Abstract

Objective

To compare rates of early morbidity after radical cystectomy in patients treated with or without induction chemoradiotherapy (CRT) using a standardized reporting methodology.

Methods

All 193 consecutive patients undergoing radical cystectomy for bladder cancer between 1989 and 2010 were retrospectively reviewed. Induction chemoradiotherapy consists of radiation at 40 Gy to the small pelvis and two cycles of concurrent cisplatin at 20 mg/day for 5 days. Deaths within 90 days after radical cystectomy and complications arising within 30 days were recorded and graded according to the Clavien–Dindo classification. Grades 1–2 were considered minor; Grades 3–5 were considered major.

Results

Eighty-seven patients underwent radical cystectomy following chemoradiotherapy (chemoradiotherapy group) while the remaining 106 primarily underwent radical cystectomy (no chemoradiotherapy group). No Grade 4–5 complication was observed. Overall, 118 patients (61%) experienced 36 major and 122 minor complications. There was no significant difference in the incidence of overall complications between the chemoradiotherapy and no chemoradiotherapy groups (67 vs. 57%). Overall urinary anastomosis-related complications and major gastrointestinal complications, most of which were Grade 3 ileus, were more frequent in the chemoradiotherapy group than the no chemoradiotherapy group (11 vs. 2%, P = 0.007; and 14 vs. 4%, P = 0.02; respectively). Multivariate analysis identified induction chemoradiotherapy as an independent risk factor for overall urinary anastomosis-related complications (relative risk 6.0, P = 0.01) but not for major gastrointestinal complications.

Conclusions

Induction chemoradiotherapy at 40 Gy in bladder-sparing protocols against MIBC is unlikely to increase the rate of severe complications of radical cystectomy.

INTRODUCTION

The reference standard of treatment for muscle-invasive bladder cancer (MIBC) has long been radical cystectomy (RC) and urinary diversion; this method, however, potentially impairs patients' quality of life (QOL) (1). To improve the QOL of MIBC patients, bladder-sparing protocols consisting of transurethral resection of the bladder tumor (TURBT), chemotherapy and radiotherapy (RT) have been developed (2–7). These trimodality therapies have yielded survival outcomes comparable to those of the traditional RC series while allowing 40% or more patients to preserve their native bladder (2–11). These therapies are now being considered as an alternative to RC for selected patients (12).

In most of the trimodality bladder-sparing protocols, patients receive induction chemo-RT (CRT) at 40 Gy following TURBT. Only those achieving a clinical complete response (CR) by this means are candidates for bladder preservation by means of consolidative CRT at 15–25 Gy; the remaining non-CR patients usually undergo RC to extirpate residual disease with curative intent (2,6,7,10).

Pelvic RT results in tissue vulnerability, desmoplastic reaction and ischemia that can affect the surrounding pelvic organs including the ureter, urethra, small bowel and rectum (13,14), potentially making subsequent RC and urinary diversion more technically demanding and morbid. Reportedly, high-dose (>60 Gy) pelvic RT is likely to increase both mortality and morbidity of RC. In patients undergoing RC after definitive RT (>60 Gy), mortality rates range from 6 to 33% (15–17), being thus higher than the rates reported in published contemporary RC series of non-irradiated subjects, which range up to 4% (18–23). As for the volume–outcome relationship for RC, lower mortality and morbidity rates are reportedly associated with higher-volume centers (24,25). According to recent reports from high-volume centers, where 30–100 RCs are performed annually, high-dose pelvic RT appears to increase the mortality and morbidity of RC in comparison to that of non-irradiated subjects (15), while intermediate-dose (45–55 Gy) pelvic RT does not significantly increase mortality but does increase morbidity associated with stomal stenosis (14). To date, however, little is known about how induction CRT at low doses (<45 Gy) affects surgical outcomes of RC at low- to moderate-volume institutions.

In the current study, we retrospectively compared the incidences of early complications of RC in patients pre-treated with or without induction CRT at 40 Gy at a single moderate-volume institution (<10 RCs performed annually) using a standardized complication reporting system.

PATIENTS AND METHODS

From April 1989 to May 2010, 193 patients underwent RC for bladder cancer at our institution. Patient and tumor demographics and operative parameters are listed in Table 1. Of all 193 patients, 142 (74%) patients were classified as American Society of Anesthesiologists (ASA) physical status class 1. As for performance status, 185 (96%) patients were scored as 0. All patients had urothelial carcinoma and 172 (89%) had high-grade disease. Clinical stage was determined according to the 2002 TNM classification (26); 134 (69%) patients had clinical T2 or greater disease while 53 (27%) had high-grade T1 or BCG refractory carcinoma in situ. Although patients with distant metastasis typically did not undergo RC, RC was performed on two relatively young patients with resectable metastatic disease in combination with perioperative chemotherapy.

Table 1.

Patient and tumor demographics and operative parameters

Variables n (% of total patients)
 
 CRT No CRT P value 
Total 87 (100) 106 (100)  
Age (years)a 66 (60–72) 69 (63–74) 0.17 
Sex 
 Male 59 (68) 85 (80) 0.07 
Body mass index 
 ≥30 kg/m2 2 (2) 0.20 
ASA 
 1 62 (71) 80 (75) 0.80 
 2 20 (23) 21 (20)  
 3 5 (6) 5 (5)  
 4  
PS 
 0 82 (94) 103 (97) 0.47 
 1 5 (6) 3 (3)  
 2  
Clinical T stage 
 Tis + T1 53 (50) <0.0001 
 T2 36 (41) 18 (17) 0.0002 
 T3 41 (47) 26 (25) 0.002 
 T4a 6 (7) 7 (7) 1.00 
 Unknown 4 (5) 2 (2) 0.41 
 Clinical N+ 5 (6) 0.02 
 Clinical M+ 2 (2) 0.20 
Surgical modality 
 MIES 63 (72) 20 (19) <0.0001 
Urinary diversion 
 Ileal conduit 70 (80) 92 (87) 0.05 
 Neobladder 10 (11) 1 (1) 0.003 
 Indiana pouch 5 (5) 0.07 
 Ureterocutaneostomy 7 (8) 7 (7) 0.78 
 None 1 (1) 1.00 
Operative time (min)a 
 Overall 555 (479–597) 467 (405–535) <0.0001 
 Open 496 (435–559) 460 (400–531) 0.07 
 MIES 573 (532–615) 547 (455–594) 0.09 
Blood loss (ml)a 1971 (1300–2650) 2000 (1368–2751) 0.54 
Blood transfusion (units)a 1 (0–3) 2.5 (0–4) 0.002 
Variables n (% of total patients)
 
 CRT No CRT P value 
Total 87 (100) 106 (100)  
Age (years)a 66 (60–72) 69 (63–74) 0.17 
Sex 
 Male 59 (68) 85 (80) 0.07 
Body mass index 
 ≥30 kg/m2 2 (2) 0.20 
ASA 
 1 62 (71) 80 (75) 0.80 
 2 20 (23) 21 (20)  
 3 5 (6) 5 (5)  
 4  
PS 
 0 82 (94) 103 (97) 0.47 
 1 5 (6) 3 (3)  
 2  
Clinical T stage 
 Tis + T1 53 (50) <0.0001 
 T2 36 (41) 18 (17) 0.0002 
 T3 41 (47) 26 (25) 0.002 
 T4a 6 (7) 7 (7) 1.00 
 Unknown 4 (5) 2 (2) 0.41 
 Clinical N+ 5 (6) 0.02 
 Clinical M+ 2 (2) 0.20 
Surgical modality 
 MIES 63 (72) 20 (19) <0.0001 
Urinary diversion 
 Ileal conduit 70 (80) 92 (87) 0.05 
 Neobladder 10 (11) 1 (1) 0.003 
 Indiana pouch 5 (5) 0.07 
 Ureterocutaneostomy 7 (8) 7 (7) 0.78 
 None 1 (1) 1.00 
Operative time (min)a 
 Overall 555 (479–597) 467 (405–535) <0.0001 
 Open 496 (435–559) 460 (400–531) 0.07 
 MIES 573 (532–615) 547 (455–594) 0.09 
Blood loss (ml)a 1971 (1300–2650) 2000 (1368–2751) 0.54 
Blood transfusion (units)a 1 (0–3) 2.5 (0–4) 0.002 

CRT, chemoradiotherapy; ASA, American Society of Anesthesiologists; PS, performance status; MIES, minimum incision endoscopic surgery.

aMedian (IQR).

Until 1997, our institutional protocol for MIBC was primary RC. Starting in 1997, to improve prognosis and provide a subset of MIBC patients with a chance at bladder preservation, we adopted induction CRT prior to curative surgery as an institutional prospective protocol (27–30). In this protocol, after diagnostic and debulking TURBT, a total dose of 40 Gy (200 cGy/fraction) was irradiated to the small pelvis over 4 weeks concurrently with two cycles of chemotherapy with cisplatin (20 mg/day for 5 days) during the first and fourth week of RT. Bladder preservation with partial cystectomy was considered selectively when (i) original tumors were unifocal, (ii) the bladder neck or trigone was not involved in the tumors and (iii) restaging TURBT after induction CRT revealed no residual tumor or only small amounts of residual non-MIBC. Otherwise, RC was recommended.

During RC, bilateral pelvic lymph node dissection was performed; its template included the external iliac artery and 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. As for urinary diversion, ileal conduit, orthotopic ileal neobladder and Indiana pouch were selected for 162 (84%), 11 (6%) and five (3%), respectively. Fourteen high-risk patients (7%) received ureterocutaneostomy. A patient undergoing complete urinary tract exenteration did not undergo urinary diversion.

Since 2000, RC has typically been performed by means of minimum incision endoscopic surgery (MIES), a form of gasless single-port surgery that was developed at our institution (31,32). Briefly, MIES is accomplished through a single port which narrowly permits the extraction of surgical specimens using specific reusable devices and without using gas or trocar ports.

Medical records including inpatient charts, hospital discharge summaries and outpatient charts were retrospectively reviewed and all complications within 30 days after surgery were recorded. As for perioperative death, any death within 90 days after RC was considered RC-related. A continual rise in body temperature above 38°C after post-operative day (POD) 3 was recorded as infection. Any state of bowel congestion which necessitated a limitation of oral intake and intravenous supplementations after POD 7 was recorded as ileus. Urinary leakage at ureteroileal anastomosis persisting 1 week or longer post-operatively was recorded as anastomotic urinary leakage.

All complications were graded according to the 2004 Clavien–Dindo grading system (33). Definitions for each grade in the system are as follows: Grade 0, no complications observed; Grade 1, complications causing any deviation from normal postoperative course without need for pharmacological treatment excluding antiemetics, antipyretics, analgesics, diuretics and electrolytes; Grade 2, complications requiring pharmacological treatment, use of gastrointestinal tubes or blood transfusion; Grade 3a, complications requiring surgical, endoscopic or radiological intervention without general anesthesia; Grade 3b, same as 3a but requiring general anesthesia; Grade 4, life-threatening complications with residual and lasting disability requiring major rehabilitation or organ resection; Grade 5, death. Complications in Grades 1 and 2 were classified as ‘minor’ complications while those in Grade 3 or higher were classified as ‘major’.

For statistical analysis, the Wilcoxon rank-sum test and Fisher's exact test were performed for quantitative and categorical variables, respectively. Univariate and then multivariate logistic regression analyses following a forward stepwise procedure were conducted to identify predictors of specific RC complications. Differences were considered significant at a P value of <0.05.

RESULTS

As shown in Table 1, 87 patients underwent induction CRT prior to RC (CRT group) while 106 did not (no CRT group). The CRT group consisted of significantly more patients with advanced disease (clinical T2 or greater and clinical N+) than the no CRT group did. As MIES has been typically employed since its introduction in 2000, MIES was performed more frequently (P< 0.0001) in the CRT group than in the no CRT group. In the CRT group, more patients received orthotopic ileal neobladder reconstruction (P = 0.003). The operative time was significantly longer in the CRT group (P < 0.0001) due to a higher prevalence of patients undergoing MIES, which takes more time than open surgery does. There was no significant difference in estimated blood loss between the two groups, but significantly fewer units of blood transfusion were required in the CRT group.

Overall, 118 patients (61%) experienced one or more complications (Table 2). There was no difference in the overall incidence of complications between the CRT and no CRT groups (67 vs. 57%). Neither death (Grade 5) within 90 days after RC nor life-threatening complications (Grade 4) within 30 days after RC was observed. Twenty-nine (15%) patients experienced more than one complication.

Table 2.

Early complications (highest grade complication per patient) according to the Clavien–Dindo classification

 n (% of total patients)
 
 Total (%) CRT No CRT P value 
Total 118 (61) 58 (67) 60 (57) 0.18 
Grade 
 1 8 (4) 6 (7) 2 (2) 0.14 
 2 79 (41) 33 (38) 46 (43) 0.47 
 3a 21 (11) 13 (15) 8 (8) 0.06 
 3b 10 (5) 6 (7) 4 (4) 0.35 
 4 or 5  
No. of complications 
 1 89 (46) 42 (48) 47 (44) 0.47 
 2 20 (10) 9 (10) 11 (10) 1.00 
 3 7 (4) 5 (6) 2 (2) 0.25 
 4 2 (1) 1 (1) 1 (1) 1.00 
 5 or more  
 n (% of total patients)
 
 Total (%) CRT No CRT P value 
Total 118 (61) 58 (67) 60 (57) 0.18 
Grade 
 1 8 (4) 6 (7) 2 (2) 0.14 
 2 79 (41) 33 (38) 46 (43) 0.47 
 3a 21 (11) 13 (15) 8 (8) 0.06 
 3b 10 (5) 6 (7) 4 (4) 0.35 
 4 or 5  
No. of complications 
 1 89 (46) 42 (48) 47 (44) 0.47 
 2 20 (10) 9 (10) 11 (10) 1.00 
 3 7 (4) 5 (6) 2 (2) 0.25 
 4 2 (1) 1 (1) 1 (1) 1.00 
 5 or more  

A summary of complications is shown in Table 3. Of all complication types, infection was most frequently observed followed by gastrointestinal and urinary anastomosis-related complications, with respective incidences of 42, 23 and 6%. Only urinary anastomosis-related complications, particularly anastomotic leakage, were observed more frequently in the CRT group than in the no CRT group (11 vs. 2%, P = 0.007 and 9 vs. 1%, P = 0.01, respectively). These differences can be explained by a higher incidence of minor anastomotic leakage in the CRT group than in the no CRT group (7 vs. 0%, P = 0.008). The incidence of overall major complications was higher in the CRT group than in the no CRT group with marginal significance (22 vs. 11%, P = 0.052), which was underlain by a higher incidence of gastrointestinal complications (14 vs. 4%, P = 0.02), particularly ileus requiring decompression with an ileus tube (12 vs. 4%, P = 0.051). An incidence of ileus of Grade 1 or 2 was, however, lower in the CRT group than in the no CRT group (5 vs. 14%, P = 0.03).

Table 3.

Summary of complications

 Complications of any grade, N (% of total patients)
 
Major complications (Grade 3a or 3b), N (% of total patients)
 
Minor complications (Grade 1 or 2), N (% of total patients)
 
 Total, n= 193 CRT, n = 87 No CRT, n = 106 P value Total, n = 193 CRT, n = 87 No CRT, n = 106 P value Total, n = 193 CRT, n = 87 No CRT, n = 106 P value 
No. of patients 118 (61) 58 (67) 60 (57) 0.18 31 (16) 19 (22) 12 (11) 0.052 100 (52) 48 (55) 52 (49) 0.47 
No. of complications 158 79 79  36 23 13  122 56 66  
Infection 
 Total 80 (42) 40 (46) 40 (38) 0.30 7 (4) 3 (3) 4 (4) 1.00 74 (38) 37 (43) 37 (35) 0.30 
 Wound 35 (18) 13 (15) 22 (21) 0.35  35 (18) 13 (15) 22 (21) 0.35 
 Urinary tract 29 (15) 17 (20) 12 (11) 0.16 3 (2) 2 (2) 1 (1) 0.59 26 (13) 15 (17) 11 (10) 0.20 
 Pelvic abscess 7 (4) 4 (5) 3 (3) 0.70 2 (1) 1 (1) 1 (1) 1.00 5 (3) 3 (5) 2 (2) 0.66 
 Other sites 16 (8) 8 (9) 8 (8) 0.79 2 (1) 2 (2) 0.50 14 (7) 8 (9) 6 (6) 0.41 
Gastrointestinal 
 Total 44 (23) 21 (24) 23 (22) 0.73 16 (8) 12 (14) 4 (4) 0.02 28 (15) 9 (10) 19 (18) 0.15 
 Enterocolitis 10 (5) 5 (6) 5 (5) 0.76  10 (5) 5 (6) 5 (5) 0.76 
 Ileus 33 (17) 14 (16) 19 (18) 0.84 14 (7) 10 (12) 4 (4) 0.051 19 (10) 4 (5) 15 (14) 0.03 
 Bowel perforation 2 (1) 2 (2) 0.20 2 (1) 2 (2) 0.20  
Cardiovascular 
 Total 5 (3) 1 (1) 4 (4) 0.38 2 (1) 1 (1) 1 (1) 1.00 3 (2) 3 (3) 0.25 
 Angina 1 (1) 1 (1) 1.00  1 (1) 1 (1) 1.00 
 Atrial fibrillation 1 (1) 1 (1) 1.00  1 (1) 1 (1) 1.00 
 Hypertensive crisis 1 (1) 1 (1) 1.00  1 (1) 1 (1) 1.00 
 Pulmonary embolism 1 (1) 1 (1) 0.45 1 (1) 1 (1) 0.45  
 Sick sinus syndrome 1 (1) 1 (1) 1.00 1 (1) 1 (1) 1.00  
Urinary anastomosis-related 
 Total 12 (6) 10 (11) 2 (2) 0.007 6 (3) 4 (5) 2 (2) 0.42 6 (3) 6 (7) 0.008 
 Stricture 3 (2) 2 (2) 1 (1) 0.59 3 (2) 2 (2) 1 (1) 0.59  
 Leakage 9 (5) 8 (9) 1 (1) 0.01 3 (2) 2 (2) 1 (1) 0.59 6 (3) 6 (7) 0.008 
Miscellaneous 
 Surgical dehiscence 4 (2) 2 (2) 2 (2) 1.00 4 (2) 2 (2) 2 (2) 1.00  
 Penile necrosis 1 (1) 1 (1) 0.45 1 (1) 1 (1) 0.45  
 Pain 1 (1) 1 (1) 0.45  1 (1) 1 (1) 0.45 
 Delirium 1 (1) 1 (1) 0.45  1 (1) 1 (1) 0.45 
 Acidosis 1 (1) 1 (1) 1.00  1 (1) 1 (1) 1.00 
 Vertigo 1 (1) 1 (1) 1.00  1 (1) 1 (1) 1.00 
 Complications of any grade, N (% of total patients)
 
Major complications (Grade 3a or 3b), N (% of total patients)
 
Minor complications (Grade 1 or 2), N (% of total patients)
 
 Total, n= 193 CRT, n = 87 No CRT, n = 106 P value Total, n = 193 CRT, n = 87 No CRT, n = 106 P value Total, n = 193 CRT, n = 87 No CRT, n = 106 P value 
No. of patients 118 (61) 58 (67) 60 (57) 0.18 31 (16) 19 (22) 12 (11) 0.052 100 (52) 48 (55) 52 (49) 0.47 
No. of complications 158 79 79  36 23 13  122 56 66  
Infection 
 Total 80 (42) 40 (46) 40 (38) 0.30 7 (4) 3 (3) 4 (4) 1.00 74 (38) 37 (43) 37 (35) 0.30 
 Wound 35 (18) 13 (15) 22 (21) 0.35  35 (18) 13 (15) 22 (21) 0.35 
 Urinary tract 29 (15) 17 (20) 12 (11) 0.16 3 (2) 2 (2) 1 (1) 0.59 26 (13) 15 (17) 11 (10) 0.20 
 Pelvic abscess 7 (4) 4 (5) 3 (3) 0.70 2 (1) 1 (1) 1 (1) 1.00 5 (3) 3 (5) 2 (2) 0.66 
 Other sites 16 (8) 8 (9) 8 (8) 0.79 2 (1) 2 (2) 0.50 14 (7) 8 (9) 6 (6) 0.41 
Gastrointestinal 
 Total 44 (23) 21 (24) 23 (22) 0.73 16 (8) 12 (14) 4 (4) 0.02 28 (15) 9 (10) 19 (18) 0.15 
 Enterocolitis 10 (5) 5 (6) 5 (5) 0.76  10 (5) 5 (6) 5 (5) 0.76 
 Ileus 33 (17) 14 (16) 19 (18) 0.84 14 (7) 10 (12) 4 (4) 0.051 19 (10) 4 (5) 15 (14) 0.03 
 Bowel perforation 2 (1) 2 (2) 0.20 2 (1) 2 (2) 0.20  
Cardiovascular 
 Total 5 (3) 1 (1) 4 (4) 0.38 2 (1) 1 (1) 1 (1) 1.00 3 (2) 3 (3) 0.25 
 Angina 1 (1) 1 (1) 1.00  1 (1) 1 (1) 1.00 
 Atrial fibrillation 1 (1) 1 (1) 1.00  1 (1) 1 (1) 1.00 
 Hypertensive crisis 1 (1) 1 (1) 1.00  1 (1) 1 (1) 1.00 
 Pulmonary embolism 1 (1) 1 (1) 0.45 1 (1) 1 (1) 0.45  
 Sick sinus syndrome 1 (1) 1 (1) 1.00 1 (1) 1 (1) 1.00  
Urinary anastomosis-related 
 Total 12 (6) 10 (11) 2 (2) 0.007 6 (3) 4 (5) 2 (2) 0.42 6 (3) 6 (7) 0.008 
 Stricture 3 (2) 2 (2) 1 (1) 0.59 3 (2) 2 (2) 1 (1) 0.59  
 Leakage 9 (5) 8 (9) 1 (1) 0.01 3 (2) 2 (2) 1 (1) 0.59 6 (3) 6 (7) 0.008 
Miscellaneous 
 Surgical dehiscence 4 (2) 2 (2) 2 (2) 1.00 4 (2) 2 (2) 2 (2) 1.00  
 Penile necrosis 1 (1) 1 (1) 0.45 1 (1) 1 (1) 0.45  
 Pain 1 (1) 1 (1) 0.45  1 (1) 1 (1) 0.45 
 Delirium 1 (1) 1 (1) 0.45  1 (1) 1 (1) 0.45 
 Acidosis 1 (1) 1 (1) 1.00  1 (1) 1 (1) 1.00 
 Vertigo 1 (1) 1 (1) 1.00  1 (1) 1 (1) 1.00 

Next, multivariate logistic regression analyses were performed to assess potential involvement of variables other than induction CRT as risk factors for overall urinary anastomosis-related and major gastrointestinal complications. As shown in Table 4, induction CRT was identified as an independent risk factor for overall urinary anastomosis-related complications (relative risk 6.0, P = 0.01). Although univariate analysis demonstrated induction CRT and MIES as risk factors for major gastrointestinal complications, multivariate analysis did not identify either as a significant risk factor.

Table 4.

Clinical variables associated with incidences of overall urinary anastomosis-related and major gastrointestinal complications

Variables Overall urinary anastomosis-related
 
Major gastrointestinal
 
 Univariate Multivariate
 
Univariate Multivariate
 
 P value Relative risk P value P value Relative risk P value 
CRT (yes vs. no) 0.02 6.0 0.01 0.02 2.3 0.23 
Age 0.95 —  0.54 —  
Sex (male vs. female) 0.05 2.6 0.13 0.53 —  
ASA (2–3 vs. 1) 0.58 —  0.89 —  
PS (1–2 vs. 0) 0.46 —  0.89 —  
Clinical T stage (≥T2 vs. ≤T1) 0.33 —  0.54 —  
Surgical modality (MIES vs. open) 0.10 —  0.01 2.8 0.12 
Urinary diversion (IC/NB/IP vs. UC/none) 0.90 —  0.10 —  
Operative time 0.50 —  0.07 —  
Blood loss 0.70 —  0.09 1.0 0.13 
Variables Overall urinary anastomosis-related
 
Major gastrointestinal
 
 Univariate Multivariate
 
Univariate Multivariate
 
 P value Relative risk P value P value Relative risk P value 
CRT (yes vs. no) 0.02 6.0 0.01 0.02 2.3 0.23 
Age 0.95 —  0.54 —  
Sex (male vs. female) 0.05 2.6 0.13 0.53 —  
ASA (2–3 vs. 1) 0.58 —  0.89 —  
PS (1–2 vs. 0) 0.46 —  0.89 —  
Clinical T stage (≥T2 vs. ≤T1) 0.33 —  0.54 —  
Surgical modality (MIES vs. open) 0.10 —  0.01 2.8 0.12 
Urinary diversion (IC/NB/IP vs. UC/none) 0.90 —  0.10 —  
Operative time 0.50 —  0.07 —  
Blood loss 0.70 —  0.09 1.0 0.13 

IC, ileal conduit; NB, neobladder; IP, Indiana pouch; UC, ureterocutaneostomy.

Interventions for major complications were administered as follows: decompression using an ileus tube (Grade 3a) in 12 patients; percutaneous nephrostomy (Grade 3a) in 3 patients with urinary tract infection, 3 with anastomotic stenosis and 2 with anastomotic leakage; open laparotomy (Grade 3b) in 1 with anastomotic leakage, 1 with intra-abdominal abscess, 2 with bowel perforation and 2 with ileus; resuture of wound dehiscence under general anesthesia (Grade 3b) in 4; percutaneous drainage (Grade 3a) in 2 with pelvic abscess and 1 with cholecystitis; debridement (Grade 3b) in 1 with penile necrosis; pacemaker insertion (Grade 3a) in 1 with sick sinus syndrome; and thrombolytic therapy (Grade 3a) in 1 with pulmonary embolism.

DISCUSSION

In trimodality bladder-sparing protocols against MIBC, patients who continue to have residual disease after induction CRT usually undergo salvage RC with curative intent. Although a number of studies have demonstrated that the bladder-sparing protocol yields survival outcomes comparable to those seen in immediate RC series (2–11), little is known about how induction CRT affects the surgical outcomes of RC, particularly at non-high-volume institutions. In the current study at a single moderate-volume institution, no severe complication of Clavien Grade 4–5 was observed in the entire cohort, despite higher incidences of major gastrointestinal and overall urinary anastomosis-related complications in the CRT group than in the no CRT group. Multivariate analysis revealed induction CRT as an independent risk factor for urinary anastomosis-related complications but not for major gastrointestinal complications. Our data indicate that induction CRT at 40 Gy does not severely compromise subsequent RC.

Induction CRT increased the risk of overall urinary anastomosis-related complications independently and was associated with major gastrointestinal complications cooperatively with other factors including MIES and intraoperative blood loss. The increased risks of these complications would result, at least in part, from ischemia of irradiated tissues. These complications may be reduced through very careful handling of the intestine and ureter so as to avoid further compromising the blood supply to the tissues used for bowel and urinary reconstruction. It might also be helpful to use more proximal segments of the ureter, outside the RT field, for anastomosis.

In the current study, in a cohort of 193 bladder cancer patients undergoing RC, 90-day mortality was 0% and 30-day major (Grade 3 or greater) complication rates for patients pre-treated with and without induction CRT were 22 and 11%, respectively. Although the majority of studies do not use a standardized complication reporting system, our results may compare favorably with those of contemporary RC series in terms of both mortality and morbidity (Table 5). In terms of morbidity, our favorable results might be due, in part, to the shorter observation period of 30 days; 90-day morbidity was reported in the other studies employing the Clavien–Dindo Classification (14,15,19,23). Another explanation of our favorable results could be a difference in the prevalence of obesity, which is associated with higher morbidity of RC (20,34). Obese patients with body mass index ≥30 kg/m2 accounted for only 1% of our study cohort. This rate is apparently lower than those in Western populations, which stand at ∼30% (20,34).

Table 5.

Morbidity in contemporary radical cystectomy series in non-irradiated and irradiated patients

Investigator n RT dose (Gy) Major (%) Mortality (%) 
Non-irradiated     
 Shabsigh et al. (231142 — 13a,b 1.5b 
 Lowrance et al. (21553 — 7.4c 1.7c 
 Nieuwenhuijzen et al. (22281 — 24d 2.8c 
 Lee et al. (20262  8d 0.4c 
 Bostrom et al. (18258 — 11b 2.7b 
 The current study 106 — 11a,c 0b 
Irradiated 
 Eisenberg et al. (15) 148 60 or greater 32.4a,b 6.1b 
 Hautmann et al. (1994 N/A 26a,b 8.5b 
 Ramani (2010) (1470 45–55 N/A 4.7b 
 Chahal et al. (3757 55 49b 15.7b 
 The current study 87 40 22a,c 0b 
Investigator n RT dose (Gy) Major (%) Mortality (%) 
Non-irradiated     
 Shabsigh et al. (231142 — 13a,b 1.5b 
 Lowrance et al. (21553 — 7.4c 1.7c 
 Nieuwenhuijzen et al. (22281 — 24d 2.8c 
 Lee et al. (20262  8d 0.4c 
 Bostrom et al. (18258 — 11b 2.7b 
 The current study 106 — 11a,c 0b 
Irradiated 
 Eisenberg et al. (15) 148 60 or greater 32.4a,b 6.1b 
 Hautmann et al. (1994 N/A 26a,b 8.5b 
 Ramani (2010) (1470 45–55 N/A 4.7b 
 Chahal et al. (3757 55 49b 15.7b 
 The current study 87 40 22a,c 0b 

N/A, not assessed.

aComplications of Grade 3 or higher according to the Clavien–Dindo classification.

bObservation period, 90 days.

cObservation period, 30 days.

dObservation period, >30 days.

The limitations of the current study are a relatively small cohort size, a short observation period for morbidity and the retrospective nature of the study design. In some recent studies, major complications have occurred in 17–40% of patients, even 3 months or longer after RC and neobladder construction following definitive pelvic RT (19,35). In our cohort, on the other hand, no RC-related deaths or life-threatening major complications have been documented to date even if the observation period is extended to 3 months or longer. As for the study design, all patients in the CRT group underwent RC in the year 1997 or later, while the majority of patients in the no CRT group underwent RC before 1997. Since the morbidity associated with RC has improved over the last few decades (36), surgical outcomes might have been biased in favor of the CRT group.

In bladder-sparing protocols, induction CRT is indispensable for achieving bladder preservation while maintaining survival outcomes comparable to immediate RC series (2–11). Furthermore, induction CRT potentially improves cancer-specific survival of MIBC patients with clinical perivesical disease extension (T3) as a neoadjuvant therapy (29). The current study demonstrated that induction CRT at 40 Gy is unlikely to increase the incidence of mortality or life-threatening complications of RC at a non-high-volume institution but potentially increases the incidence of urinary anastomosis-related complications. We believe that the advantages of induction CRT incorporated into a bladder-sparing approach justify the risk of salvage RC and its associated potential morbidity.

Conflict of interest statement

None declared.

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