Therapy (case series)

Level of Evidence 4

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

In bladder-sparing approach incorporating TURBT and chemoradiotherapy (CRT) to MIBC, patients who clinically achieve complete response to induction CRT enjoy favourable prognosis and quality of life with preserved functioning bladder, whereas those with persisting disease have poor prognosis despite salvage radical cystectomy. Risk factors for cancer death among the non-responders remain fully unknown. The current study showed that survival of the non-responders is clearly stratified into low- and high-risk groups based on pathology of cystectomy specimens; 5-yr CSS rates for low- (pTO-2pNO) and high-risk (pT3-4a or pN+) patients were 85% and 20%, respectively.

OBJECTIVE

  • • To stratify patients with a clinical non-complete response (CR) after induction chemoradiotherapy (CRT) according to their risk of death from cancer, based on pathology of cystectomy specimens.

PATIENTS AND METHODS

  • • From 1997 to 2009, 170 patients with cT2-4aN0M0 bladder cancer underwent transurethral resection followed by induction CRT (40 Gy with cisplatin). Clinical response was evaluated 4–6 weeks after completion of CRT.
  • • Patients who met partial cystectomy (PC) criteria underwent PC plus pelvic lymph node dissection for bladder preservation. Otherwise, radical cystectomy (RC) was recommended.
  • • PC criteria were unifocal tumours, intact bladder neck and trigone, and CR (defined as no evidence of residual disease) or minimal amounts of residual non-muscle-invasive bladder cancer after induction CRT.
  • • Pathological variables associated with cancer death were analysed in patients who underwent PC or RC using a multivariate Cox proportional hazard model.

RESULTS

  • • Of 170 patients, 81 (48%) achieved a CR and 62 (36%) met the PC criteria. After CRT, 122 patients (72%) ultimately underwent PC (n= 44, 26%) or RC (n= 78, 46%).
  • • The 5-year cancer-specific survival (CSS) rate was 96% for the patients with a CR and 50% for patients with non-CR (P < 0.001, median follow-up for survivors: 48 months).
  • • In the 122 patients who underwent cystectomy, pT3-4a (hazard ratio [HR] 8.3 versus pTO-2, P < 0.001) and pN+ (HR 3.0 versus pNO, P = 0.037) were identified as significant and independent risk factors among variables including pT stage, lymph node yield at cystectomy, pN stage, and Iymphovascular invasion. A similar result was obtained through analysis of a sub-cohort of 69 patients with non-CR.
  • • Patients with non-CR were stratified according to their risk factors into low- (pT0-2pN0, 5-year CSS rate 85%) and high-risk (pT3-4a or pN+, 5-year CSS rate 20%) groups.

CONCLUSION

  • • In CRT-based bladder-sparing approaches, patients with a clinical non-CR after induction CRT can be stratified into low- and high-risk groups for death from cancer based on pathology of cystectomy specimens. Patients at high risk are potential candidates for intensive adjuvant therapy including clinical trials.
Abbreviations
CR

complete response

CRT

chemoradiotherapy

CIBM

carcinoma invading bladder muscle

PC

partial cystectomy

CSS

cancer-specific survival

HR

hazard ratio

RC

radical cystectomy

PLND

pelvic lymph node dissection

QoL

quality of life

TURBT

transurethral resection of bladder tumour

RT

radiotherapy

NMIBC

non-muscle-invasive bladder cancer

IQR

interquartile range

OS

overall survival

LVI

lymphovascular invasion.

INTRODUCTION

The reference standard treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy (RC) with urinary diversion, which potentially impairs patients’ quality of life (QoL) [1]. To improve patients’ QoL without compromising oncological outcomes, various bladder-sparing approaches have been investigated [2–4]. Of these, a combination of transurethral resection of bladder tumour (TURBT), chemotherapy and radiotherapy (RT) has yielded the most favourable oncological outcomes [5–10]; the trimodal therapy allows bladder preservation in 40% of patients with MIBC while maintaining survival outcomes similar to those of RC series [11,12], thus contributing to improvement of the patients’ QoL [13]. The favourable local control obtained with this trimodal therapy is attributed partly to the radiosensitizing effects of cytotoxic agents including cisplatin [14,15].

In most of the trimodality protocols for treating MIBC, patients receive induction chemoradiotherapy (CRT) at 40 Gy after TURBT. Those achieving a clinical complete response (CR), i.e. those patients who have no evidence of residual disease, are candidates for bladder preservation using consolidative CRT at 15–25 Gy; the patients with CR enjoy good QoL and a favourable prognosis while those with non-CR have a poorer prognosis despite salvage RC [5–10]. To date, most studies on bladder-sparing approaches have focused on successful patients who survive with preserved functional bladders. To the best of our knowledge, the risk factors for cancer death have not been fully investigated in patients with non-CR undergoing salvage cystectomy. Risk stratification of the patients with non-CR would allow personalized adjuvant therapy for those at truly high risk and may eventually improve the survival outcomes of bladder-sparing approaches overall.

The limitations of trimodality protocols include MIBC recurrence in the preserved bladder at the original MIBC site and potential lack of curative intervention in the regional lymph nodes [5–10]. Attempting to overcome these limitations, we have selectively performed consolidative partial cystectomy (PC) with pelvic lymph node dissection (PLND) after induction CRT when MIBC regresses. This leads to CR or small amounts of non-muscle-invasive bladder cancer (NMIBC) after CRT, when anatomical location and intravesical extent of original tumours permit complete resection of the original MIBC site, while conserving the functional bladder [16–18]. Our bladder-sparing approach yields favourable survival outcomes overall and excellent local control and survival outcomes in patients with bladder preservation [16–18].

In the present study, we evaluated the risk factors for cancer death based on pathology of cystectomy specimens in patients with MIBC who underwent PC or RC after induction CRT.

PATIENTS AND METHODS

From March 1997 to September 2009, 170 patients (43 women and 127 men) with clinical stage T2-4aN0M0 bladder cancer were treated with induction CRT. In our selective bladder-sparing protocol [16–18], patients who desired bladder preservation and who met our criteria for PC underwent PC with PLND; otherwise, RC was recommended (Fig. 1). Our PC criteria included (i) unifocal tumours involving roughly 1/4 or less of the whole bladder, (ii) no involvement of the bladder neck or trigone, and (iii) no residual tumour or only small amounts of residual NMIBC in the original MIBC site at restaging TURBT after completion of induction CRT. After debulking TURBT and random biopsy, patients underwent PC if they fulfilled criteria (i) and (ii). For all patients, a total dose of 40 Gy (fraction dose, 200 cGy/d) was irradiated to the small pelvis over a 4-week period, concurrent with two cycles of chemotherapy with cisplatin (20 mg/day for 5 days) during the first and fourth week of RT. The dose of cisplatin could be adjusted to accommodate each patient's general condition and renal function. Tumours were restaged 4–6 weeks after completion of induction CRT, based on findings obtained through cystoscopy, urine cytology and CT and/or MRI [19]. In addition, PC candidates underwent restaging TURBT of the original MIBC site. At the restaging process, patients who had no evidence of residual disease were considered to have achieved clinical CR. Only patients who ultimately met all of the PC criteria selectively underwent PC with PLND with curative intent. This therapeutic protocol was approved by our institutional ethics committee. In conjunction with PC and RC, patients underwent PLND; its template included the external iliac artery and the internal obturator muscle laterally, the internal iliac artery medially, the bifurcation of the common iliac artery cranially, and the origin of the epigastric vessels caudally. PC and RC were conducted using gasless single-port access endoscopic surgical techniques [20].

Figure 1.

Therapeutic protocol for patients with clinical stage T2-4aN0M0 bladder cancer. Numbers beside the arrows indicate the numbers of patients (%) who advanced to each next step in the algorithm.

Clinical and pathological stage was determined according to the 2002 TNM system [21,22] based on findings obtained through TURBT and CT of the chest, abdomen and pelvis. MRI of the pelvis was also included from 2007.

Patients were followed up at 3-month intervals for the first 2 years, at 6-month intervals for the following 3 years, and yearly thereafter. Evaluations consisted of medical history, physical examination, complete blood counts and blood chemistry, and CT of the chest, abdomen and pelvis. Patients with preserved bladders were placed on surveillance with the possibility of deferred RC. Urine cytology, cystoscopy and pelvic MRI were added for such patients. Survival intervals were calculated from the first day of the induction CRT to the time of death.

The primary endpoint of this study was bladder cancer death. Pathological variables associated with bladder cancer death were analysed in sub-populations of patients who had ultimately received PC or RC.

Continuous variables were expressed as median values and interquartile ranges (IQRs). Categorical data and continuous variables were compared using Fisher's exact test and the Wilcoxon rank-sum test, respectively. Survival curves for overall survival (OS) and cancer-specific survival (CSS) were plotted using the Kaplan–Meier method, and the difference between survival curves was analysed using the log-rank test. Variables associated with cancer death were analysed using a Cox proportional hazard model. A P value of P < 0.05 was considered to indicate statistical significance.

RESULTS

Patient, tumour and treatment characteristics are shown in Table 1. In all cases, tumours consisted of high-grade urothelial carcinoma. Of the 170 patients, 79 (46%) were underwent PC before induction CRT (Fig. 1). Eighty-one patients (48%) achieved CR after induction CRT (Table 1) and 62 (36%) met the PC criteria (Fig. 1). Ultimately, 44 (26%) and 78 (46%) underwent PC and RC, respectively (Fig. 1 and Table 1). The median (range) interval between CRT completion and subsequent cystectomy was 8 (5–24) weeks. A total of 48 (28%) patients had no cystectomy after induction CRT because of the development of metastatic or unresectable disease in eight cases, a poor general condition in another eight cases, and patient refusal in 32 cases. These 48 patients were treated using the following methods: additional RT of 10–20 Gy to the bladder in four patients who had CR and one with non-CR, surveillance in 23 patients with CR, TURBT followed by intravesical instillation in 11 patients with non-CR, systemic chemotherapy in one patient who developed distant metastases, palliative CRT to distant lymph node metastases in one patient and best supportive care in seven patients with progressive disease.

Table 1.  Patient, tumour and treatment characteristics
CharacteristicsOverallCystectomy
No. of patients170122
Gender, n (%)  
 Women43 (25)34 (28)
 Men127 (75)88 (72)
Median (IQR) age, years70 (63–77)69 (62–75)
Clinical T stage, n (%)  
 T296 (56)68 (56)
 T364 (38)49 (40)
 T4a10 (6)5 (4)
Clinical response after induction CRT, n (%)
 CR81 (48)53 (43)
 Non-CR89 (52)69 (57)
Surgical method, n (%)  
 PC44 (26)44 (36)
 RC78 (46)78 (64)
 TURBT11 (6)
 None38 (22)

Of the 170 patients, 42 died from bladder cancer and 13 died from other causes during the follow-up period (median [IQR] 48 [24–107] months for survivors). Overall, 5-year OS and CSS rates were 62% and 70%, respectively. As shown in Fig. 2, CSS was significantly worse in the non-CR group (n= 89) than in the CR group (n= 81) with respective 5-year CSS rates of 50% and 96% (P < 0.001). In the non-CR group, all of the eight patients who had developed metastatic or unresectable disease died of the disease within 24 months of the initiation of induction CRT. The 5-year CSS rate for the remaining 81 patients who had non-CR with persistent and resectable disease was 55%. Of these 81 patients, 69 actually underwent cystectomy (PC in eight and RC in 61 patients); their 5-year CSS rate was 58%, while that for 12 patients without cystectomy was 33% (P= 0.22).

Figure 2.

Kaplan–Meier estimated CSS curves according to clinical response after induction CRT in 170 patients with MIBC.

The associations of pathological findings of cystectomy specimens with pretreatment cT stage and clinical response after induction CRT are shown in Table 2. Of 122 patients who underwent cystectomy, 59 (48%), 36 (30%) and 27 (22%) had pT0, pTa-2 and pT3-4a stage disease, respectively. The median (range) of lymph node yield was 9 (0–27). Positive lymph node metastasis and lymphovascular invasion (LVI) were detected in eight (7%) and 31 (25%) patients, respectively. Pretreatment cT stage was significantly associated with pT stage (P= 0.027) and the incidence of LVI (P= 0.017) but not pN stage. Tumour was pathologically down-staged after induction CRT in 56/68 patients with cT2 (82%), 30/49 patients with cT3 (61%) and 4/5 patients with cT4 disease (80%). Of the 122 patients who underwent cystectomy, clinical and pathological response were discordant in 16 patients (13%); of 53 patients with CR, residual disease was missed in five (9%), four of whom had infiltrative disease (≥pT1), while 11 (16%) of the 69 patients with non-CR had pT0 disease. CR was significantly associated with fewer incidences of pN+ (P= 0.016) and LVI (P < 0.001); notably, none of the 53 patients with CR had pN+ disease. Since the proportion exhibiting discordance between clinical and pathological response was not negligible, pathology-based risk factors for cancer death were evaluated in the whole cohort of 122 patients who underwent cystectomy and a sub-cohort of the 69 patients with non-CR undergoing cystectomy.

Table 2.  Associations of pathological findings of cystectomy specimens with pretreatment clinical T stage and clinical response after induction CRT in122 patients
VariablesPathological T stage, n (%) P Median (range) lymph node yield P Pathological N stage, n (%) P LVI +, n (%) P
pT0pTa/ispT1pT2pT3pT4pN0pN1/2pNx
  1. NS, nonsignificant.

Pretreatment clinical T stage      0.027  NS     NS  0.017
 cT238 (56)11 (16)7 (10)4 (6)8 (12)0 8 (0–27) 59 (87)3 (4)6 (9) 11 (16) 
 cT320 (41)2 (4)6 (12)4 (8)15 (31)2 (4) 9 (0–27) 39 (80)5 (10)5 (10) 17 (35) 
 cT41 (20)002 (40)1 (20)1 (20) 8 (0–17) 4 (80)01 (20) 3 (60) 
Clinical response after induction CRT      <0.001  NS    0.016 <0.001
 CR48 (39)1 (1)1 (1)2 (2)1 (1)0 7 (0–25) 46 (87)07 (13) 3 (6) 
 Non-CR11 (9)12 (10)12 (10)8 (7)23 (19)3 (2) 9 (0–27) 56 (81)2/6 (3/9)5 (7) 28 (41) 
 Total59 (48)13 (11)13 (11)10 (8)24 (20)3 (2) 9 (0–27) 102 (84)8 (7)12 (10) 31 (25) 

Prognostic values of each pathological finding of the 122 cystectomy specimens are shown in Table 3. Of the pathological variables pT stage, lymph node yield, pN stage and LVI, univariate analyses identified pT stage, pN stage and LVI as significant prognosticators. Regarding pT stage, patients were categorized into pT0-2 and pT3-4a groups because the difference in CSS rates was greatest between pT2 and pT3-4a (the 5-year CSS rate was 95% for pT0/a, 83% for pTis/1, 72% for pT2 and 24% for pT3-4a). Multivariate analysis showed that pT3-4a (hazard ratio [HR] 8.3 vs pT0-2, P < 0.001) and pN+ (HR 3.0 vs pN0, P= 0.037) were significant and independent risk factors for bladder cancer death. When limited to the 69 patients with non-CR undergoing cystectomy, multivariate analysis similarly identified pT3-4a (HR 4.9 vs pT0-2, P < 0.001) as the strongest and independent risk factor, followed by pN+ (HR 2.5 vs pN0, P= 0.07).

Table 3.  Univariate and multivariate analysis of variables predicting bladder cancer death based on pathology of cystectomy specimens
VariablesUnivariateMultivariate
P HR (95% CI) P
  1. NS, not significant.

Pathological T stage   
 pT3-4a vs. pT0-2<0.0018.3 (3.3–22)<0.001
Lymph node yield   
 <10 vs. ≥10 NS  
Pathological lymph node metastasis   
 Yes vs. No0.0013.0 (1.1–8.0)0.037
LVI   
 Yes vs. No<0.001  NS

Based on the pathology of their cystectomy specimens, the 69 patients with non-CR undergoing cystectomy were clearly stratified into low-risk (pT0-2pN0) and high-risk (pT3-4a or pN+) groups with regard to CSS; the two groups had 5-year CSS rates of 86% and 20%, respectively (Fig. 3).

Figure 3.

Kaplan–Meier estimated CSS curves according to pathology-based risk stratification in 69 patients with non-CR undergoing cystectomy.

DISCUSSION

In trimodal bladder-sparing strategies for treating MIBC, the prognosis of patients who have achieved CR after induction CRT is favourable, while that of the remaining patients with non-CR is poor, despite salvage RC [6,8,10]. To the best of our knowledge, however, no study has specifically addressed risk stratification of the patients with non-CR. The present study shows for the first time that patients with non-CR, treated with salvage cystectomy, can be clearly stratified into low- and high-risk groups based on the pathology of their cystectomy specimens.

In trimodality bladder-sparing protocols incorporating CRT, patients with MIBC who have achieved a CR after induction CRT can enjoy both good QoL with preserved functional bladder and favourable survival outcomes with 5-year CSS rates of ≈ 80% [6,10]. The present study shows that, even though patients with MIBC had not achieved a CR, a favourable prognosis could be expected unless residual cancer had either extended extravesically or involved lymph nodes as evidenced by pathology of cystectomy specimens. Patients with non-CR and pathologically organ-confined disease (≤pT2pN0) had a 5-year CSS rate of 86% and did not require any adjuvant therapy after cystectomy.

By contrast, patients with non-CR with extravesical or nodal residual disease on cystectomy specimens were shown to have a high risk for cancer death: those in the present study had a 5-year CSS rate of 20%. These patients are potential candidates for intensive adjuvant therapy including clinical trials. Although adjuvant chemotherapy for patients with high-risk disease after immediate RC is still controversial [23], a recent randomized phase III study showed significant improvement of OS and CSS in patients receiving a combination of paclitaxel, gemcitabine and cisplatin [24]. A major cause of concern in adjuvant settings after salvage cystectomy, however, is potential cross-resistance of micrometastasis from bladder cancer cells resistant to induction CRT. In this situation, the adjunctive use of targeting agents that inhibit the intracellular pathways conferring such resistance might improve the effects of adjuvant chemotherapy.

Partial cystectomy is not a standard of care for MIBC but could be selectively curative as a primary therapeutic option for a small proportion of patients with MIBC who have small and solitary lesions [25,26]. We have shown that PC is also effective as a consolidative therapy of the bladder-sparing approach when selectively performed on patients with relatively small and unifocal lesions that have responded well to induction CRT, resulting in a 5-year CSS rate of 100% to date [16–18]. Since the bladder wall at the original MIBC sites is completely excised by PC, and pathological information on the invasive front of tumours reflects the prognosis of patients better than the other parts of the tumours [27,28], prognostic information would be obtained through pathological examination of PC specimens, as it is through examination of RC specimens.

In the present cohort of 170 patients, eight patients (5%) developed progressive disease after induction CRT; these patients might have lost a chance to undergo curative surgical treatment in compensation for receiving induction CRT. This is an inherent limitation of presurgical therapies. Given that our protocol enables bladder preservation in up to 40% of patients with MIBC with excellent oncological outcomes [17] and that induction CRT is indispensable for bladder-sparing approaches, the advantages of induction CRT justify the inherent limitation of presurgical therapies.

One of limitations of the present study is the small number of patients; the number of patients in our analysis of pathology-based risk stratification of patients who had non-CR was 69. When the subjects were extended to the whole cohort of patients who underwent cystectomy, as a result of inherent inaccuracy in evaluating clinical CRT response, this number increased to 122. External validation in larger cohorts is needed to confirm whether the current risk stratification system is generally applicable to patients who have not achieved CR after induction CRT and have subsequently received salvage cystectomy in the course of trimodal bladder-sparing treatment of MIBC. Another limitation is a possible bias attributed to the lack of salvage cystectomy in 15% of patients with non-CR having surgically resectable disease, most of whom declined to have cystectomy despite our recommendation. Their 5-year CSS rate was 33%, while that for patients with non-CR undergoing cystectomy was 55%; the difference was not significant, probably owing to the small number of subjects in the analysis (n= 12 vs 69, respectively).

In conclusion, patients who have not achieved a CR after induction CRT and have subsequently received salvage cystectomy can be clearly stratified into low- and high-risk groups based on the pathology of their cystectomy specimens. Patients in the low-risk group (pT0-2pN0) should not require any adjuvant therapy after cystectomy, whereas those in the high-risk group (pT3-4a or pN+) are potential candidates for intensive adjuvant therapy including clinical trials.

CONFLICT OF INTEREST

None declared.

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